On the design principles of peptide–drug conjugates for targeted drug delivery to the malignant tumor site

• Eirinaios I. Vrettos,
• Gábor Mező and
• Andreas G. Tzakos

Beilstein J. Org. Chem. 2018, 14, 930–954, doi:10.3762/bjoc.14.80

• . Another natural isoform of GnRH is GnRH-III (pGlu-His-Trp-Ser-His-Asp-Trp-Lys-Pro-Gly-NH2), which has been isolated from sea lamprey. GnRH-III binds to GnRH-R overexpressed on the cancer cell surface, resulting in an antiproliferative effect but seems to be less potent than the rest GnRH analogs regarding

Synthesis and in vitro biochemical evaluation of oxime bond-linked daunorubicin–GnRH-III conjugates developed for targeted drug delivery

• Sabine Schuster,
• Beáta Biri-Kovács,
• Bálint Szeder,
• Viktor Farkas,
• László Buday,
• Zsuzsanna Szabó,
• Gábor Halmos and
• Gábor Mező

Beilstein J. Org. Chem. 2018, 14, 756–771, doi:10.3762/bjoc.14.64

• antiproliferative activity. Furthermore, the absence of the free ε-amino group additionally reduced the endocrine effect [23][24]. Thus, the 8Lys can be utilized as conjugation site for cytotoxic agents like anthracyclines. In the past decade, a variety of different linkage systems has been carried out including

• receptor binding affinity and an enhanced antiproliferative activity without substantial effect on the endocrine activity [31][32][33], we developed six novel GnRH-III–Dau conjugates in which the 6Asp was replaced by D-Aaa. Here we report on the synthesis of GnRH-III bioconjugates containing D-Asp, D-Glu

• of the antiproliferative activity between the 4Ser and the corresponding 4Lys(Bu) derivatives could be observed which is not in line with our previous data [29]. This might be a result of the prolonged incubation time which was modified from 6 hours up to 24 hours because of the decreased antitumor

Synthesis and biological evaluation of RGD and isoDGR peptidomimetic-α-amanitin conjugates for tumor-targeting

• Lizeth Bodero,
• Paula López Rivas,
• Barbara Korsak,
• Torsten Hechler,
• Andreas Pahl,
• Christoph Müller,
• Daniela Arosio,
• Luca Pignataro,
• Cesare Gennari and
• Umberto Piarulli

Beilstein J. Org. Chem. 2018, 14, 407–415, doi:10.3762/bjoc.14.29

• antiproliferative activity of the conjugates was evaluated in three cell lines possessing different levels of αVβ3 integrin expression: human glioblastoma U87 (αVβ3+), human lung carcinoma A549 (αVβ3−) and breast adenocarcinoma MDA-MB-468 (αVβ3−). In the U87, in the MDA-MB-468, and partly in the A549 cancer cell

• , cyclo[DKP-RGD]-Val-Ala-PTX 5 and cyclo[DKP-isoDGR]-Val-Ala-PTX 6). Their tumor targeting ability was assessed in vitro in antiproliferative assays comparing an αVβ3 positive with an αVβ3 negative cell line [29][30]. The cyclo[DKP-isoDGR]-Val-Ala-PTX conjugate 6 displayed a remarkable targeting index (TI

• αVβ3 expressing tumor cells. Cell viability assays The antiproliferative activity of the conjugates was evaluated in three cell lines expressing different levels of αVβ3 integrin. U87 cells (human glioblastoma) were selected as αVβ3 positive, while A549 cells (human lung carcinoma) and MDA-MB-468

Recent developments in the asymmetric Reformatsky-type reaction

• Hélène Pellissier

Beilstein J. Org. Chem. 2018, 14, 325–344, doi:10.3762/bjoc.14.21

• actually 30-epiapratoxin E, thus correcting the originally proposed absolute configuration. Both diastereomers were tested for their antiproliferative activities in HCT116 cells, showing that natural (30R)-apratoxin E exhibited a higher activity than its (30S)-epimer. Due to their lower basicity, samarium

• constituted the key step of a nine-step total synthesis of the eastern fragment of jatrophane diterpene Pl-3, which is a complex natural product with high promising biological activities, such as antiproliferative activity and inhibition of the efflux-pump activity of multidrug resistance P-glycoprotein. The

• under mild and neutral conditions. Among them, many syntheses of naturally occurring products have been described for the first time, such as those of the glucose-regulated protein 78 expression inhibitor agent prunustatin A, the antiproliferative agent apratoxin E and its C30 epimer, prebiscibactin

