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Search for "anticancer drug" in Full Text gives 52 result(s) in Beilstein Journal of Organic Chemistry.
(Bio)isosteres of ortho- and meta-substituted benzenes
- H. Erik Diepers and
- Johannes C. L. Walker
Beilstein J. Org. Chem. 2024, 20, 859–890, doi:10.3762/bjoc.20.78
- -2 (both 189 and iso-189 were obtained and investigated as a mixture of four diastereomers). Comparative physicochemical data of the anticancer drug sonidegib and its 1,3-cuneane isostere 190 was reported by Lam and co-workers (Figure 27) [71]. Unfortunately, in this case, isosteric replacement of
Graphical Abstract
Figure 1: Scaffolds commonly reported as bioisosteric replacements of para-substituted benzene and examples p...
Figure 2: 1,2-BCPs as isosteres for ortho-and meta-substituted benzenes: comparison of reported exit vector p...
Scheme 1: 1,2-Disubstituted bicyclo[1.1.1]pentanes as isosteres of ortho-substituted benzenes. A: Baran, Coll...
Scheme 2: Synthesis of 1,2-BCPs from BCP 15 by bridge C–H bromination as reported by MacMillan and co-workers ...
Figure 3: Comparative physicochemical data of telmisartan, lomitapide and their BCP isosteres [26,33]. Shake flask d...
Figure 4: 1,2-Disubstituted bicyclo[2.1.1]hexanes as isosteres of ortho-benzenes: Exit vector parameters of t...
Scheme 3: Synthesis of 1,2-disubstituted bicyclo[2.1.1]hexanes via alkene insertion into bicyclo[1.1.0]butane...
Scheme 4: Synthesis of 1,2-disubstituted bicyclo[2.1.1]hexanes via intramolecular crossed [2 + 2] cycloadditi...
Figure 5: Comparison of physicochemical data of fluxapyroxad and boscalid and their 1,2-BCH bioisosteres [36]. Sh...
Figure 6: Antifungal activity of fluxapyroxad, its 1,5-BCH bioisostere (±)-55, boscalid and its bioisostere 1...
Figure 7: 1,5-Disubstituted bicyclo[2.1.1]hexanes as isosteres of ortho-substituted benzenes. Comparison of e...
Scheme 5: Synthesis of 1,5-disubstituted bicyclo[2.1.1]hexanes as isosteres of ortho-benzenes via intramolecu...
Figure 8: Comparison of physicochemical data of fluxapyroxad and boscalid and their 1,5-BCH bioisosteres [45]. Sh...
Figure 9: Antifungal activity of fluxapyroxad, its 1,5-BCH bioisostere (±)-64, boscalid and its bioisostere 1...
Figure 10: 1,5-Disubstituted 3-oxabicylco[2.1.1]hexanes as isosteres for ortho-benzenes: Comparison of exit ve...
Scheme 6: Synthesis of 1,5-disubstituted 3-oxabicyclo[2.1.1]hexanes as isosteres for ortho-benzenes via intra...
Figure 11: Comparison of physicochemical data of fluxapyroxad and boscalid and their 3-oxa-1,5-BCH bioisostere...
Figure 12: Antifungal activity of fluxapyroxad and boscalid and their 3-oxa-1,5-BCH bioisosteres (±)-75 and (±...
Figure 13: 1,2-Disubstituted bicyclo[3.1.1]heptanes as isosteres of ortho-benzenes. Schematic representation o...
Scheme 7: Synthesis of 1,2-disubstituted bicyclo[3.1.1]heptanes as isosteres for ortho-benzenes via alkene in...
Figure 14: 1,2-Disubstituted stellanes as ortho-benzene isosteres: Comparison of selected exit vector paramete...
Scheme 8: Synthesis of 1,2-disubstituted stellanes as isosteres for ortho-benzenes reported by Ryabukhin, Vol...
Figure 15: 1,2-Disubstituted cubanes as ortho-benzene isosteres: Comparison of substituent distances and angle...
Scheme 9: Synthesis of 1,2-disubsituted cubanes as isosteres for ortho-benzenes. A: Synthesis of 1,2-cubane d...
Figure 16: 1,3-Disubstituted bicyclo[2.1.1]hexanes as isosteres of meta-benzenes: comparative exit vector para...
Scheme 10: Synthesis of 1,3-disubstituted bicyclo[2.1.1]hexanes as isosteres for meta-benzenes reported by Wal...
Figure 17: 1,4-Disubstituted bicyclo[2.1.1]hexanes as isosteres of meta-benzenes: comparative exit vector para...
Scheme 11: Synthesis of 1,4-disubstituted bicyclo[2.1.1}hexanes as isosteres for ortho-benzenes via intramolec...
Figure 18: 1,4-Disubstituted-2-oxabicyclo[2.1.1]hexanes as meta-benzene isosteres: comparison of selected exit...
Scheme 12: Synthesis of 1,4-disubstituted 2-oxabicyclo[2.1.1]hexanes as isosteres for meta-benzenes. A: Mykhai...
Figure 19: Comparative physicochemical data for 2- and 3-oxa-1,4-BCHs and para-substituted benzene equivalents...
Figure 20: 1,5-Disubstituted bicyclo[3.1.1]heptanes as isosteres of meta-benzenes: comparison of exit vector p...
Scheme 13: Synthesis of [3.1.1]propellane as a precursor for 1,5-disubsituted bicyclo[3.1.1]heptanes. A: aGass...
Scheme 14: Synthesis of iodine-substituted 1,5-disubstituted bicyclo[3.1.1]heptanes as isosteres for meta-benz...
Scheme 15: Synthesis of nitrogen-, chalcogen- and tin-substituted 1,5-disubstituted bicyclo[3.1.1]heptanes as ...
Figure 21: Comparative physicochemical data of URB597 and 1,5-BCHep isostere 146 [27]. Kinetic aqueous solubility ...
Figure 22: [2]-Ladderanes as isosteres of meta-benzenes: comparison of reported exit vector parameters [63].
Scheme 16: Synthesis of cis-2,6-disubstituted bicyclo[2.2.0]hexanes as isosteres for meta-benzenes. A: Brown a...
Figure 23: Comparative physicochemical data of meta-benzene 158 and [2]-ladderane isostere 159 [63]. Partition coe...
Figure 24: 1,3-Disubstituted cubanes as isosteres of meta-benzenes: comparison of selected exit vector paramet...
Scheme 17: Synthesis of 1,3-disubsituted cubanes as isosteres for meta-benzenes. A: MacMillan and co-workers’ ...
Figure 25: Comparative physicochemical data of lumacaftor and its 1,3-cubane bioisostere 183 [51]. Distribution co...
Figure 26: 1,3-Disubstituted cuneanes as isosteres of meta-benzenes: comparison of selected exit vector parame...
Scheme 18: Synthesis of 1,3-cuneanes as isosteres of meta-benzene. A: Synthesis of 1,3-cuneanes reported by La...
Figure 27: Comparative physicochemical data of sonidegib and its 1,3-cuneane isostere 190 [71]. aSolubility was to...
Figure 28: Exemplary polysubstituted scaffolds related to disubstituted scaffolds suggested as isosteres of or...
Synthesis of ether lipids: natural compounds and analogues
- Marco Antônio G. B. Gomes,
- Alicia Bauduin,
- Chloé Le Roux,
- Romain Fouinneteau,
- Wilfried Berthe,
- Mathieu Berchel,
- Hélène Couthon and
- Paul-Alain Jaffrès
Beilstein J. Org. Chem. 2023, 19, 1299–1369, doi:10.3762/bjoc.19.96
- with the development of edelfosine (an anticancer drug). More recently, ohmline, a glyco glycero ether lipid that modulates selectively SK3 ion channels and reduces in vivo the occurrence of bone metastases, and other glyco glycero ether also identified as GAEL (glycosylated antitumor ether lipids
Graphical Abstract
Figure 1: Chemical structure of some natural ether lipids (ELs).
Figure 2: Synthesis of lyso-PAF and PAF from 1-O-alkylglycerol [64].
Figure 3: Synthesis of lyso-PAF from 1,3-benzylideneglycerol 3.1 [69].
Figure 4: A) Synthesis of the two enantiomers of octadecylglycerol (4.6 and 4.10) from ᴅ-mannitol (4.1); B) s...
Figure 5: Four-step synthesis of PAF 5.6 from (S)-glycidol [73].
Figure 6: Synthesis of 1-O-alkylglycerol A) from solketal, B) from ᴅ- or ʟ-tartaric acid and the intermediate ...
Figure 7: Synthesis of EL building blocks starting from substituted glycidol 7.1a–c [82].
Figure 8: Synthesis of PAF 8.5 by using phosphoramidite 8.2 [86].
Figure 9: Synthesis of oleyl-PAF 9.7 from ʟ-serine [88].
Figure 10: Synthesis of racemic analogues of lyso-PAF 10.8 and PAF 10.9 featuring a phenyl group between the g...
Figure 11: Synthesis of racemic deoxy-lyso-PAF 11.7 and deoxy-PAF 11.8 [91].
Figure 12: Synthesis of racemic thio-PAF 12.8 [93].
Figure 13: Racemic synthesis of 13.6 to illustrate the modification of the glycerol backbone by adding a methy...
Figure 14: Racemic synthesis of 14.5 as an illustration of the introduction of methyl substituents on the glyc...
Figure 15: Synthesis of functionalized sn-2-acyl chains of PC-EL; A) Steglich esterification or acylation reac...
Figure 16: Synthesis of racemic mc-PAF (16.3), a carbamate analogue of PAF [102].
Figure 17: A) Synthesis of (R)-17.2 and (S)-17.6 starting from (S)-solketal (17.1); B) synthesis of N3-PAF (17...
Figure 18: Modification of the phosphocholine polar head to produce PAF analogues [81].
Figure 19: Racemic PAF analogues 19.3 and 19.5 characterized by the absence of the phosphate group [107].
Figure 20: Synthesis of PIP3-PAF (20.7) [108].
Figure 21: Large-scale synthesis of C18-edelfosine (21.8) [116].
Figure 22: Synthesis of C16-edelfosine (22.10) starting from isopropylidene-ʟ-glyceric acid methyl ester (22.1...
Figure 23: Phosphocholine moiety installation by the use of chlorophosphite 23.2 as key reagent [119].
Figure 24: Synthesis of rac-1-alkyl-2-O-methylglycerol (AMG) [120].
Figure 25: Synthesis of stereocontrolled 1-alkyl-2-O-methyl glycerol 25.9 (AMG) from dimethyl ᴅ-tartrate [81].
Figure 26: A) Racemic synthesis of thioether 26.4 [129,130], B) structure of sulfone analogue 26.5 [129].
Figure 27: Stereocontrolled synthesis of C18-edelfosine thioether analogue 27.8 [118].
Figure 28: Synthesis of thioether 28.4 that include a thiophosphate function [134].
Figure 29: Synthesis of ammonium thioether 29.4 and 29.6 [135].
Figure 30: Synthesis of the N-methylamino analogue of edelfosine 30.6 (BN52211) [138].
Figure 31: Synthesis of 1-desoxy analogues of edelfosine; A) with a saturated alkyl chain; B) synthesis of the...
Figure 32: Stereocontrolled synthesis of edelfosine analogue (S)-32.8 featuring a C18:1 lipid chain [142].
Figure 33: Synthesis of edelfosine analogues with modulation of the lipid chain; A) illustration with the synt...
Figure 34: Synthesis of phospholipid featuring a carbamate function to link the lipid chain to the glycerol un...
Figure 35: Synthesis of sesquiterpene conjugates of phospho glycero ether lipids [148].
Figure 36: Racemic synthesis of methyl-substituted glycerol analogues 36.7 and 36.10: A) synthesis of diether ...
Figure 37: Racemic synthesis of ilmofosine (37.6) [155,156].
Figure 38: A) Stereoselective synthesis of 38.5 via a stereoselective hydroboration reaction; B) synthesis of ...
Figure 39: Racemic synthesis of SRI62-834 (39.6) featuring a spiro-tetrahydrofurane heterocycle in position 2 ...
Figure 40: Racemic synthesis of edelfosine analogue 40.5 featuring an imidazole moiety in sn-2 position [160].
Figure 41: Racemic synthesis of fluorine-functionalized EL: A) Synthesis of 41.6 and B) synthesis of 41.8 [161-163].
Figure 42: A) Synthesis of the β-keto-ester 42.6 that also features a decyl linker between the phosphate and t...
Figure 43: Synthesis of phosphonate-based ether lipids; A) edelfosine phosphonate analogue 43.7 and B) thioeth...
