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Search for "DPP-4" in Full Text gives 6 result(s) in Beilstein Journal of Organic Chemistry.
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
- level of blood sugar in patients with type 2 diabetes and belongs to the dipeptidyl peptidase-4 (DPP-4) class of inhibitors [114][115]. This enzyme breaks down the incretins GLP-1 and GIP, gastrointestinal hormones released in response to a meal. By preventing the breakdown of GLP-1 and GIP, they are
- able to increase the secretion of insulin by the pancreas that modulates blood sugar level when it is high. Sitagliptin was granted FDA approval in October, 2006 [116]. Retagliptin phosphate: Retagliptin phosphate (184) is under investigation as a DPP-4 inhibitor for treating type-2 diabetes. It is an
- synthesis of compound 184 [119][120] (Figure 7). Evogliptin: (R)-2,4,5-Trifluorophenylalanine 38b is required for the synthesis of evogliptin (185, Figure 8), an antidiabetic drug in the dipeptidyl peptidase-4 (DPP-4) inhibitor or "gliptin" class of drugs. The South Korean pharmaceutical company Dong-A ST
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.
Development of a fluorogenic small substrate for dipeptidyl peptidase-4
- Futa Ogawa,
- Masanori Takeda,
- Kanae Miyanaga,
- Keita Tani,
- Ryuji Yamazawa,
- Kiyoshi Ito,
- Atsushi Tarui,
- Kazuyuki Sato and
- Masaaki Omote
Beilstein J. Org. Chem. 2017, 13, 2690–2697, doi:10.3762/bjoc.13.267
- by converting 2,4-disubstituted aniline 1 to the non-fluorescent dipeptide analogue H-Gly-Pro-1 for the use as a fluorogenic substrate for dipeptidyl peptidase-4 (DPP-4). The progress of the enzymatic hydrolysis of H-Gly-Pro-1 with DPP-4 was monitored by fluorometric determination of 1 released into
- application as an OFF–ON-type fluorogenic probe for determining dipeptidyl peptidase-4 (DPP-4) activity. Results and Discussion Synthesis of fluorescent compounds as fluorophores It has been reported that the introduction of a TFPE group changes the properties of electron-rich aromatics and leads to a good
- fluorescence push–pull system would be destroyed. To confirm this, we modified 1 to provide a peptidic substrate for an enzyme. The serine protease DPP-4 was used as the test enzyme because its substrate specificity is clear: it hydrolyses the C-terminal of proline or alanine second to the N-terminal of the
Graphical Abstract
Figure 1: (a) UV–vis absorption and (b) fluorescence spectra of 1–4 in THF.
Figure 2: Fluorescence spectra of 1 and 3 in H2O:DMSO (9:1).
Scheme 1: Use of 1 as fluorogenic probe for DPP-4 activity.
Scheme 2: Synthesis of fluorogenic probe H-Gly-Pro-1.
Figure 3: Fluorescence spectra of 1 and H-Gly-Pro-1. Measurement conditions: 1.0 × 10−5 M in H2O:DMSO (9:1), ...
Figure 4: Fluorescence intensity changes of H-Gly-Pro-1 on addition of DPP-4.
An overview of the synthetic routes to the best selling drugs containing 6-membered heterocycles
- Marcus Baumann and
- Ian R. Baxendale
Beilstein J. Org. Chem. 2013, 9, 2265–2319, doi:10.3762/bjoc.9.265
- (2.71, Januvia) and vildagliptin (2.72, Zomelis, Figure 7). These compounds are all members of the dipeptidyl peptidase 4 class (DPP-4), a transmembrane protein that is responsible for the degradation of incretins; hormones which up-regulate the concentration of insulin excreted in a cell. As DPP-4
- single crystal X-ray structure of carmegliptin bound in the human DPP-4 active site has been published indicating how the fluoromethylpyrrolidone moiety extends into an adjacent lipophilic pocket [81]. Additional binding is provided by π–π interaction between the aromatic substructure and an adjacent
Graphical Abstract
Scheme 1: Scaled industrial processes for the synthesis of simple pyridines.
Scheme 2: Synthesis of nicotinic acid from 2-methyl-5-ethylpyridine (1.11).
Scheme 3: Synthesis of 3-picoline and nicotinic acid.
Scheme 4: Synthesis of 3-picoline from 2-methylglutarodinitrile 1.19.
Scheme 5: Picoline-based synthesis of clarinex (no yields reported).
Scheme 6: Mode of action of proton-pump inhibitors and structures of the API’s.
Scheme 7: Hantzsch-like route towards the pyridine rings in common proton pump inhibitors.
Figure 1: Structures of rosiglitazone (1.40) and pioglitazone (1.41).
Scheme 8: Synthesis of rosiglitazone.
Scheme 9: Syntheses of 2-pyridones.
Scheme 10: Synthesis and mechanism of 2-pyrone from malic acid.
Scheme 11: Polymer-assisted synthesis of rosiglitazone.
Scheme 12: Synthesis of pioglitazone.