The chemistry and biology of mycolactones

• Matthias Gehringer and
• Karl-Heinz Altmann

Beilstein J. Org. Chem. 2017, 13, 1596–1660, doi:10.3762/bjoc.13.159

Synthesis of novel 13α-estrone derivatives by Sonogashira coupling as potential 17β-HSD1 inhibitors

• Ildikó Bacsa,
• Rebeka Jójárt,
• János Wölfling,
• Gyula Schneider,
• Bianka Edina Herman,
• Mihály Szécsi and
• Erzsébet Mernyák

Beilstein J. Org. Chem. 2017, 13, 1303–1309, doi:10.3762/bjoc.13.126

• bearing promising biological activities. We recently published the syntheses and the in vitro biological evaluations of several 13α-estrone derivatives [6][7][8][9]. Certain compounds proved to be biologically active, bearing substantial antiproliferative or enzyme inhibitory potential [7][8]. Most

Synthesis of spiro[isoindole-1,5’-isoxazolidin]-3(2H)-ones as potential inhibitors of the MDM2-p53 interaction

• Salvatore V. Giofrè,
• Santa Cirmi,
• Raffaella Mancuso,
• Francesco Nicolò,
• Giuseppe Lanza,
• Laura Legnani,
• Agata Campisi,
• Maria A. Chiacchio,
• Michele Navarra,
• Bartolo Gabriele and
• Roberto Romeo

Beilstein J. Org. Chem. 2016, 12, 2793–2807, doi:10.3762/bjoc.12.278

• -benzylnitrone with isoindolin-3-methylene-1-ones. The regio- and stereoselectivity of the process have been rationalized by computational methods. The obtained compounds show cytotoxic properties and antiproliferative activity in the range of 9–22 μM. Biological tests suggest that the antitumor activity could

• have resulted in the identification of a number of potential MDM2-p53 interaction inhibitors. Biological tests confirm our initial hypothesis indicating for compounds 3 an antiproliferative activity in the range of 9–22 μM: the antitumor activity appears to be linked to the inhibition of the protein

• have been performed using 6e as model compound. In general, all the synthesized compounds showed a certain degree of antiproliferative effect against all the examined cancer cells with a similar trend (see Supporting Information File 1, Figure S1). Noteworthy, compound 6e exhibited superior activity

Marine-derived myxobacteria of the suborder Nannocystineae: An underexplored source of structurally intriguing and biologically active metabolites

• Antonio Dávila-Céspedes,
• Peter Hufendiek,
• Max Crüsemann,
• Till F. Schäberle and
• Gabriele M. König

Beilstein J. Org. Chem. 2016, 12, 969–984, doi:10.3762/bjoc.12.96

• of compounds that have recently been shown to have antiproliferative effects on leukemic K-562 cells [27]. Halotolerant and halophilic marine myxobacteria are poorly investigated regarding secondary metabolite production. Therefore, the pool of secondary metabolites isolated from organisms of this

• . Only recently it was recognized that members of this genus have a great potential as producers of metabolites with relevant biological activities. One striking example is the 2015 described nannocystin A (10, Figure 6), a macrocyclic compound of NRPS-PKS origin with strong antiproliferative properties

Synthesis and in vitro cytotoxicity of acetylated 3-fluoro, 4-fluoro and 3,4-difluoro analogs of D-glucosamine and D-galactosamine

• Štěpán Horník,
• Lucie Červenková Šťastná,
• Petra Cuřínová,
• Jan Sýkora,
• Kateřina Káňová,
• Roman Hrstka,
• Ivana Císařová,
• Martin Dračínský and
• Jindřich Karban

Beilstein J. Org. Chem. 2016, 12, 750–759, doi:10.3762/bjoc.12.75

• galectin-mediated antitumor T cell apoptosis [16]. Some acetylated fluoro hexosamines also displayed antiproliferative properties in vitro [17]. For example, 3- and 4-fluoro-D-glucosamine analogs 5 [18] and 1 [19], and 4-fluoro-D-galactosamine analog 4 [19] (Figure 1), inhibited the growth of murine L1210

• 2) [2]. The remarkable ability of acetylated fluoro analogs of GlcNAc and GalNAc to perturb the (glycosamino)glycan biosynthesis and their antiproliferative properties aroused our interest in developing a methodology for the preparation of a complete series of acetylated 3-fluoro, 4-fluoro-, and 3,4