Figure 44: Enantioselective synthesis of phosphonates 44.3 and 44.4 [171].
Figure 45: Racemic synthesis of phosphinate-based ether lipid 45.10 [172].
Figure 46: Racemic synthesis of edelfosine arsonium analogue 46.5 [173].
Figure 47: Synthesis of edelfosine dimethylammonium analogue 47.2 [118].
Figure 48: Synthesis of rac-C18-edelfosine methylammonium analogue 48.4 [176].
Figure 49: A) Synthesis of edelfosine N-methylpyrrolidinium analogue 49.2 or N-methylmorpholinium analogue 49.3...
Figure 50: A) Synthesis of edelfosine’s analogue 50.4 with a PE polar group; B) illustration of a pyridinium d...
Figure 51: A) Synthesis of 51.4 featuring a thiazolium cationic moiety; B) synthesis of thiazolium-based EL 51...
Figure 52: Synthesis of cationic ether lipids 52.3, 52.4 and 52.6 [135,183].
Figure 53: Synthesis of cationic carbamate ether lipid 53.5 [184].
Figure 54: Synthesis of cationic sulfonamide 54.5 [185].
Figure 55: Chemical structure of ONO-6240 (55.1) and SRI-63-119 (55.2).
Figure 56: Synthesis of non-ionic ether lipids 56.2–56.9 [188].
Figure 57: Synthesis of ether lipid conjugated to foscarnet 57.6 [189].
Figure 58: A) Synthesis of ether lipid conjugated to arabinofuranosylcytosine; B) synthesis of AZT conjugated ...
Figure 59: Synthesis of quercetin conjugate to edelfosine [191].
Figure 60: Synthesis of 60.8 (Glc-PAF) [194].
Figure 61: A) Synthesis of amino ether lipid 61.7 functionalized with a rhamnose unit and its amide analogue 6...
Figure 62: A) Synthesis of glucose ether lipid 62.4; B) structure of ether lipid 62.5 possessing a maltose uni...
Figure 63: A) Synthesis of glucuronic methyl ester 63.8; B) structure of cellobiose 63.9 and maltose 63.10 ana...
Figure 64: A) Synthesis of maltosyl glycerolipid 64.7; B) structure of lactose analogue 64.8 prepared followin...
Figure 65: A) Asymmetric synthesis of the aglycone moiety starting from allyl 4-methoxyphenyl ether; B) glycos...
Figure 66: A) Synthesis of ohmline possessing a lactose moiety. B) Structure of other glyco glycero lipids pre...
Figure 67: A) Synthesis of lactose-glycerol ether lipid 67.5; B) analogues possessing a maltose (67.6) or meli...
Figure 68: Synthesis of digalactosyl EL 68.6, A) by using trityl, benzyl and acetyl protecting groups, B) by u...
Figure 69: A) Synthesis of α-ohmline; B) structure of disaccharide ether lipids prepared by using similar meth...
Figure 70: Synthesis of lactose ether lipid 70.3 and its analogue 70.6 featuring a carbamate function as linke...
Figure 71: Synthesis of rhamnopyranoside diether 71.4 [196].
Figure 72: Synthesis of 1-O-hexadecyl-2-O-methyl-3-S-(α-ᴅ-1'-thioglucopyranosyl)-sn-glycerol (72.5) [225].
Figure 73: A) Preparation of lipid intermediate 73.4; B) synthesis of 2-desoxy-C-glycoside 73.10 [226].
Figure 74: Synthesis of galactose-pyridinium salt 74.3 [228].
Figure 75: Synthesis of myo-inositol derivative Ino-C2-PAF (75.10) [230].
Figure 76: A) Synthesis of myo-inositol phosphate building block 76.7; B) synthesis of myo-inositolphosphate d...
Figure 77: A) Synthesis of phosphatidyl-3-desoxy-inositol 77.4; B) synthesis of phosphono-3-desoxyinositol 77.9...
Figure 78: A) Structure of diether phosphatidyl-myo-inositol-3,4-diphosphate 78.1; B) synthesis of phosphatidy...
Figure 79: A) Synthesis of diether-phosphatidyl derivative 79.4 featuring a hydroxymethyl group in place of a ...
Figure 80: Synthesis of Glc-amine-PAF [78].
Figure 81: Synthesis of glucosamine ether lipid 81.4 and its analogues functionalized in position 3 of the ami...
Figure 82: Synthesis of fully deprotected aminoglucoside ether lipid 82.5 [246].
Figure 83: Synthesis of C-aminoglycoside 83.12 using Ramberg–Bäcklund rearrangement as a key step [250].
Figure 84: A) List of the most important glyco lipids and amino glyco lipids included in the study of Arthur a...
Figure 85: Synthesis of mannosamine ether lipid 85.6 [254].
Figure 86: A) Synthesis of glucosamine ether lipids with a non-natural ʟ-glucosamine moiety; B) synthesis of e...
Figure 87: A) Structure of the most efficient anticancer agents 87.1–87.4 featuring a diamino glyco ether lipi...
Figure 88: A) Synthesis of diamino glyco ether lipid 87.4; B) synthesis of bis-glycosylated ether lipid 88.10 [256]....
Figure 89: Synthesis of triamino ether lipid 89.4 [260].
Figure 90: Synthesis of chlorambucil conjugate 90.7 [261].
Figure 91: Three main methods for the preparation of glycerol ether lipid 91.3; A) from solketal and via a tri...
Figure 92: Four different methods for the installation of the phosphocholine polar head group; A) method using...
Figure 93: Illustration of two methods for the installation of saccharides or aminosaccharides; A) O-glycosyla...
Insight into oral amphiphilic cyclodextrin nanoparticles for colorectal cancer: comprehensive mathematical model of drug release kinetic studies and antitumoral efficacy in 3D spheroid colon tumors
- Sedat Ünal,
- Gamze Varan,
- Juan M. Benito,
- Yeşim Aktaş and
- Erem Bilensoy
Beilstein J. Org. Chem. 2023, 19, 139–157, doi:10.3762/bjoc.19.14
- using polymeric nanoparticles for anticancer drug delivery have not been developed yet. Previous data showed encapsulation in non-ionic uncoated or coated cyclodextrin (CD) nanoparticles enhanced the CPT stability and GI absorption [9][11], and compared to PCL and PLGA nanoparticles, CD nanoparticles
Graphical Abstract
Figure 1: In vitro release profile of CPT from nanoparticle formulations (n = 3, ± SD).
Figure 2: Results for release kinetics obtained automatically by the DDSolver software for SGF release medium...
Figure 3: Results for release kinetics obtained automatically by the DDSolver software for SIF release medium...
Figure 4: Results for release kinetics obtained automatically by the DDSolver software for SCoF release mediu...
Figure 5: Anticancer effect of blank or CPT-loaded CD nanoparticles and camptothecin solution against 2D CT26...
Figure 6: Live/dead analysis of CT26 and HT29 cells using double staining with calcein AM and ethidium homodi...
Figure 7: Murine (CT26) and human (HT29) colon cancer spheroid was formed by scaffold-based method, and the m...
Figure 8: Anticancer effect of blank or drug-loaded cyclodextrin nanoparticles and CPT solution against 3D CT...
Figure 9: Chemical structures of 6-O-capro-β-CD, poly-β-CD-C6, and chitosan.
On drug discovery against infectious diseases and academic medicinal chemistry contributions
- Yves L. Janin
Beilstein J. Org. Chem. 2022, 18, 1355–1378, doi:10.3762/bjoc.18.141
- combinatorial approach [232][233] appeared to have only led to one anticancer drug [234], major progresses in the design, selection, generation and purification of libraries have since then turned this type of chemistry into a central tool for drug discovery [235][236][237] along with more recent success
- drug vinorelbine (45). This provided in one step vinflunine (46) which, from 2009, became another anticancer drug. Past the historical case of fluoroquinolones [295], many more examples of the possible advantages of introducing fluorine(s) in a drug are provided in recent reviews [289][296]. Another
- [288][289][290][291][292][293]. Moreover, the use/design of new chemical reactions may lead to hard-to-get and original analogues possibly better than the one reported. One example, depicted in Scheme 2, would be the fluorination, under superacid conditions [294], of the highly elaborated anticancer
Graphical Abstract
Figure 1: Structure of halicin (1).
Figure 2: Structures of compounds 2–7.
Figure 3: Structures of compounds 8–12.
Figure 4: Structures of compounds 13–17.
Figure 5: Structures of compounds 18–21.
Figure 6: Structures of compounds 22–36 and SAR of compound 22.
Figure 7: Structures of compounds 37 and 38.
Figure 8: Structures of compounds 39–44.
Scheme 1: Retrosynthesis of pyrazolones A and B.
Scheme 2: Reaction conditions: i: HF, SbF6, CCl4. ii: (CF3SO2)2Zn, t-BuO2H, CH2Cl2/H2O.
Figure 9: Structures of compounds 49–61.
Figure 10: Structures of compounds 62–65.
Figure 11: Structures of compounds 66 and 67.
Synthesis of a new water-soluble hexacarboxylated tribenzotriquinacene derivative and its competitive host–guest interaction for drug delivery
- Man-Ping Li,
- Nan Yang and
- Wen-Rong Xu
Beilstein J. Org. Chem. 2022, 18, 539–548, doi:10.3762/bjoc.18.56
- larger cavity as compared to TBTQ-C6 due to the introduction of triazole rings. Two anticancer drug molecules, dimethyl viologen (MV) with a smaller size and DOX with a larger size, were selected as model anticancer agents for encapsulation by TBTQ-CB6 to form the host–guest complexes of TBTQ-CB6MV and
Graphical Abstract
Scheme 1: (a) Synthesis route to TBTQ-CB6. Conditions: (i) ethyl azidoacetate, CuSO4, sodium ascorbate, THF/H2...
Figure 1: (a) 1H NMR spectra (400 MHz, D2O, 25 °C) of (1) MV, (2) TBTQ-CB6 and MV, (3) TBTQ-CB6 with [TBTQ-CB6...
Figure 2: (a) 1H NMR spectra (400 MHz, D2O, 25 °C) of (1) DOX, (2) TBTQ-CB6 and DOX, (3) TBTQ-CB6 with [TBTQ-...
Figure 3: (a) 1H NMR spectra (400 MHz, D2O, 25 °C) and (b) partial magnified 1H NMR spectra of (1) SM, (2) TB...
Figure 4: (a) Fluorescence spectra of the mixture of TBTQ-CB6 and SM in different molar ratios at a constant ...
Figure 5: 1H NMR spectra (400 MHz, D2O, 25 °C) of (1) MV (3 mM), (2) TBTQ-CB6 and MV (3 mM each), (3–9) TBTQ-...
Figure 6: 1H NMR spectra (400 MHz, D2O, 25 °C) of (1) DOX (3 mM), (2) TBTQ-CB6 and DOX (3 mM each), (3–9) TBT...
Ready access to 7,8-dihydroindolo[2,3-d][1]benzazepine-6(5H)-one scaffold and analogues via early-stage Fischer ring-closure reaction
- Irina Kuznetcova,
- Felix Bacher,
- Daniel Vegh,
- Hsiang-Yu Chuang and
- Vladimir B. Arion
Beilstein J. Org. Chem. 2022, 18, 143–151, doi:10.3762/bjoc.18.15
- to isomer C and a number of closely related derivatives with modified electronic and steric properties, e.g., bromo-substituted species, backbone with 8-membered azocinone ring, will trigger the design and synthesis of new exciting anticancer drug candidates, including metal-based, by targeting
Graphical Abstract
Figure 1: Paullone related indolobenzazepinone isomers. 7,12-Dihydroindolo[3,2-d][1]benzazepin-6(5H)-one or p...
Scheme 1: Investigated retrosynthetic pathways to scaffold C.
Scheme 2: Attempted synthesis of scaffold C by route (a).
Scheme 3: Attempted synthesis of C by route (b).
Scheme 4: Attempted synthesis of N-benzylated indole-2-acetic acid.
Scheme 5: Attempt to obtain open-chain precursor N-(2-bromophenyl)-2-(1H-indol-2-yl)acetamide.
Scheme 6: Synthesis of scaffold C and analogues by route (c).
Figure 2: ORTEP view of 1a with thermal ellipsoids drawn at the 50% probability level.
Figure 3: ORTEP view of 3a with thermal ellipsoids drawn at the 50% probability level.
Scheme 7: Attempted Ullmann cross-coupling of 23 with o-bromo-nitrobenzene.