Scheme 13: Meerwein arylation reaction towards pioglitazone.
Scheme 14: Route towards pioglitazone utilising tyrosine.
Scheme 15: Route towards pioglitazone via Darzens ester formation.
Scheme 16: Syntheses of the thiazolidinedione moiety.
Scheme 17: Synthesis of etoricoxib utilising Negishi and Stille cross-coupling reactions.
Scheme 18: Synthesis of etoricoxib via vinamidinium condensation.
Figure 2: Structures of nalidixic acid, levofloxacin and moxifloxacin.
Scheme 19: Synthesis of moxifloxacin.
Scheme 20: Synthesis of (S,S)-2,8-diazabicyclo[4.3.0]nonane 1.105.
Scheme 21: Synthesis of levofloxacin.
Scheme 22: Alternative approach to the levofloxacin core 1.125.
Figure 3: Structures of nifedipine, amlodipine and clevidipine.
Scheme 23: Mg3N2-mediated synthesis of nifedipine.
Scheme 24: Synthesis of rac-amlodipine as besylate salt.
Scheme 25: Aza Diels–Alder approach towards amlodipine.
Scheme 26: Routes towards clevidipine.
Figure 4: Examples of piperidine containing drugs.
Figure 5: Discovery of tiagabine based on early leads.
Scheme 27: Synthetic sequences to tiagabine.
Figure 6: Structures of solifenacin (2.57) and muscarine (2.58).
Scheme 28: Enantioselective synthesis of solifenacin.
Figure 7: Structures of DPP-4 inhibitors of the gliptin-type.
Scheme 29: Formation of inactive diketopiperazines from cis-rotameric precursors.
Figure 8: Co-crystal structure of carmegliptin bound in the human DPP-4 active site (PDB 3kwf).
Scheme 30: Improved route to carmegliptin.
Figure 9: Structures of lamivudine and zidovudine.
Scheme 31: Typical routes accessing uracil, thymine and cytosine.
Scheme 32: Coupling between pyrimidones and riboses via the Vorbrüggen nucleosidation.
Scheme 33: Synthesis of lamivudine.
Scheme 34: Synthesis of raltegravir.
Scheme 35: Mechanistic studies on the formation of 3.22.
Figure 10: Structures of selected pyrimidine containing drugs.
Scheme 36: General preparation of pyrimidines and dihydropyrimidones.
Scheme 37: Synthesis of imatinib.
Scheme 38: Flow synthesis of imatinib.
Scheme 39: Syntheses of erlotinib.
Scheme 40: Synthesis of erlotinib proceeding via Dimroth rearrangement.
Scheme 41: Synthesis of lapatinib.
Scheme 42: Synthesis of rosuvastatin.
Scheme 43: Alternative preparation of the key aldehyde towards rosuvastatin.
Figure 11: Structure comparison between nicotinic acetylcholine receptor agonists.
Scheme 44: Syntheses of varenicline and its key building block 4.5.
Scheme 45: Synthetic access to eszopiclone and brimonidine via quinoxaline intermediates.
Figure 12: Bortezomib bound in an active site of the yeast 20S proteasome ([114], pdb 2F16).
Scheme 46: Asymmetric synthesis of bortezomib.
Figure 13: Structures of some prominent piperazine containing drugs.
Figure 14: Structural comparison between the core of aplaviroc (4.35) and a type-1 β-turn (4.36).
Scheme 47: Examplary synthesis of an aplaviroc analogue via the Ugi-MCR.
Scheme 48: Syntheses of azelastine (5.1).
Figure 15: Structures of captopril, enalapril and cilazapril.
Scheme 49: Synthesis of cilazapril.
Figure 16: Structures of lamotrigine, ceftriaxone and azapropazone.
Scheme 50: Synthesis of lamotrigine.
Scheme 51: Alternative synthesis of lamotrigine (no yields reported).
Figure 17: Structural comparison between imiquimod and the related adenosine nucleoside.
Scheme 52: Conventional synthesis of imiquimod (no yields reported).
Scheme 53: Synthesis of imiquimod.
Scheme 54: Synthesis of imiquimod via tetrazole formation (not all yields reported).
Figure 18: Structures of various anti HIV-medications.
Scheme 55: Synthesis of abacavir.
Figure 19: Structures of diazepam compared to modern replacements.
Scheme 56: Synthesis of ocinaplon.
Scheme 57: Access to zaleplon and indiplon.
Scheme 58: Different routes towards the required N-methylpyrazole 6.65 of sildenafil.
Scheme 59: Polymer-supported reagents in the synthesis of key aminopyrazole 6.72.
Scheme 60: Early synthetic route to sildenafil.
Scheme 61: Convergent preparations of sildenafil.
Figure 20: Comparison of the structures of sildenafil, tadalafil and vardenafil.
Scheme 62: Short route to imidazotriazinones.
Scheme 63: Alternative route towards vardenafils core imidazotriazinone (6.95).
Scheme 64: Bayer’s approach to the vardenafil core.
Scheme 65: Large scale synthesis of vardenafil.