• -HexNAc [19], and 4,6-difluoro-D-GalNAc [19] were reported to exhibit antiproliferative properties against L1210 leukemia cells in micromolar concentrations (IC50 24–43 μM). It was found that O-deacetylated amino sugars were often inactive due to low lipophilicity and poor cellular uptake [19]. Compound 5

Three new trixane glycosides obtained from the leaves of Jungia sellowii Less. using centrifugal partition chromatography

• Luíse Azevedo,
• Larissa Faqueti,
• Marina Kritsanida,
• Antonia Efstathiou,
• Despina Smirlis,
• Gilberto C. Franchi Jr,
• Grégory Genta-Jouve,
• Sylvie Michel,
• Louis P. Sandjo,
• Raphaël Grougnet and
• Maique W. Biavatti

Beilstein J. Org. Chem. 2016, 12, 674–683, doi:10.3762/bjoc.12.68

• amastigotes with an IC50 value of 100 μg/mL. Except for compound 1 that exhibited a weak antileishmanial activity at 50 μM (20%) against L. amazonensis intracellular amastigotes, none of the other sesquiterpenes displayed antiparasitic activity. Compounds 1–3 showed less than 50% antiproliferative effect on

Unconventional application of the Mitsunobu reaction: Selective flavonolignan dehydration yielding hydnocarpins

• Guozheng Huang,
• Simon Schramm,
• Jörg Heilmann,
• David Biedermann,
• Vladimír Křen and
• Michael Decker

Beilstein J. Org. Chem. 2016, 12, 662–669, doi:10.3762/bjoc.12.66

• multiple biological activities and promising therapeutic applications, such as hepatoprotection, antitumor, antiproliferative and anti-oxidant properties [1]. The standardized extract of S. marianum fruits contains the so-called silymarin complex, and is used as the main active component mixture of Legalon

The aminoindanol core as a key scaffold in bifunctional organocatalysts

• Isaac G. Sonsona,
• Eugenia Marqués-López and
• Raquel P. Herrera

Beilstein J. Org. Chem. 2016, 12, 505–523, doi:10.3762/bjoc.12.50

• work, an efficient enantioselective and sequential double Friedel–Crafts alkylation provided direct access to the tetracyclic seven-membered ring containing indoles 8. These pharmaceutically intriguing compounds exhibit anticancer [27] and antiproliferative activity [28]. In the first catalytic cycle

Copper-mediated arylation with arylboronic acids: Facile and modular synthesis of triarylmethanes

• H. Surya Prakash Rao and
• A. Veera Bhadra Rao

Beilstein J. Org. Chem. 2016, 12, 496–504, doi:10.3762/bjoc.12.49

• binding affinity [21], inhibition of hepatic cholesterol [22], inhibition of aldose reductase [23], antiproliferative [24], antiviral, cytotoxic [25], antifungal [26], anti-HIV [27][28][29] and antibacterial activity [30]. Although rare, there are a few natural products, for example, melanervin (5), a

Natural products from microbes associated with insects

• Christine Beemelmanns,
• Huijuan Guo,
• Maja Rischer and
• Michael Poulsen

Beilstein J. Org. Chem. 2016, 12, 314–327, doi:10.3762/bjoc.12.34

• derivatives have been shown to possess a variety of biological activities, such as antibiotic, antifungal and antiproliferative activity [47]. The combination of the antibiotic properties of piericidins and streptochlorin is most likely the reason for the effective inhibition of various entomopathogenic

Inclusion complexes of 2-methoxyestradiol with dimethylated and permethylated β-cyclodextrins: models for cyclodextrin–steroid interaction

• Mino R. Caira,
• Susan A. Bourne,
• Halima Samsodien and
• Vincent J. Smith

Beilstein J. Org. Chem. 2015, 11, 2616–2630, doi:10.3762/bjoc.11.281

• endogenous metabolite of the most common estrogen hormone, 17β-estradiol, has been intensively studied owing to its proven potent antiangiogenic, antiproliferative and antitumoral activities [2][3]. However, its poor bioavailability has retarded its development as a drug [4][5]. Although recent reports of

Bromotyrosine-derived alkaloids from the Caribbean sponge Aplysina lacunosa

• Qun Göthel,
• Thanchanok Sirirak and
• Matthias Köck

Beilstein J. Org. Chem. 2015, 11, 2334–2342, doi:10.3762/bjoc.11.254

• comparison with 21, compound 3 showed one extra aliphatic carbon and was named aplysinin B. The new compounds 14-debromo-11-deoxyfistularin-3 (1) and aplysinin A (2) were tested for their antimicrobial activity against different Gram-positive and Gram-negative bacteria, fungi, and for their antiproliferative