Post-functionalization of drug-loaded nanoparticles prepared by polymerization-induced self-assembly (PISA) with mitochondria targeting ligands
- Janina-Miriam Noy,
- Fan Chen and
- Martina Stenzel
Beilstein J. Org. Chem. 2021, 17, 2302–2314, doi:10.3762/bjoc.17.148
- methacrylate) (pPEGMA) and the anticancer drug PENAO (4-(N-(S-penicillaminylacetyl)amino)phenylarsenonous acid) or zwitterionic 2-methacryloyloxyethyl phosphorylcholine (MPC) and PENAO were reported. Both PISA particles were reacted with triphenylphosphonium (TPP) as mitochondria targeting units in order to
Graphical Abstract
Figure 1: (I) DLS of PPM-NP4, MPM-NP2, PPM-NP4-TPP and MPM-NP2-TPP and (II) TEM of PPM-NP4-TPP and MPM-NP2-TPP...
Figure 2: Representative 31P NMR (top) and 1H NMR (bottom) spectrum of PP3-TPP conjugation product in D2O.
Scheme 1: Synthesis of TPP-based PISA particles based on zwitterionic 2-methacryloyloxyethyl phosphorylcholin...
Figure 3: Penetration of PPM-NP4-TPP and MPM-NP2-TPP micelles and fluorescence intensity profile on (A I, II)...
Figure 4: Growth effects of PPM-NP4-TPP and MPM-NP2-TPP on SW982 spheroids after 3 and 6 days of incubation (c...
Figure 5: Cell viability of SW982 spheroids after 6 days treatment with PPM-NP4, PPM-NP-TPP, MPM-NP2 and MPM-...
Figure 6: Cell localization of PPM-NP4-TPP (I) and MPM-NP2-TPP (II) into (A) mitochondria and (B) lysosomes u...
Figure 7: Cytotoxicity study of PPM-NP4-TPP and MPM-NP2-TPP on SW982 cells in relation to the concentration o...
Constrained thermoresponsive polymers – new insights into fundamentals and applications
- Patricia Flemming,
- Alexander S. Münch,
- Andreas Fery and
- Petra Uhlmann
Beilstein J. Org. Chem. 2021, 17, 2123–2163, doi:10.3762/bjoc.17.138
Graphical Abstract
Figure 1: (a) Schematic representation of the phase stability of a binary mixture based on the free enthalpy ...
Figure 2: Illustration of the relationship between the type of miscibility gap and the temperature dependence...
Figure 3: Schematically pictured phase diagram of a binary mixture composed of a dissolved polymer with a LCS...
Figure 4: Schematic illustration of a thermo-induced swelling behavior of a star polymer composed of responsi...
Figure 5: Schematic illustration of self-assembly of block copolymer amphiphiles in a polar medium.
Figure 6: Schematic comparison of the size and conformation between free polymer chains (a), grafted polymer ...
Figure 7: Comparison of the possible phase diagrams of a polymer in solution with partially miscibility and t...
Figure 8: Selection of polymers exhibiting UCST behavior due to hydrogen bonding (blue) divided into homo- (a...
Figure 9: Part A shows the molecular structure of PDMAPS stars synthesized by Li et al. (left) demonstrating ...
Figure 10: Part A contains a schematic demonstration of conformational transitions of dual-thermoresponsive bl...
Figure 11: Part A pictures zwitterionic brushes grafted from silicon substrates obtaining a nonassociated, hyd...
Figure 12: Part A pictures the UCST phase transition of zwitterionic polymers grafted on the surface of mesopo...
On the application of 3d metals for C–H activation toward bioactive compounds: The key step for the synthesis of silver bullets
- Renato L. Carvalho,
- Amanda S. de Miranda,
- Mateus P. Nunes,
- Roberto S. Gomes,
- Guilherme A. M. Jardim and
- Eufrânio N. da Silva Júnior
Beilstein J. Org. Chem. 2021, 17, 1849–1938, doi:10.3762/bjoc.17.126
- -epoxynaphthalene as electrophiles. Several 2-alkynylbenzamide products were achieved in good yields, including a derivate of moclobemide (42), a drug used to treat depression and anxiety (Scheme 15C) [122]. It is worth mentioning here that this class of molecules can be used as effective anticancer drug carriers
- [188] described a cobalt-Cp*-catalyzed C–H methylation of several well-known pharmaceuticals, such as diazepam (a commercially available anxiolytic drug [189]), paclitaxel (a commercially available anticancer drug [190]), celecoxib (a commercially available analgesic drug [191]), and rucaparib (a
- commercially available anticancer drug [192]). They achieved the C–H methylation by following two methods (method A or method B, Scheme 36A) and obtained the methylated analogues 107–119 in moderate to very high yields (Scheme 36B and C). Ellman and co-workers described a powerful and interesting three
Graphical Abstract
Scheme 1: Schematic overview of transition metals studied in C–H activation processes.
Scheme 2: (A) Known biological activities related to benzimidazole-based compounds; (B and C) an example of a...
Scheme 3: (A) Known biological activities related to quinoline-based compounds; (B and C) an example of a sca...
Scheme 4: (A) Known biological activities related to sulfur-containing compounds; (B and C) an example of a s...
Scheme 5: (A) Known biological activities related to aminoindane derivatives; (B and C) an example of a scand...
Scheme 6: (A) Known biological activities related to norbornane derivatives; (B and C) an example of a scandi...
Scheme 7: (A) Known biological activities related to aniline derivatives; (B and C) an example of a titanium-...
Scheme 8: (A) Known biological activities related to cyclohexylamine derivatives; (B) an example of an intram...
Scheme 9: (A) Known biologically active benzophenone derivatives; (B and C) photocatalytic oxidation of benzy...
Scheme 10: (A) Known bioactive fluorine-containing compounds; (B and C) vanadium-mediated C(sp3)–H fluorinatio...
Scheme 11: (A) Known biologically active Lythraceae alkaloids; (B) synthesis of (±)-decinine (30).
Scheme 12: (A) Synthesis of (R)- and (S)-boehmeriasin (31); (B) synthesis of phenanthroindolizidines by vanadi...
Scheme 13: (A) Known bioactive BINOL derivatives; (B and C) vanadium-mediated oxidative coupling of 2-naphthol...
Scheme 14: (A) Known antiplasmodial imidazopyridazines; (B) practical synthesis of 41.
Scheme 15: (A) Gold-catalyzed drug-release mechanism using 2-alkynylbenzamides; (B and C) chromium-mediated al...
Scheme 16: (A) Examples of anti-inflammatory benzaldehyde derivatives; (B and C) chromium-mediated difunctiona...
Scheme 17: (A and B) Manganese-catalyzed chemoselective intramolecular C(sp3)–H amination; (C) late-stage modi...
Scheme 18: (A and B) Manganese-catalyzed C(sp3)–H amination; (C) late-stage modification of a leelamine deriva...
Scheme 19: (A) Known bioactive compounds containing substituted N-heterocycles; (B and C) manganese-catalyzed ...
Scheme 20: (A) Known indoles that present GPR40 full agonist activity; (B and C) manganese-catalyzed C–H alkyl...
Scheme 21: (A) Examples of known biaryl-containing drugs; (B and C) manganese-catalyzed C–H arylation through ...
Scheme 22: (A) Known zidovudine derivatives with potent anti-HIV properties; (B and C) manganese-catalyzed C–H...
Scheme 23: (A and B) Manganese-catalyzed C–H organic photo-electrosynthesis; (C) late-stage modification.
Scheme 24: (A) Example of a known antibacterial silylated dendrimer; (B and C) manganese-catalyzed C–H silylat...
Scheme 25: (A and B) Fe-based small molecule catalyst applied for selective aliphatic C–H oxidations; (C) late...
Scheme 26: (A) Examples of naturally occurring gracilioethers; (B) the first total synthesis of gracilioether ...
Scheme 27: (A and B) Selective aliphatic C–H oxidation of amino acids; (C) late-stage modification of proline-...
Scheme 28: (A) Examples of Illicium sesquiterpenes; (B) first chemical synthesis of (+)-pseudoanisatin (80) in...
Scheme 29: (A and B) Fe-catalyzed deuteration; (C) late-stage modification of pharmaceuticals.
Scheme 30: (A and B) Biomimetic Fe-catalyzed aerobic oxidation of methylarenes to benzaldehydes (PMHS, polymet...
Scheme 31: (A) Known tetrahydroquinolines with potential biological activities; (B and C) redox-selective Fe c...
Scheme 32: (A) Known drugs containing a benzofuran unit; (B and C) Fe/Cu-catalyzed tandem O-arylation to acces...
Scheme 33: (A) Known azaindolines that act as M4 muscarinic acetylcholine receptor agonists; (B and C) intramo...
Scheme 34: (A) Known indolinones with anticholinesterase activity; (B and C) oxidative C(sp3)–H cross coupling...
Scheme 35: (A and B) Cobalt-catalyzed C–H alkenylation of C-3-peptide-containing indoles; (C) derivatization b...
Scheme 36: (A) Cobalt-Cp*-catalyzed C–H methylation of known drugs; (B and C) scope of the o-methylated deriva...
Scheme 37: (A) Known lasalocid A analogues; (B and C) three-component cobalt-catalyzed C–H bond addition; (D) ...
Scheme 38: (A and B) Cobalt-catalyzed C(sp2)–H amidation of thiostrepton.
Scheme 39: (A) Known 4H-benzo[d][1,3]oxazin-4-one derivatives with hypolipidemic activity; (B and C) cobalt-ca...
Scheme 40: (A and B) Cobalt-catalyzed C–H arylation of pyrrole derivatives; (C) application for the synthesis ...
Scheme 41: (A) Known 2-phenoxypyridine derivatives with potent herbicidal activity; (B and C) cobalt-catalyzed...
Scheme 42: (A) Natural cinnamic acid derivatives; (B and C) cobalt-catalyzed C–H carboxylation of terminal alk...
Scheme 43: (A and B) Cobalt-catalyzed C–H borylation; (C) application to the synthesis of flurbiprofen.
Scheme 44: (A) Benzothiazoles known to present anticonvulsant activities; (B and C) cobalt/ruthenium-catalyzed...
Scheme 45: (A and B) Cobalt-catalyzed oxygenation of methylene groups towards ketone synthesis; (C) synthesis ...
Scheme 46: (A) Known anticancer tetralone derivatives; (B and C) cobalt-catalyzed C–H difluoroalkylation of ar...
Scheme 47: (A and B) Cobalt-catalyzed C–H thiolation; (C) application in the synthesis of quetiapine (153).
Scheme 48: (A) Known benzoxazole derivatives with anticancer, antifungal, and antibacterial activities; (B and...
Scheme 49: (A and B) Cobalt-catalyzed C–H carbonylation of naphthylamides; (C) BET inhibitors 158 and 159 tota...
Scheme 50: (A) Known bioactive pyrrolo[1,2-a]quinoxalin-4(5H)-one derivatives; (B and C) cobalt-catalyzed C–H ...
Scheme 51: (A) Known antibacterial cyclic sulfonamides; (B and C) cobalt-catalyzed C–H amination of propargyli...
Scheme 52: (A and B) Cobalt-catalyzed intramolecular 1,5-C(sp3)–H amination; (C) late-stage functionalization ...
Scheme 53: (A and B) Cobalt-catalyzed C–H/C–H cross-coupling between benzamides and oximes; (C) late-state syn...
Scheme 54: (A) Known anticancer natural isoquinoline derivatives; (B and C) cobalt-catalyzed C(sp2)–H annulati...
Scheme 55: (A) Enantioselective intramolecular nickel-catalyzed C–H activation; (B) bioactive obtained motifs;...
Scheme 56: (A and B) Nickel-catalyzed α-C(sp3)–H arylation of ketones; (C) application of the method using kno...
Scheme 57: (A and B) Nickel-catalyzed C(sp3)–H acylation of pyrrolidine derivatives; (C) exploring the use of ...
Scheme 58: (A) Nickel-catalyzed C(sp3)–H arylation of dioxolane; (B) library of products obtained from biologi...
Scheme 59: (A) Intramolecular enantioselective nickel-catalyzed C–H cycloalkylation; (B) product examples, inc...
Scheme 60: (A and B) Nickel-catalyzed C–H deoxy-arylation of azole derivatives; (C) late-stage functionalizati...
Scheme 61: (A and B) Nickel-catalyzed decarbonylative C–H arylation of azole derivatives; (C) application of t...
Scheme 62: (A and B) Another important example of nickel-catalyzed C–H arylation of azole derivatives; (C) app...