Scheme 66: Mode of action of temozolomide (6.105) as methylating agent.
Scheme 67: Different routes to temozolomide.
Scheme 68: Safer route towards temozolomide.
Figure 21: Some unreported heterocyclic scaffolds in top market drugs.
Preparation and ring-opening reactions of N-diphenylphosphinyl vinyl aziridines
- Ashley N. Jarvis,
- Andrew B. McLaren,
- Helen M. I. Osborn and
- Joseph Sweeney
Beilstein J. Org. Chem. 2013, 9, 852–859, doi:10.3762/bjoc.9.98
- copper-based organometallic species, to give N-Dpp-4-aminoallylstannanes in good yield (Table 3, entries 1–3). To our knowledge, such allylstannanes had not previously been prepared. Gratified by the good selectivity shown in the ring openings effected by the stannylcuprate, we next examined the
Graphical Abstract
Scheme 1: Aza-Darzens synthesis of an N-Dpp vinyl aziridine.
Scheme 2: Closed transition state delivers E-aziridines.
Scheme 3: Open transition state leading to (Z)-5.
Scheme 4: Ring opening by Grignard reagent.
Chemistry of polyhalogenated nitrobutadienes, 10: Synthesis of highly functionalized heterocycles with a rigid 6-amino-3-azabicyclo[3.1.0]hexane moiety
- Viktor A. Zapol’skii,
- Jan C. Namyslo,
- Armin de Meijere and
- Dieter E. Kaufmann
Beilstein J. Org. Chem. 2012, 8, 621–628, doi:10.3762/bjoc.8.69
- substituents, exhibit remarkable antibacterial as well as antiprotozoal activity [11][12][13][14][15]. Furthermore, the 2-azabicyclo[3.1.0]hexane derivative of 3-hydroxyadamantylglycine, named Saxagliptin, is a pharmaceutical of the dipeptidyl peptidase IV (DPP-4) inhibitor class against type 2 diabetes
Graphical Abstract
Figure 1: Promising starting materials for biologically active compounds.
Figure 2: Pharmaceuticals bearing an azabicyclo[3.1.0]hexane unit.
Scheme 1: Synthesis of the azabicyclic hydrazone 6.
Scheme 2: Novel imidacloprid analogues 11, 12.
Figure 3: Stabilizing hydrogen bond in nitrobutadiene-derived imidacloprid analogues 9–12.
Scheme 3: Synthesis of the 4,4-bis(aminoazabicyclo[3.1.0]hexyl)-1-chloro-1,3-dinitrobutadiene 13.
Scheme 4: Synthesis of the highly substituted trisaminodichloronitrobutadiene 16.
Figure 4: Conceivable tautomeric structures of 16.
Scheme 5: Syntheses of the perfunctionalized isothiazole derivatives 20, 21.
Scheme 6: Preparation of the pyrazoles 27, 28, the pyrimidine 26 and the pyridopyrimidine 24.
Scheme 7: Proposed reaction mechanism for the formation of 27, 28.
Scheme 8: Attempted deprotection of the azabicyclic compounds 21,12, and 28.
Synthesis of a novel analogue of DPP-4 inhibitor Alogliptin: Introduction of a spirocyclic moiety on the piperidine ring
- Arumugam Kodimuthali,
- Padala Lakshmi Prasunamba and
- Manojit Pal
Beilstein J. Org. Chem. 2010, 6, No. 71, doi:10.3762/bjoc.6.71
- aminopiperidine derivative bearing a spirocyclic ring on the piperidine moiety. Preparation of the aminopiperidine intermediate was carried out by constructing the cyclopropyl ring prior to assembling the piperidine ring. Keywords: Alogliptin; cyclopropyl ring; DPP-4; piperidine; Introduction Inhibition of
- dipeptidyl peptidase-4 (DPP-4; CD26; E.C. 3.4.14.5) by small molecules has emerged as one of the key approaches for the treatment of type-2 diabetes [1][2][3][4][5]. DPP-4, a member of the prolyl oligopeptidase family of serine protease, cleaves the N-terminal dipeptide from peptides with proline or alanine
- in the second position. A large number of DPP-4 inhibitors have been reported in the literature [6][7] including NVP-LAF237 (Vildagliptin), MK-0431 (Sitagliptin) and BMS-477118 (Saxagliptin). Presently, Sitagliptin is available for clinical use and Vildagliptin has been launched in Europe only
Graphical Abstract
Figure 1: Design of a new DPP-4 inhibitor (C) based on Alogliptin (A) and other inhibitors (B).
Figure 2: Strategy to prepare compound C (PG = protecting group).
Scheme 1: Reagents and conditions: (i) EtONa, BrCH2CH2Br, EtOH, reflux, 3.5 h (70% yield); (ii) Pd/C, MeOH, H2...
Scheme 2: Reagents and conditions: (i) NaH, LiBr, DMF - DMSO, 12 h (55% yield); (ii) NaH, LiBr, CH3I, DMF - T...
Figure 3: Predicted interactions of compound C with DPP-4.