Scheme 63: (A and B) Another notable example of a nickel-catalyzed C–H arylation of azole derivatives; (C) lat...
Scheme 64: (A and B) Nickel-based metalorganic framework (MOF-74-Ni)-catalyzed C–H arylation of azole derivati...
Scheme 65: (A) Known commercially available benzothiophene-based drugs; (B and C) nickel-catalyzed C–H arylati...
Scheme 66: (A) Known natural tetrahydrofuran-containing substances; (B and C) nickel-catalyzed photoredox C(sp3...
Scheme 67: (A and B) Another notable example of a nickel-catalyzed photoredox C(sp3)–H alkylation/arylation; (...
Scheme 68: (A) Electrochemical/nickel-catalyzed C–H alkoxylation; (B) achieved scope, including three using na...
Scheme 69: (A) Enantioselective photoredox/nickel catalyzed C(sp3)–H arylation; (B) achieved scope, including ...
Scheme 70: (A) Known commercially available trifluoromethylated drugs; (B and C) nickel-catalyzed C–H trifluor...
Scheme 71: (A and B) Stereoselective nickel-catalyzed C–H difluoroalkylation; (C) late-stage functionalization...
Scheme 72: (A) Cu-mediated ortho-amination of oxalamides; (B) achieved scope, including derivatives obtained f...
Scheme 73: (A) Electro-oxidative copper-mediated amination of 8-aminoquinoline-derived amides; (B) achieved sc...
Scheme 74: (A and B) Cu(I)-mediated C–H amination with oximes; (C) derivatization using telmisartan (241) as s...
Scheme 75: (A and B) Cu-mediated amination of aryl amides using ammonia; (C) late-stage modification of proben...
Scheme 76: (A and B) Synthesis of purine nucleoside analogues using copper-mediated C(sp2)–H activation.
Scheme 77: (A) Copper-mediated annulation of acrylamide; (B) achieved scope, including the synthesis of the co...
Scheme 78: (A) Known bioactive compounds containing a naphthyl aryl ether motif; (B and C) copper-mediated eth...
Scheme 79: (A and B) Cu-mediated alkylation of N-oxide-heteroarenes; (C) late-stage modification.
Scheme 80: (A) Cu-mediated cross-dehydrogenative coupling of polyfluoroarenes and alkanes; (B) scope from know...
Scheme 81: (A) Known anticancer acrylonitrile compounds; (B and C) Copper-mediated cyanation of unactivated al...
Scheme 82: (A) Cu-mediated radiofluorination of 8-aminoquinoline-derived aryl amides; (B) achieved scope, incl...
Scheme 83: (A) Examples of natural β-carbolines; (B and C) an example of a zinc-catalyzed C–H functionalizatio...
Scheme 84: (A) Examples of anticancer α-aminophosphonic acid derivatives; (B and C) an example of a zinc-catal...
Amino- and polyaminophthalazin-1(2H)-ones: synthesis, coordination properties, and biological activity
- Zbigniew Malinowski,
- Emilia Fornal,
- Agata Sumara,
- Renata Kontek,
- Karol Bukowski,
- Beata Pasternak,
- Dariusz Sroczyński,
- Joachim Kusz,
- Magdalena Małecka and
- Monika Nowak
Beilstein J. Org. Chem. 2021, 17, 558–568, doi:10.3762/bjoc.17.50
- anticancer drug vatalanib [26][27][28] (Figure 1). On the other hand, aminophthalazinones can be prospective candidates as N- and O-donor ligands to form complexes with biological significant metal ions, such as copper or zinc [29]. Recently, we have demonstrated a strategy for the synthesis of phthalazinone
Graphical Abstract
Figure 1: Structure of biologically active phthalazine derivatives.
Scheme 1: Synthetic route to aminophthalazinones 5 and 6.
Figure 2: Proposed catalytic cycles for the amination of 4-bromophthalazinones of type 3 (Phthal: phthalazino...
Scheme 2: Synthesis of 4-amino- and 4-polyaminophthalazinones 5 and 6 (the yields refer to the isolated compo...
Figure 3: The phthalazinone derivatives that were used to test the complexation of Cu(II) ions.
Scheme 3: The proposal of the fragmentation pathway of the Cu(II) complex with compound 7.
Figure 4: Structure of complex 17.
Figure 5: Molecular structure of complex 17 with atom numbering scheme. The anisotropic displacement paramete...
Figure 6: Determination of relative cell viability (% of control) in different cell lines (HT-29; PC-3 and L-...
Figure 7: Cytotoxic properties of the phthalazinone derivatives expressed as IC50 after 72 h of cell treatmen...
The preparation and properties of 1,1-difluorocyclopropane derivatives
- Kymbat S. Adekenova,
- Peter B. Wyatt and
- Sergazy M. Adekenov
Beilstein J. Org. Chem. 2021, 17, 245–272, doi:10.3762/bjoc.17.25
Graphical Abstract
Scheme 1: Synthesis of 1,1-difluoro-2,3-dimethylcyclopropane (2).
Scheme 2: Cyclopropanation via dehydrohalogenation of chlorodifluoromethane.
Scheme 3: Difluorocyclopropanation of methylstyrene 7 using dibromodifluoromethane and zinc.
Scheme 4: Synthesis of difluorocyclopropanes from the reaction of dibromodifluoromethane and triphenylphosphi...
Scheme 5: Generation of difluorocarbene in a catalytic two-phase system and its addition to tetramethylethyle...
Scheme 6: The reaction of methylstyrene 7 with chlorodifluoromethane (11) in the presence of a tetraarylarson...
Scheme 7: Pyrolysis of sodium chlorodifluoroacetate (12) in refluxing diglyme in the presence of alkene 13.
Scheme 8: Synthesis of boron-substituted gem-difluorocyclopropanes 16.
Scheme 9: Addition of sodium bromodifluoroacetate (17) to alkenes.
Scheme 10: Addition of sodium bromodifluoroacetate (17) to silyloxy-substituted cyclopropanes 20.
Scheme 11: Synthesis of difluorinated nucleosides.
Scheme 12: Addition of butyl acrylate (26) to difluorocarbene generated from TFDA (25).
Scheme 13: Addition of difluorocarbene to propargyl esters 27 and conversion of the difluorocyclopropenes 28 t...
Scheme 14: The generation of difluorocyclopropanes using MDFA 30.
Scheme 15: gem-Difluorocyclopropanation of styrene (32) using difluorocarbene generated from TMSCF3 (31) under...
Scheme 16: Synthesis of a gem-difluorocyclopropane derivative using HFPO (41) as a source of difluorocarbene.
Scheme 17: Cyclopropanation of (Z)-2-butene in the presence of difluorodiazirine (44).
Scheme 18: The cyclopropanation of 1-octene (46) using Seyferth's reagent (45) as a source of difluorocarbene.
Scheme 19: Alternative approaches for the difluorocarbene synthesis from trimethyl(trifluoromethyl)tin (48).
Scheme 20: Difluorocyclopropanation of cyclohexene (49).
Scheme 21: Synthesis of difluorocyclopropane derivative 53 using bis(trifluoromethyl)cadmium (51) as the diflu...
Scheme 22: Addition of difluorocarbene generated from tris(trifluoromethyl)bismuth (54).
Scheme 23: Addition of a stable (trifluoromethyl)zinc reagent to styrenes.
Scheme 24: The preparation of 2,2-difluorocyclopropanecarboxylic acids of type 58.
Scheme 25: Difluorocyclopropanation via Michael cyclization.
Scheme 26: Difluorocyclopropanation using N-acylimidazolidinone 60.
Scheme 27: Difluorocyclopropanation through the cyclization of phenylacetonitrile (61) and 1,2-dibromo-1,1-dif...
Scheme 28: gem-Difluoroolefins 64 for the synthesis of functionalized cyclopropanes 65.
Scheme 29: Preparation of aminocyclopropanes 70.
Scheme 30: Synthesis of fluorinated methylenecyclopropane 74 via selenoxide elimination.
Scheme 31: Reductive dehalogenation of (1R,3R)-75.
Scheme 32: Synthesis of chiral monoacetates by lipase catalysis.
Scheme 33: Transformation of (±)-trans-81 using Rhodococcus sp. AJ270.
Scheme 34: Transformation of (±)-trans-83 using Rhodococcus sp. AJ270.
Scheme 35: Hydrogenation of difluorocyclopropenes through enantioselective hydrocupration.
Scheme 36: Enantioselective transfer hydrogenation of difluorocyclopropenes with a Ru-based catalyst.
Scheme 37: The thermal transformation of trans-1,2-dichloro-3,3-difluorocyclopropane (84).
Scheme 38: cis–trans-Epimerization of 1,1-difluoro-2,3-dimethylcyclopropane.
Scheme 39: 2,2-Difluorotrimethylene diradical intermediate.
Scheme 40: Ring opening of stereoisomers 88 and 89.
Scheme 41: [1,3]-Rearrangement of alkenylcyclopropanes 90–92.
Scheme 42: Thermolytic rearrangement of 2,2-difluoro-1-vinylcyclopropane (90).
Scheme 43: Thermal rearrangement for ethyl 3-(2,2-difluoro)-3-phenylcyclopropyl)acrylates 93 and 95.
Scheme 44: Possible pathways of the ring opening of 1,1-difluoro-2-vinylcyclopropane.
Scheme 45: Equilibrium between 1,1-difluoro-2-methylenecyclopropane (96) and (difluoromethylene)cyclopropane 97...
Scheme 46: Ring opening of substituted 1,1-difluoro-2,2-dimethyl-3-methylenecyclopropane 98.
Scheme 47: 1,1-Difluorospiropentane rearrangement.
Scheme 48: Acetolysis of (2,2-difluorocyclopropyl)methyl tosylate (104) and (1,1-difluoro-2-methylcyclopropyl)...
Scheme 49: Ring opening of gem-difluorocyclopropyl ketones 106 and 108 by thiolate nucleophiles.
Scheme 50: Hydrolysis of gem-difluorocyclopropyl acetals 110.
Scheme 51: Ring-opening reaction of 2,2-difluorocyclopropyl ketones 113 in the presence of ionic liquid as a s...
Scheme 52: Ring opening of gem-difluorocyclopropyl ketones 113a by MgI2-initiated reaction with diarylimines 1...
Scheme 53: Ring-opening reaction of gem-difluorocyclopropylstannanes 117.
Scheme 54: Preparation of 1-fluorovinyl vinyl ketone 123 and the synthesis of 2-fluorocyclopentenone 124. TBAT...
Scheme 55: Iodine atom-transfer ring opening of 1,1-difluoro-2-(1-iodoalkyl)cyclopropanes 125a–c.
Scheme 56: Ring opening of bromomethyl gem-difluorocyclopropanes 130 and formation of gem-difluoromethylene-co...
Scheme 57: Ring-opening aerobic oxidation reaction of gem-difluorocyclopropanes 132.
Scheme 58: Dibrominative ring-opening functionalization of gem-difluorocyclopropanes 134.
Scheme 59: The selective formation of (E,E)- and (E,Z)-fluorodienals 136 and 137 from difluorocyclopropyl acet...
Scheme 60: Proposed mechanism for the reaction of difluoro(methylene)cyclopropane 139 with Br2.
Scheme 61: Thermal rearrangement of F2MCP 139 and iodine by CuI catalysis.
Scheme 62: Synthesis of 2-fluoropyrroles 142.
Scheme 63: Ring opening of gem-difluorocyclopropyl ketones 143 mediated by BX3.
Scheme 64: Lewis acid-promoted ring-opening reaction of 2,2-difluorocyclopropanecarbonyl chloride (148).
Scheme 65: Ring-opening reaction of the gem-difluorocyclopropyl ketone 106 by methanolic KOH.
Scheme 66: Hydrogenolysis of 1,1-difluoro-3-methyl-2-phenylcyclopropane (151).
Scheme 67: Synthesis of monofluoroalkenes 157.
Scheme 68: The stereoselective Ag-catalyzed defluorinative ring-opening diarylation of 1-trimethylsiloxy-2,2-d...
Scheme 69: Synthesis of 2-fluorinated allylic compounds 162.
Scheme 70: Pd-catalyzed cross-coupling reactions of gem-difluorinated cyclopropanes 161.
Scheme 71: The (Z)-selective Pd-catalyzed ring-opening sulfonylation of 2-(2,2-difluorocyclopropyl)naphthalene...
Figure 1: Structures of zosuquidar hydrochloride and PF-06700841.
Scheme 72: Synthesis of methylene-gem-difluorocyclopropane analogs of nucleosides.
Figure 2: Anthracene-difluorocyclopropane hybrid derivatives.
Figure 3: Further examples of difluorcyclopropanes in modern drug discovery.
One-pot multicomponent green Hantzsch synthesis of 1,2-dihydropyridine derivatives with antiproliferative activity
- Giovanna Bosica,
- Kaylie Demanuele,
- José M. Padrón and
- Adrián Puerta
Beilstein J. Org. Chem. 2020, 16, 2862–2869, doi:10.3762/bjoc.16.235
- lines, in the low micromolar range. The most active compound was 5e, which exhibited GI50 values in the range of 2.7–5.6 μM. The results obtained are comparable to those of the standard anticancer drug cisplatin (CDDP), which was used as reference drug. Conclusion The one-pot multicomponent Hantzsch
Graphical Abstract
Scheme 1: The classical Hantzsch synthesis between benzaldehyde (1a), ethyl acetoacetate (2), and ammonium ac...
Figure 1: Optimization trials with the selected solid catalysts.
Figure 2: Graphical representation of the results obtained in the reusability test.
The B & B approach: Ball-milling conjugation of dextran with phenylboronic acid (PBA)-functionalized BODIPY
- Patrizia Andreozzi,
- Lorenza Tamberi,
- Elisamaria Tasca,
- Gina Elena Giacomazzo,
- Marta Martinez,
- Mirko Severi,
- Marco Marradi,
- Stefano Cicchi,
- Sergio Moya,
- Giacomo Biagiotti and
- Barbara Richichi
Beilstein J. Org. Chem. 2020, 16, 2272–2281, doi:10.3762/bjoc.16.188
- nanoparticles, depending on the degree of substitution. For example, reaction of vicinal diols of dextran with hydrophobic PBA generates boronate esters, which form nanoparticles in water and are capable to host the anticancer drug doxorubicin [27]. In this report, the advantages of the milling process, such as
Graphical Abstract
Figure 1: Structure of PBA-BODIPY (1) and schematic representation of dextran (Dex) and PBA-BODIPY conjugated...
Scheme 1: Schematic representation of dextran/PBA-BODIPY bioconjugations in: A. conventional solution-based c...
Figure 2: A) Amount of recovered PBA-BODIPY (1, i.e., nonreacted 1) in the mixtures DMSO/EtOH and in the seri...
Figure 3: A) UV–vis absorption and B) fluorescence emission spectra (λexc = 380 nm) of the BODIPY-dextran con...
Figure 4: A) Hydrodynamic diameter of (nm) conjugate Dex-1b (at 1 mg/mL in H2O, black curve) and PBS (red cur...
Figure 5: Fluorescence emission spectra of pyrene (4.4 × 10−8 M) in water and in a water solution in the pres...
Recent synthesis of thietanes
- Jiaxi Xu
Beilstein J. Org. Chem. 2020, 16, 1357–1410, doi:10.3762/bjoc.16.116
- D-ring-modified thia derivatives 4 and 5 of the anticancer drug taxoids and docetaxels [6], thiathromboxane A2 6 [7], pesticide 7 [8], and the sweetener 8 [9] (Figure 1). Thietanes also serve as important and useful intermediates and versatile building blocks in organic synthesis for the preparation
Graphical Abstract
Figure 1: Examples of biologically active thietane-containing molecules.
Figure 2: The diverse methods for the synthesis of thietanes.
Scheme 1: Synthesis of 1-(thietan-2-yl)ethan-1-ol (10) from 3,5-dichloropentan-2-ol (9).
Scheme 2: Synthesis of thietanose nucleosides 2,14 from 2,2-bis(bromomethyl)propane-1,3-diol (11).
Scheme 3: Synthesis of methyl 3-vinylthietane-3-carboxylate (19).
Scheme 4: Synthesis of 1,6-thiazaspiro[3.3]heptane (24).
Scheme 5: Synthesis of 6-amino-2-thiaspiro[3.3]heptane hydrochloride (28).
Scheme 6: Synthesis of optically active thietane 31 from vitamin C.
Scheme 7: Synthesis of an optically active thietane nucleoside from diethyl L-tartrate (32).
Scheme 8: Synthesis of thietane-containing spironucleoside 40 from 5-aldo-3-O-benzyl-1,2-O-isopropylidene-α-D...
Scheme 9: Synthesis of optically active 2-methylthietane-containing spironucleoside 43.
Scheme 10: Synthesis of a double-linked thietane-containing spironucleoside 48.
Scheme 11: Synthesis of two diastereomeric thietanose nucleosides via 2,4-di(benzyloxymethyl)thietane (49).
Scheme 12: Synthesis of the thietane-containing PI3k inhibitor candidate 54.
Scheme 13: Synthesis of the spirothietane 57 as the key intermediate to Nuphar sesquiterpene thioalkaloids.
Scheme 14: Synthesis of spirothietane 61 through a direct cyclic thioetherification of 3-mercaptopropan-1-ol.
Scheme 15: Synthesis of thietanes 66 from 1,3-diols 62.
Scheme 16: Synthesis of thietanylbenzimidazolone 75 from (iodomethyl)thiazolobenzimidazole 70.
Scheme 17: Synthesis of 2-oxa-6-thiaspiro[3.3]heptane (80) from bis(chloromethyl)oxetane 76 and thiourea.
Scheme 18: Synthesis of the thietane-containing glycoside, 2-O-p-toluenesulfonyl-4,6-thioanhydro-α-D-gulopyran...
Scheme 19: Synthesis of methyl 4,6-thioanhydro-α-D-glucopyranoside (89).
Scheme 20: Synthesis of thietane-fused α-D-galactopyranoside 93.
Scheme 21: Synthesis of thietane-fused α-D-gulopyranoside 100.
Scheme 22: Synthesis of 3,5-anhydro-3-thiopentofuranosides 104.
Scheme 23: Synthesis of anhydro-thiohexofuranosides 110, 112 and 113 from from 1,2:4,5-di-O-isopropylidene D-f...
Scheme 24: Synthesis of optically active thietanose nucleosides from D- and L-xyloses.
Scheme 25: Synthesis of thietane-fused nucleosides.
Scheme 26: Synthesis of 3,5-anhydro-3-thiopentofuranosides.
Scheme 27: Synthesis of 2-amino-3,5-anhydro-3-thiofuranoside 141.
Scheme 28: Synthesis of thietane-3-ols 145 from (1-chloromethyl)oxiranes 142 and hydrogen sulfide.
Scheme 29: Synthesis of thietane-3-ol 145a from chloromethyloxirane (142a).
Scheme 30: Synthesis of thietane-3-ols 145 from 2-(1-haloalkyl)oxiranes 142 and 147 with ammonium monothiocarb...
Scheme 31: Synthesis of 7-deoxy-5(20)thiapaclitaxel 154a, a thietane derivative of taxoids.
Scheme 32: Synthesis of 5(20)-thiadocetaxel 158 from 10-deacetylbaccatin III (155).
Scheme 33: Synthesis of thietane derivatives 162 as precursors for deoxythiataxoid synthesis through oxiraneme...
Scheme 34: Synthesis of 7-deoxy 5(20)-thiadocetaxel 154b.
Scheme 35: Mechanism for the formation of the thietane ring in 171 from oxiranes with vicinal leaving groups 1...
Scheme 36: Synthesis of cis-2,3-disubstituted thietane 175 from thiirane-2-methanol 172.
Scheme 37: Synthesis of a bridged thietane 183 from aziridine cyclohexyl tosylate 179 and ammonium tetrathiomo...
Scheme 38: Synthesis of thietanes via the photochemical [2 + 2] cycloaddition of thiobenzophenone 184a with va...
Scheme 39: Synthesis of spirothietanes through the photo [2 + 2] cycloaddition of cyclic thiocarbonyls with ol...
Scheme 40: Photochemical synthesis of spirothietane-thioxanthenes 210 from thioxanthenethione (208) and butatr...
Scheme 41: Synthesis of thietanes 213 from 2,4,6-tri(tert-butyl)thiobenzaldehyde (211) with substituted allene...
Scheme 42: Photochemical synthesis of spirothietanes 216 and 217 from N-methylthiophthalimide (214) with olefi...
Scheme 43: Synthesis of fused thietanes from quadricyclane with thiocarbonyl derivatives 219.
Scheme 44: Synthesis of tricyclic thietanes via the photo [2 + 2] cycloaddition of N-methyldithiosuccinimides ...
Scheme 45: Synthesis of tricyclic thietanes via the photo [2 + 2] cycloaddition of N-methylthiosuccinimide/thi...
Scheme 46: Synthesis of tricyclic thietanes via the photo [2 + 2] cycloaddition of N-alkylmonothiophthalimides...
Scheme 47: Synthesis of spirothietanes from dithiosuccinimides 223 with 2,3-dimethyl-2-butene (215a).
Scheme 48: Synthesis of thietanes 248a,b from diaryl thione 184b and ketene acetals 247a,b.
Scheme 49: Photocycloadditions of acridine-9-thiones 249 and pyridine-4(1H)-thione (250) with 2-methylacrynitr...
Scheme 50: Synthesis of thietanes via the photo [2 + 2] cycloaddition of mono-, di-, and trithiobarbiturates 2...
Scheme 51: Synthesis of spirothietanes via the photo [2 + 2] cycloaddition of 1,1,3-trimethyl-2-thioxo-1,2-dih...
Scheme 52: Synthesis of spirothietanes via the photo [2 + 2] cycloaddition of thiocoumarin 286 with olefins.
Scheme 53: Photochemical synthesis of thietanes 296–299 from semicyclic and acyclic thioimides 292–295 and 2,3...
Scheme 54: Photochemical synthesis of spirothietane 301 from 1,3,3-trimethylindoline-2-thione (300) and isobut...
Scheme 55: Synthesis of spirobenzoxazolethietanes 303 via the photo [2 + 2] cycloaddition of alkyl and aryl 2-...
Scheme 56: Synthesis of spirothietanes from tetrahydrothioxoisoquinolines 306 and 307 with olefins.
Scheme 57: Synthesis of spirothietanes from 1,3-dihydroisobenzofuran-1-thiones 311 and benzothiophene-1-thione...
Scheme 58: Synthesis of 2-triphenylsilylthietanes from phenyl triphenylsilyl thioketone (316) with electron-po...
Scheme 59: Diastereoselective synthesis of spiropyrrolidinonethietanes 320 via the photo [2 + 2] cycloaddition...
Scheme 60: Synthesis of bicyclic thietane 323 via the photo [2 + 2] cycloaddition of 2,4-dioxo-3,4-dihydropyri...
Scheme 61: Photo-induced synthesis of fused thietane-2-thiones 325 and 326 from silacyclopentadiene 324 and ca...
Scheme 62: Synthesis of highly strained tricyclic thietanes 328 via the intramolecular photo [2 + 2] cycloaddi...
Scheme 63: Synthesis of tri- and pentacyclic thietanes 330 and 332, respectively, through the intramolecular p...
Scheme 64: Synthesis of tricyclic thietanes 334 via the intramolecular photo [2 + 2] cycloaddition of N-vinylt...
Scheme 65: Synthesis of tricyclic thietanes 336 via the intramolecular photo [2 + 2] cycloaddition of N-but-3-...
Scheme 66: Synthesis of tricyclic thietanes via the intramolecular photo [2 + 2] cycloaddition of N-but-3-enyl...
Scheme 67: Synthesis of tetracyclic thietane 344 through the intramolecular photo [2 + 2] cycloaddition of N-[...
Scheme 68: Synthesis of tri- and tetracyclic thietanes 348, 350, and 351, through the intramolecular photo [2 ...
Scheme 69: Synthesis of tetracyclic fused thietane 354 via the photo [2 + 2] cycloaddition of vinyl 2-thioxo-3H...
Scheme 70: Synthesis of highly rigid thietane-fused β-lactams via the intramolecular photo [2 + 2] cycloadditi...
Scheme 71: Asymmetric synthesis of a highly rigid thietane-fused β-lactam 356a via the intramolecular photo [2...
Scheme 72: Diastereoselective synthesis of the thietane-fused β-lactams via the intramolecular photo [2 + 2] c...
Scheme 73: Asymmetric synthesis of thietane-fused β-lactams 356 via the intramolecular photo [2 + 2] cycloaddi...
Scheme 74: Synthesis of the bridged bis(trifluoromethyl)thietane from 2,2,4,4-tetrakis(trifluoromethyl)-1,3-di...
Scheme 75: Synthesis of the bridged-difluorothietane 368 from 2,2,4,4-tetrafluoro-1,3-dithietane (367) and qua...
Scheme 76: Synthesis of bis(trifluoromethyl)thietanes from 2,2,4,4-tetrakis(trifluoromethyl)-1,3-dithietane (3...
Scheme 77: Synthesis of 2,2-dimethylthio-4,4-di(trifluoromethyl)thietane (378) from 2,2,4,4-tetrakis(trifluoro...
Scheme 78: Formation of bis(trifluoromethyl)thioacetone (381) through nucleophilic attack of dithietane 363 by...
Scheme 79: Synthesis of 2,2-bis(trifluoromethyl)thietanes from 2,2,4,4-tetrakis(trifluoromethyl)-1,3-dithietan...
Scheme 80: Synthesis of the bridged bis(trifluoromethyl)thietane 364 from of 2,2,4,4-tetrakis(trifluoromethyl)...
Scheme 81: Synthesis of 2,4-diiminothietanes 390 from alkenimines and 4-methylbenzenesulfonyl isothiocyanate (...
Scheme 82: Synthesis of arylidene 2,4-diiminothietanes 393 starting from phosphonium ylides 391 and isothiocya...
Scheme 83: Synthesis of thietane-2-ylideneacetates 397 through a DABCO-catalyzed formal [2 + 2] cycloaddition ...
Scheme 84: Synthesis of 3-substituted thietanes 400 from (1-chloroalkyl)thiiranes 398.
Scheme 85: Synthesis of N-(thietane-3-yl)azaheterocycles 403 and 404 through reaction of chloromethylthiirane (...
Scheme 86: Synthesis of 3-sulfonamidothietanes 406 from sulfonamides and chloromethylthiirane (398a).
Scheme 87: Synthesis of N-(thietane-3-yl)isatins 408 from chloromethylthiirane (398a) and isatins 407.
Scheme 88: Synthesis of 3-(nitrophenyloxy)thietanes 410 from nitrophenols 409 and chloromethylthiirane (398a).
Scheme 89: Synthesis of N-aryl-N-(thietane-3-yl)cyanamides 412 from N-arylcyanamides 411 and chloromethylthiir...
Scheme 90: Synthesis of 1-(thietane-3-yl)pyrimidin-2,4(1H,3H)-diones 414 from chloromethylthiirane (398a) and ...
Scheme 91: Synthesis of 2,4-diiminothietanes 418 from 2-iminothiiranes 416 and isocyanoalkanes 415.
Scheme 92: Synthesis of 2-vinylthietanes 421 from thiiranes 419 and 3-chloroallyl lithium (420).
Scheme 93: Synthesis of thietanes from thiiranes 419 and trimethyloxosulfonium iodide 424.
Scheme 94: Mechanism for synthesis of thietanes 425 from thiiranes 419 and trimethyloxosulfonium iodide 424.
Scheme 95: Synthesis of functionalized thietanes from thiiranes and dimethylsulfonium acylmethylides.
Scheme 96: Mechanism for the rhodium-catalyzed synthesis of functionalized thietanes 429 from thiiranes 419 an...
Scheme 97: Synthesis of 3-iminothietanes 440 through thermal isomerization from 4,5-dihydro-1,3-oxazole-4-spir...
Scheme 98: Synthesis of thietanes 443 from 3-chloro-2-methylthiolane (441) through ring contraction.
Scheme 99: Synthesis of an optically active thietanose 447 from D-xylose involving a ring contraction.
Scheme 100: Synthesis of optically thietane 447 via the DAST-mediated ring contraction of 448.
Scheme 101: Synthesis of the optically thietane nucleoside 451 via the ring contraction of thiopentose in 450.
Scheme 102: Synthesis of spirothietane 456 from 3,3,5,5-tetramethylthiolane-2,4-dithione (452) and benzyne (453...
Scheme 103: Synthesis of thietanes 461 via photoisomerization of 2H,6H-thiin-3-ones 459.
Scheme 104: Phosphorodithioate-mediated synthesis of 1,4-diarylthietanes 465.
Scheme 105: Mechanism of the phosphorodithioate-mediated synthesis of 1,4-diarylthietanes 465.
Scheme 106: Phosphorodithioate-mediated synthesis of trisubstituted thietanes (±)-470.
Scheme 107: Mechanism on the phosphorodithioate-mediated synthesis of trisubstituted thietanes.
Scheme 108: Phosphorodithioate-mediated synthesis of thietanes (±)-475.
Scheme 109: Phosphorodithioate-mediated synthesis of 1,2-disubstituted thietanes from aldehydes 476 and acrylon...
Scheme 110: Phosphorodithioate-mediated synthesis of 1,2-disubstituted thietanes via a one-pot three-component ...
Scheme 111: Mechanism for the phosphorodithioate-mediated synthesis of 1,2-disubstituted thietanes via three-co...
Scheme 112: Phosphorodithioate-mediated synthesis of substituted 3-nitrothietanes.
Scheme 113: Mechanism on the phosphorodithioate-mediated synthesis of 1,2-disubstituted thietanes (±)-486.
Scheme 114: Asymmetric synthesis of (S)-2-phenylthietane (497).
Scheme 115: Asymmetric synthesis of optically active 2,4-diarylthietanes.
Scheme 116: Synthesis of 3-acetamidothietan-2-one 503 via the intramolecular thioesterification of 3-mercaptoal...
Scheme 117: Synthesis of 4-substituted thietan-2-one via the intramolecular thioesterification of 3-mercaptoalk...
Scheme 118: Synthesis of 4,4-disubstituted thietan-2-one 511 via the intramolecular thioesterification of the 3...
Scheme 119: Synthesis of a spirothietan-2-one 514 via the intramolecular thioesterification of 3-mercaptoalkano...
Scheme 120: Synthesis of thiatetrahydrolipstatin starting from (S)-(−)-epichlorohydrin ((S)-142a).
Scheme 121: Synthesis of 2-phenethyl-4-(propan-2-ylidene)thietane (520) from 5-bromo-6-methyl-1-phenylhept-5-en...
Scheme 122: Synthesis of 2-phenethyl-4-(propan-2-ylidene)thietane (520) directly from S-(5-bromo-6-methyl-1-phe...
Scheme 123: Synthesis of 2-alkylidenethietanes from S-(2-bromoalk-1-en-4-yl)thioacetates.
Scheme 124: Synthesis of 2-alkylidenethietanes from S-(2-bromo/chloroalk-1-en-4-yl)thiols.
Scheme 125: Synthesis of spirothietan-3-ol 548 from enone 545 and ammonium hydrosulfide.
Scheme 126: Asymmetric synthesis of the optically active thietanoside from cis-but-2-ene-1,4-diol (47).
Scheme 127: Synthesis of 2-alkylidenethietan-3-ols 557 via the fluoride-mediated cyclization of thioacylsilanes ...
Scheme 128: Synthesis of 2-iminothietanes via the reaction of propargylbenzene (558) and isothiocyanates 560 in...
Scheme 129: Synthesis of 2-benzylidenethietane 567 via the nickel complex-catalyzed electroreductive cyclizatio...
Scheme 130: Synthesis of 2-iminothietanes 569 via the photo-assisted electrocyclic reaction of N-monosubstitute...
Scheme 131: Synthesis of ethyl 3,4-diiminothietane-2-carboxylates from ethyl thioglycolate (570) and bis(imidoy...
Scheme 132: Synthesis of N-(thietan-3-yl)-α-oxoazaheterocycles from azaheterocyclethiones and chloromethyloxira...
Scheme 133: Synthesis of thietan-3-yl benzoate (590) via the nickel-catalyzed intramolecular reductive thiolati...
Scheme 134: Synthesis of 2,2-bis(trifluoromethyl)thietane from 3,3-bis(trifluoromethyl)-1,2-dithiolane.
Scheme 135: Synthesis of thietanes from enamines and sulfonyl chlorides.
Scheme 136: Synthesis of spirothietane 603 via the [2 + 3] cycloaddition of 2,2,4,4-tetramethylcyclobutane-1,3-...
Scheme 137: Synthesis of thietane (605) from 1-bromo-3-chloropropane and sulfur.
Synthesis and anticancer activity of bis(2-arylimidazo[1,2-a]pyridin-3-yl) selenides and diselenides: the copper-catalyzed tandem C–H selenation of 2-arylimidazo[1,2-a]pyridine with selenium
- Mio Matsumura,
- Tsutomu Takahashi,
- Hikari Yamauchi,
- Shunsuke Sakuma,
- Yukako Hayashi,
- Tadashi Hyodo,
- Tohru Obata,
- Kentaro Yamaguchi,
- Yasuyuki Fujiwara and
- Shuji Yasuike
Beilstein J. Org. Chem. 2020, 16, 1075–1083, doi:10.3762/bjoc.16.94
- , the 4-methoxyphenyl group appeared to enhance the anticancer activity of the bis(2-arylimidazo[1,2-a]pyridin-3-yl) diselenides and selenides. Furthermore, only the compound 2f showed a higher anticancer activity than doxorubicin (DOX), a well-known anthracycline-based anticancer drug. As shown in
Graphical Abstract
Figure 1: Biologically active selenides and diselenides having heteroaryl groups.
Figure 2: Ortep drawings of 2a (a and b) and 3a (c and d, thermal elipsoids indicate 50% probability).
Figure 3: The synthesis of bis(2-arylimidazopyridin-3-yl) diselenides. Reaction conditions: 1 (2 mmol), Se (2...
Figure 4: The synthesis of bis(2-arylimidazopyridin-3-yl) selenides. Reaction conditions: 1 (2 mmol), Se (1 m...
Scheme 1: Control reactions.
Scheme 2: Proposed mechanism (1).
Scheme 3: Proposed mechanism (2).
Figure 5: The cytotoxic effect of the bis(2-arylimidazo[1,2-a]pyridin-3-yl) diselenides 2 and selenides 3 on ...
Figure 6: The cytotoxic effect of the bis[2-(4-methoxyphenyl)imidazo[1,2-a]pyridin-3-yl] diselenide 2f on can...
Figure 7: Cytotoxic effect of the bis[2-(4-methoxyphenyl)imidazo[1,2-a]pyridin-3-yl] diselenide 2f on a cance...
Fluorinated phenylalanines: synthesis and pharmaceutical applications
- Laila F. Awad and
- Mohammed Salah Ayoup
Beilstein J. Org. Chem. 2020, 16, 1022–1050, doi:10.3762/bjoc.16.91
- affinity and specificity for system L [58]. Accordingly, 2-[18F]FELP 95 emerged as a promising PET radiotracer for brain tumor imaging [97][98][99][100][101] (Figure 2). 5.2. Incorporation of FPhe for the synthesis of fluorinated drugs 5.2.1. Melflufen, an anticancer drug: 4-Fluoro-ʟ-phenylalanine ester is
- required for the synthesis of melflufen (179), an anticancer drug currently being in clinical trials for the treatment of relapsed and refractory multiple myeloma (RRMM) [102][103]. Melflufen is a next generation form of the more historical drug, melphalan 180 (Figure 3). 5.2.2. Gastrazole (JB95008), a
Graphical Abstract
Figure 1: Categories I–V of fluorinated phenylalanines.
Scheme 1: Synthesis of fluorinated phenylalanines via Jackson’s method.
Scheme 2: Synthesis of all-cis-tetrafluorocyclohexylphenylalanines.
Scheme 3: Synthesis of ʟ-4-[sulfono(difluoromethyl)]phenylalanine (nPt: neopentyl, TCE: trichloroethyl).
Scheme 4: Synthesis of ʟ-4-[sulfono(difluoromethyl)]phenylalanine derivatives 17.
Scheme 5: Synthesis of fluorinated Phe analogues from Cbz-protected aminomalonates.
Scheme 6: Synthesis of tetrafluorophenylalanine analogues via the 3-methyl-4-imidazolidinone auxiliary 25.
Scheme 7: Synthesis of tetrafluoro-Phe derivatives via chiral auxiliary 31.
Scheme 8: Synthesis of 2,5-difluoro-Phe and 2,4,5-trifluoro-Phe via Schöllkopf reagent 34.
Scheme 9: Synthesis of 2-fluoro- and 2,6-difluoro Fmoc-Phe derivatives starting from chiral auxiliary 39.
Scheme 10: Synthesis of 2-[18F]FPhe via chiral auxiliary 43.
Scheme 11: Synthesis of FPhe 49a via photooxidative cyanation.
Scheme 12: Synthesis of FPhe derivatives via Erlenmeyer azalactone synthesis.
Scheme 13: Synthesis of (R)- and (S)-2,5-difluoro Phe via the azalactone method.
Scheme 14: Synthesis of 3-bromo-4-fluoro-(S)-Phe (65).
Scheme 15: Synthesis of [18F]FPhe via radiofluorination of phenylalanine with [18F]F2 or [18F]AcOF.
Scheme 16: Synthesis of 4-borono-2-[18F]FPhe.
Scheme 17: Synthesis of protected 4-[18F]FPhe via arylstannane derivatives.
Scheme 18: Synthesis of FPhe derivatives via intermediate imine formation.
Scheme 19: Synthesis of FPhe derivatives via Knoevenagel condensation.
Scheme 20: Synthesis of FPhe derivatives 88a,b from aspartic acid derivatives.
Scheme 21: Synthesis of 2-(2-fluoroethyl)phenylalanine derivatives 93 and 95.
Scheme 22: Synthesis of FPhe derivatives via Zn2+ complexes.
Scheme 23: Synthesis of FPhe derivatives via Ni2+ complexes.
Scheme 24: Synthesis of 3,4,5-trifluorophenylalanine hydrochloride (109).
Scheme 25: Synthesis of FPhe derivatives via phenylalanine aminomutase (PAM).
Scheme 26: Synthesis of (R)-2,5-difluorophenylalanine 115.
Scheme 27: Synthesis of β-fluorophenylalanine via 2-amino-1,3-diol derivatives.
Scheme 28: Synthesis of β-fluorophenylalanine derivatives via the oxazolidinone chiral auxiliary 122.
Scheme 29: Synthesis of β-fluorophenylalanine from pyruvate hemiketal 130.
Scheme 30: Synthesis of β-fluorophenylalanine (136) via fluorination of β-hydroxyphenylalanine (137).
Scheme 31: Synthesis of β-fluorophenylalanine from aziridine derivatives.
Scheme 32: Synthesis of β-fluorophenylalanine 136 via direct fluorination of pyruvate esters.
Scheme 33: Synthesis of β-fluorophenylalanine via fluorination of ethyl 3-phenylpyruvate enol using DAST.
Scheme 34: Synthesis of β-fluorophenylalanine derivatives using photosensitizer TCB.
Scheme 35: Synthesis of β-fluorophenylalanine derivatives using Selectflour and dibenzosuberenone.
Scheme 36: Synthesis of protected β-fluorophenylalanine via aziridinium intermediate 150.
Scheme 37: Synthesis of β-fluorophenylalanine derivatives via fluorination of α-hydroxy-β-aminophenylalanine d...
Scheme 38: Synthesis of β-fluorophenylalanine derivatives from α- or β-hydroxy esters 152a and 155.
Scheme 39: Synthesis of a series of β-fluoro-Phe derivatives via Pd-catalyzed direct fluorination of β-methyle...
Scheme 40: Synthesis of series of β-fluorinated Phe derivatives using quinoline-based ligand 162 in the Pd-cat...
Scheme 41: Synthesis of β,β-difluorophenylalanine derivatives from 2,2-difluoroacetaldehyde derivatives 164a,b....
Scheme 42: Synthesis of β,β-difluorophenylalanine derivatives via an imine chiral auxiliary.
Scheme 43: Synthesis of α-fluorophenylalanine derivatives via direct fluorination of protected Phe 174.
Figure 2: Structures of PET radiotracers of 18FPhe derivatives.
Figure 3: Structures of melfufen (179) and melphalan (180) anticancer drugs.
Figure 4: Structure of gastrazole (JB95008, 181), a CCK2 receptor antagonist.
Figure 5: Dual CCK1/CCK2 antagonist 182.
Figure 6: Structure of sitagliptin (183), an antidiabetic drug.
Figure 7: Structure of retaglpitin (184) and antidiabetic drug.
Figure 8: Structure of evogliptin (185), an antidiabetic drug.
Figure 9: Structure of LY2497282 (186) a DPP-4 inhibitor for the treatment of type II diabetes.
Figure 10: Structure of ulimorelin (187).
Figure 11: Structure of GLP1R (188).
Figure 12: Structures of Nav1.7 blockers 189 and 190.
α,ß-Didehydrosuberoylanilide hydroxamic acid (DDSAHA) as precursor and possible analogue of the anticancer drug SAHA
- Shital K. Chattopadhyay,
- Subhankar Ghosh,
- Sarita Sarkar and
- Kakali Bhadra
Beilstein J. Org. Chem. 2019, 15, 2524–2533, doi:10.3762/bjoc.15.245
- the important anticancer drug suberoylanilide hydroxamic acid (SAHA) from its α,ß-didehydro derivative is described. The didehydro derivative is obtained through a cross metathesis reaction between a suitable terminal alkene and N-benzyloxyacrylamide. Some of the didehydro derivatives of SAHA were
- species (ROS) as some apoptotic features. Keywords: anticancer drug; cross metathesis; HDAC inhibition; hydroxamates; reactive oxygen species; Introduction Suberoylanilide hydroxamic acid (SAHA, 1, Figure 1, vorinostat [1][2], has now emerged as a FDA approved drug for the treatment of relapsed and
- significant changes in biological activity [14]. Three syntheses of this important anticancer drug have been described [15][16][17]. However, need for the development of alternative synthetic routes amenable for SAR studies does exist. Although a number of α,ß-dehydrohydroxamates (e.g., 2 and 3) display an
Graphical Abstract
Figure 1: Some hydroxamic acid-based anti-tumor drugs.
Scheme 1: Synthesis of SAHA and DDSAHA.
Figure 2: Cell viability from MTT assay for SAHA, 11b, 11f and 11g on HeLa after 24 h treatment.
Figure 3: Percent of cell death by LDH assay at a GI50 dose of SAHA, 11b, 11f and 11g after 24 h incubation a...
Figure 4: ROS generation by DCFDA.
Figure 5: The quantitative results of bivariate FITC-Annexin V/PI FCM of HeLa cells after treatment with 11b ...
Figure 6: Fluorescence microscopic images of 11b at different concentrations (8.9, and 14.2 µM, respectively)...
Figure 7: DNA Ladder formation in a gel electrophoresis study of 11b at different concentrations (at 8.9, and...
Current understanding and biotechnological application of the bacterial diterpene synthase CotB2
- Ronja Driller,
- Daniel Garbe,
- Norbert Mehlmer,
- Monika Fuchs,
- Keren Raz,
- Dan Thomas Major,
- Thomas Brück and
- Bernhard Loll
Beilstein J. Org. Chem. 2019, 15, 2355–2368, doi:10.3762/bjoc.15.228
- inexpensive carbon sources. Prominent examples of optimized terpene production pathways in E. coli are taxadiene, a precursor of the anticancer drug taxol [28], amorpha‐4,11‐diene, an antimalarial drug precursor [29], and cyclooctatin [30]. The scope of this review encompasses a detailed consideration of the
Graphical Abstract
Figure 1: CotB1 synthesizes geranylgeranyl diphosphate (GGDP) 3 from the substrates dimethylallyl diphosphate...
Figure 2: The bacterial diterpene synthase CotB2wt·Mg2+3·F-Dola in the closed, active conformation (PDB-ID 6G...
Figure 3: Conformational changes of CotB2 upon ligand binding. Superposition of CotB2’s open (teal), pre-cata...
Figure 4: View into the active site of CotB2wt·Mg2+3·F-Dola [37] superimposed with CotB2wt·Mg2+B·GGSDP [36]. (A) The ...
Figure 5: View into the active site of CotB2wt·Mg2+3·F-Dola [37]. Identical view as in Figure 4. (A) The bound F-Dola rea...
Figure 6: The WXXXXXRY motif in protein sequences of diterpene TPS from different bacteria. Highlighted is th...
Scheme 1: Overview of the altered product portfolio as a result of introduced point mutations in the active s...
Scheme 2: Catalytic mechanism of CotB2, derived from isotope labeling experiments [34,35], density functional theory...
Figure 7: (A) The inner surface of the active site is shown in gray. The bound F-Dola reaction intermediate i...
Scheme 3: Variants of CotB2 open the route to a novel product portfolio with altered cyclic carbon skeletons,...
Repurposing the anticancer drug cisplatin with the aim of developing novel Pseudomonas aeruginosa infection control agents
- Mingjun Yuan,
- Song Lin Chua,
- Yang Liu,
- Daniela I. Drautz-Moses,
- Joey Kuok Hoong Yam,
- Thet Tun Aung,
- Roger W. Beuerman,
- May Margarette Santillan Salido,
- Stephan C. Schuster,
- Choon-Hong Tan,
- Michael Givskov,
- Liang Yang and
- Thomas E. Nielsen
Beilstein J. Org. Chem. 2018, 14, 3059–3069, doi:10.3762/bjoc.14.284
Graphical Abstract
Figure 1: Structures and MICs of Pt-based compounds against P. aeruginosa PAO1.
Figure 2: Transcriptomic analysis of control and cisplatin-treated PAO1 cultures. Heatmap comparing the trans...
Figure 3: Function enrichment of differentially expressed genes from the transcriptomic analysis. A dot-lot f...
Figure 4: Cisplatin fast-kill assay against the P. aeruginosa PAO1, ΔrecA mutant and the ΔrecACOM strain. P. ...
Figure 5: Cisplatin treatment represses T3SS associated virulence. (A) Cisplatin treatment downregulated the ...
Figure 6: P. aeruginosa biofilm killing assay by cisplatin, tobramycin and their combinations. P. aeruginosa ...
Figure 7: Cisplatin treatment attenuates P. aeruginosa infections. CFU mL−1 of PAO1 obtained from corneas wit...
Comparative cell biological study of in vitro antitumor and antimetastatic activity on melanoma cells of GnRH-III-containing conjugates modified with short-chain fatty acids
- Eszter Lajkó,
- Sarah Spring,
- Rózsa Hegedüs,
- Beáta Biri-Kovács,
- Sven Ingebrandt,
- Gábor Mező and
- László Kőhidai
Beilstein J. Org. Chem. 2018, 14, 2495–2509, doi:10.3762/bjoc.14.226
- anticancer drug resistance as they are co-administrated with other chemotherapeutics [29][30]. Nevertheless, there is some controversy about the effects of short-chain fatty acids on the metastatic ability of melanoma cells, since both pro-invasive [31] and anti-invasive [29][32] activities have been
Graphical Abstract
Figure 1: Schematic structure of Dau-conjugated GnRH-III or its derivatives containing 4Lys with acetyl or bu...
Figure 2: Cellular uptake of Dau–GnRH-III conjugates and free daunorubicin (Dau) by A2058 cells. Cellular upt...
Figure 3: Short-term growth inhibitory effects of the conjugates and daunorubicin (Dau) on A2058 cells. The m...
Figure 4: Effects of conjugates and daunorubicin (Dau) on cell cycle progression of A2058 melanoma cells. The...
Figure 5: Effects of the conjugates and daunorubicin (Dau) on melanoma cell adhesion. The Delta CI (Delta Cel...
Figure 6: Chemotactic effects of Dau–GnRH-III conjugates on A2058 cell line. The ‘Chemotaxis index’ (Chtx. in...
Figure 7: Effects of GnRH-III(Dau=Aoa) (a–c), [4Lys(Ac)]-GnRH-III(Dau=Aoa) (d–f) and [4Lys(Bu)]-GnRH-III(Dau=...
Figure 8: Schematic representation of the proposed mechanisms of the effects of GnRH-III conjugates containin...
Applications of organocatalysed visible-light photoredox reactions for medicinal chemistry
- Michael K. Bogdos,
- Emmanuel Pinard and
- John A. Murphy
Beilstein J. Org. Chem. 2018, 14, 2035–2064, doi:10.3762/bjoc.14.179
- published by Cook [76]. The authors also further establish the immediate value of the procedure to LSF by exploring SAR of camptothecin, a molecule identified as an anticancer drug candidate. The authors selectively manipulated the C-7 position, which has been shown to improve efficacy when alkylated
Graphical Abstract
Figure 1: Depiction of the energy levels of a typical organic molecule and the photophysical processes it can...
Figure 2: General catalytic cycle of a photocatalyst in a photoredox organocatalysed reaction. [cat] – photoc...
Figure 3: Structures and names of the most common photocatalysts encountered in the reviewed literature.
Figure 4: General example of a reductive quenching catalytic cycle. [cat] – photocatalyst, [cat]* – photocata...
Figure 5: General example of an oxidative quenching catalytic cycle. [cat] – photocatalyst, [cat]* – photocat...
Scheme 1: Oxidative coupling of aldehydes and amines to amides using acridinium salt photocatalysis.
Figure 6: Biologically active molecules containing a benzamide linkage.
Scheme 2: The photocatalytic reduction of amino acids to produce the corresponding free or protected amines.
Scheme 3: The organocatalysed photoredox base-mediated oxidation of thiols to disulfides.
Scheme 4: C-Terminal modification of peptides and proteins using organophotoredox catalysis.
Scheme 5: The reduction and aryl coupling of aryl halides using a doubly excited photocatalyst (PDI).
Figure 7: Mechanism for the coupling of aryl halides using PDI, which is excited sequentially by two photons.
Scheme 6: The arylation of five-membered heteroarenes using arenediazonium salts under organophotoredox condi...
Scheme 7: The C–H (hetero)arylation of five-membered heterocycles under Eosin Y photocatalysis.
Scheme 8: The C–H sulfurisation of imidazoheterocycles using Eosin B-catalyzed photochemical methods.
Scheme 9: The introduction of the thiocyanate group using Eosin Y photocatalysis.
Scheme 10: Sulfonamidation of pyrroles using oxygen as the terminal oxidant.
Scheme 11: DDQ-catalysed C–H amination of arenes and heteroarenes.
Scheme 12: Photoredox-promoted radical Michael addition reactions of allylic or benzylic carbons.
Figure 8: Proposed mechanistic rationale for the observed chemoselectivities.
Scheme 13: The photocatalytic manipulation of C–H bonds adjacent to amine groups.
Scheme 14: The perylene-catalysed organophotoredox tandem difluoromethylation–acetamidation of styrene-type al...
Figure 9: Examples of biologically active molecules containing highly functionalised five membered heterocycl...
Scheme 15: The [3 + 2]-cycloaddition leading to the formation of pyrroles, through the reaction of 2H-azirines...
Figure 10: Proposed intermediate that determines the regioselectivity of the reaction.
Figure 11: Comparison of possible pathways of reaction and various intermediates involved.
Scheme 16: The acridinium salt-catalysed formation of oxazoles from aldehydes and 2H-azirines.
Scheme 17: The synthesis of oxazolines and thiazolines from amides and thioamides using organocatalysed photor...
Figure 12: Biologically active molecules on the market containing 1,3,4-oxadiazole moieties.
Scheme 18: The synthesis of 1,3,4-oxadiazoles from aldehyde semicarbazones using Eosin Y organophotocatalysis.
Scheme 19: The dimerization of primary thioamides to 1,2,4-thiadiazoles catalysed by the presence of Eosin Y a...
Scheme 20: The radical cycloaddition of o-methylthioarenediazonium salts and substituted alkynes towards the f...
Scheme 21: The dehydrogenative cascade reaction for the synthesis of 5,6-benzofused heterocyclic systems.
Figure 13: Trifluoromethylated version of compounds which have known biological activities.
Scheme 22: Eosin Y-catalysed photoredox formation of 3-substituted benzimidazoles.
Scheme 23: Oxidation of dihydropyrimidines by atmospheric oxygen using photoredox catalysis.
Scheme 24: Photoredox-organocatalysed transformation of 2-substituted phenolic imines to benzoxazoles.
Scheme 25: Visible light-driven oxidative annulation of arylamidines.
Scheme 26: Methylene blue-photocatalysed direct C–H trifluoromethylation of heterocycles.
Scheme 27: Photoredox hydrotrifluoromethylation of terminal alkenes and alkynes.
Scheme 28: Trifluoromethylation and perfluoroalkylation of aromatics and heteroaromatics.
Scheme 29: The cooperative asymmetric and photoredox catalysis towards the functionalisation of α-amino sp3 C–...
Scheme 30: Organophotoredox-catalysed direct C–H amidation of aromatics.
Scheme 31: Direct C–H alkylation of heterocycles using BF3K salts. CFL – compact fluorescent lamp.
Figure 14: The modification of camptothecin, demonstrating the use of the Molander protocol in LSF.
Scheme 32: Direct C–H amination of aromatics using acridinium salts.
Scheme 33: Photoredox-catalysed nucleophilic aromatic substitution of nucleophiles onto methoxybenzene derivat...
Scheme 34: The direct C–H cyanation of aromatics with a focus on its use for LSF.
Synthesis and photophysical studies of a multivalent photoreactive RuII-calix[4]arene complex bearing RGD-containing cyclopentapeptides
- Sofia Kajouj,
- Lionel Marcelis,
- Alice Mattiuzzi,
- Adrien Grassin,
- Damien Dufour,
- Pierre Van Antwerpen,
- Didier Boturyn,
- Eric Defrancq,
- Mathieu Surin,
- Julien De Winter,
- Pascal Gerbaux,
- Ivan Jabin and
- Cécile Moucheron
Beilstein J. Org. Chem. 2018, 14, 1758–1768, doi:10.3762/bjoc.14.150
- , once incorporated into targeted cancer cells thanks to the multivalent platform. Keywords: anticancer drug; calixarene; cell targeting; RGD peptide; ruthenium complex; Introduction Long-living luminescent polyazaaromatic ruthenium(II) complexes are intensively studied in a biological context, in
Graphical Abstract
Figure 1: Targeted multivalent phototherapeutic agent and its calix[4]arene-based precursor. RGD = Arg–Gly–As...
Scheme 1: Synthesis of RuII-calix[4]arene complex 7.
Scheme 2: Synthesis of RuII-calix[4]arene-[c-(RGDfK)]4 conjugate 9.
Figure 2: MD snapshot showing an optimized model of conjugate 9. RGDfK units are depicted in orange ribbons, ...
Figure 3: Absorption and emission spectra of RuII-calix[4]arene-[c-(RGDfK)]4 conjugate 9 in water.
Figure 4: Luminescence intensity and excited state lifetime of conjugate 9 in the presence of GMP measured in...
Figure 5: Transient absorption spectra of RuII-calix[4]arene-[c-(RGDfK)]4 conjugate 9 (in 10 mM Tris·HCl buff...
Figure 6: MALDI–MS analysis of a solution containing conjugate 9 and GMP after continuous light irradiation. ...
Drug targeting to decrease cardiotoxicity – determination of the cytotoxic effect of GnRH-based conjugates containing doxorubicin, daunorubicin and methotrexate on human cardiomyocytes and endothelial cells
- Livia Polgár,
- Eszter Lajkó,
- Pál Soós,
- Orsolya Láng,
- Marilena Manea,
- Béla Merkely,
- Gábor Mező and
- László Kőhidai
Beilstein J. Org. Chem. 2018, 14, 1583–1594, doi:10.3762/bjoc.14.136
- in compounds with increased therapeutic efficacy. The objective of the present study was to examine the cytotoxic effect of anticancer drug–GnRH-conjugates against two essential cardiovascular cell types, such as cardiomyocytes and endothelial cells. Sixteen different previously developed GnRH
- ) – exerted no cytotoxic effect on cardiomyocytes. Mixed conjugates containing methotrexate and daunorubicin – GnRH-III(Mtx-K(Dau=Aoa)) and [4Lys(Mtx)]-GnRH-III(Dau=Aoa) – showed no cytotoxic effect on cardiomyocytes, as well. Conclusion: Based on these results, anticancer drug–GnRH-based conjugates with no
Graphical Abstract
Figure 1: Chemical structures of the GnRH-drug conjugates synthesized and investigated in the present work. A...
Figure 2: Chemical structures of the bifunctional GnRH-drug conjugates synthesized and investigated in the pr...
Figure 3: Long-term cytotoxic effects – impedimetrically registered negative effect on cell proliferation/via...
Figure 4: Long-term cytotoxic effects – impedimetrically registered negative effect on cell proliferation and...
Design and biological characterization of novel cell-penetrating peptides preferentially targeting cell nuclei and subnuclear regions
- Anja Gronewold,
- Mareike Horn and
- Ines Neundorf
Beilstein J. Org. Chem. 2018, 14, 1378–1388, doi:10.3762/bjoc.14.116
- [4]. Selective inhibition of the ribosomal machinery has been shown to be an effective anticancer therapeutic strategy [5]. That is why selective drug transport to the nucleoli has emerged a potent new strategy in anticancer drug development [6][7]. Based on these homing domains, a substantial number
- initial study for the delivery of the anticancer drug doxorubicin. Results and Discussion Peptide synthesis and analysis of the secondary structure We chose two different nuclear-targeting sequences, on the one hand the N50 peptide, which was derived from the NF-κB/p50 subunit. N50 binds the adaptor
- uptake was not completely reduced, indicating the involvement of direct entry processes that may play a role during cellular uptake. Use of novel peptides as cargo delivery systems In the last experiment, we investigated if the peptides could be used to enhance the efficacy of an anticancer drug
Graphical Abstract
Figure 1: Circular dichroism spectra of the novel peptides solved in 10 mM phosphate buffer (pH 7) (A), or ph...
Figure 2: Cytotoxicity profiles of the peptides in MCF-7 and HeLa cells. Cells were incubated for 24 h with d...
Figure 3: Cellular uptake in HeLa and MCF-7 cells. Cells were incubated for 30 min with 10 µM of CF-labeled p...
Figure 4: Cellular uptake in MCF-7 and HeLa cells was quantified by flow cytometry. Cells were incubated with...
Figure 5: Distribution pattern of the peptides in HeLa and MCF-7 cells when incubating 10 µM CF-labeled pepti...
Figure 6: Cellular uptake in HeLa and MCF-7 cells when incubating the cells at 4 °C for 30 min with the CF-la...
Figure 7: Uptake and delivery of DOX into HeLa and MCF-7 cells. Fluorescence microscopic images after 30 min ...
An overview of recent advances in duplex DNA recognition by small molecules
- Sayantan Bhaduri,
- Nihar Ranjan and
- Dev P. Arya
Beilstein J. Org. Chem. 2018, 14, 1051–1086, doi:10.3762/bjoc.14.93
- anticancer drug due to its improved cytotoxicity/myelotoxicity ratio [47][48]. Brostacillin acts as an effective DNA alkylator only in presence of high levels of cellular thiols such as glutathione [49]. Moreover, it was thirty-fold more active in comparison to TAM in inducing apoptosis in A2780 human
- , DNA-melting experiments, and circular dichroism (CD) analysis revealed these conjugates are high affinity sequence specific DNA groove binders and could successfully recognize a C·C mismatch in a DNA duplex. Recently, the binding mechanism of the anticancer drug cytarabine with calf thymus DNA (ct-DNA
Graphical Abstract
Figure 1: A figure showing the hydrogen bonding patterns observed in (a) duplex (b) triplex and (c) quadruple...
Figure 2: (a) Portions of MATα1–MATα2 are shown contacting the minor groove of the DNA substrate. Key arginin...
Figure 3: Chemical structures of naturally occurring and synthetic hybrid minor groove binders.
Figure 4: Synthetic structural analogs of distamycin A by replacing one or more pyrrole rings with other hete...
Figure 5: Pictorial representation of the binding model of pyrrole–imidazole (Py/Im) polyamides based on the ...
Figure 6: Chemical structures of synthetic “hairpin” pyrrole–imidazole (Py/Im) conjugates.
Figure 7: (a) Minor groove complex formation between DNA duplex and 8-ring cyclic Py/Im polyamide (conjugate ...
Figure 8: Telomere-targeting tandem hairpin Py/Im polyamides 23 and 24 capable of recognizing >10 base pairs; ...
Figure 9: Representative examples of recently developed DNA minor groove binders.
Figure 10: Chemical structures of bisbenzamidazoles Hoechst 33258 and 33342 and their synthetic structural ana...
Figure 11: Chemical structures of bisamidines such as diminazene, DAPI, pentamidine and their synthetic struct...
Figure 12: Representative examples of recently developed bisamidine derivatives.
Figure 13: Chemical structures of chromomycin, mithramycin and their synthetic structural analogs 91 and 92.
Figure 14: Chemical structures of well-known naturally occurring DNA binding intercalators.
Figure 15: Naturally occurring indolocarbazole rebeccamycin and its synthetic analogs.
Figure 16: Representative examples of naturally occurring and synthetic derivatives of DNA intercalating agent...
Figure 17: Several recent synthetic varieties of DNA intercalators.
Figure 18: Aminoglycoside (neomycin)–Hoechst 33258/intercalator conjugates.
Figure 19: Chemical structures of triazole linked neomycin dimers and neomycin–bisbenzimidazole conjugates.
Figure 20: Representative examples of naturally occurring and synthetic analogs of DNA binding alkylating agen...
Figure 21: Chemical structures of naturally occurring and synthetic analogs of pyrrolobenzodiazepines.