Cu(I)-catalyzed N,N’-diarylation of natural diamines and polyamines with aryl iodides

• Svetlana P. Panchenko,
• Alexei D. Averin,
• Maksim V. Anokhin,
• Olga A. Maloshitskaya and
• Irina P. Beletskaya

Beilstein J. Org. Chem. 2015, 11, 2297–2305, doi:10.3762/bjoc.11.250

• found to possess respiratory stimulating effects [12], N-substituted putrescine and cadaverine have shown antiproliferative and cytotoxic activity [13][14], N-decyl and N-dodecyl derivatives of putrescine, N-(p-tolyl) derivatives of cadaverine and hexane-1,6-diamine have demonstrated affinity to NMDA

Total synthesis of panicein A₂

• Lili Yeung,
• Lisa I. Pilkington,
• Melissa M. Cadelis,
• Brent R. Copp and
• David Barker

Beilstein J. Org. Chem. 2015, 11, 1991–1996, doi:10.3762/bjoc.11.215

• structure of the natural product has been confirmed. When tested by the NCI against a range of human cancer cell lines, it was found that panicein A2 exhibits very little antiproliferative activity at 10 μM – an observation that is at odds with the earlier report that stated panicein A2 exhibits in vitro

• MEL28 human melanoma) with an ED50 of 5 μg/mL [3]. Panicein F1 (4) was active against P388, A549 and MEL20 cell lines (ED50 = 2.5 μg/mL). The diversity of antiproliferative activities shown by these compounds, and particularly panicein A2 (5), presents them to be attractive synthetic targets. We

• compared to control. These results indicated panicein A2 (5) to have poor antiproliferative activity and the possibility that the originally tested natural material was contaminated with trace amounts of an even more active compound. Conclusion In conclusion, the first total synthesis of aromatic

Synthesis, antimicrobial and cytotoxicity evaluation of new cholesterol congeners

• Mohamed Ramadan El Sayed Aly,
• Hosam Ali Saad and
• Shams Hashim Abdel-Hafez

Beilstein J. Org. Chem. 2015, 11, 1922–1932, doi:10.3762/bjoc.11.208

• and death. This explains why it is down-regulated during carcinogenesis and opens the door for nucleophilic addition of amines to 5,6α-EC as a new lead for developing potential anticancer drugs [15]. Apart from antimicrobial and antiproliferative activities of cholesterol derivatives, other

• different forms and with a hexyl spacer. Retaining the dimethylmaleoyl (DMM) group in targets 16 and 20 was based on the finding that NDMM-protected phosphatidylcholine showed better antiproliferative activity than its natural hydrochloride congener [38]. Thus, to prepare these targets glucosyl donor 14 [39

Pyridinoacridine alkaloids of marine origin: NMR and MS spectral data, synthesis, biosynthesis and biological activity

• Louis P. Sandjo,
• Victor Kuete and
• Maique W. Biavatti

Beilstein J. Org. Chem. 2015, 11, 1667–1699, doi:10.3762/bjoc.11.183

• h. Therefore, the second Negishi coupling needed to be performed with N,N-dimethylnicotinamidezinc chloride. Synthesis of pyridoacridine analogues The strong antiproliferative activities shown by these alkaloids inspired the design and the synthesis of many pyridoacridines analogues. Scheme 9 shows

• . Its structural motif, 7H-pyrido[2,3,4-kl]acridine fusing with a 2H-1,4-thiazin-3(4H)-one ring (Figure 11) seems to be less potent than that of 62 [46][79][80]. Ascididemin (42) demonstrated interesting antiproliferative activitiy and its pharmacophore 9H-quinolino[4,3,2-de][1,10]phenanthrolin-9-one

Deproto-metallation of N-arylated pyrroles and indoles using a mixed lithium–zinc base and regioselectivity-computed CH acidity relationship

• Mohamed Yacine Ameur Messaoud,
• Ghenia Bentabed-Ababsa,
• Madani Hedidi,
• Aïcha Derdour,
• Floris Chevallier,
• Yury S. Halauko,
• Oleg A. Ivashkevich,
• Vadim E. Matulis,
• Laurent Picot,
• Valérie Thiéry,
• Thierry Roisnel,
• Vincent Dorcet and
• Florence Mongin

Beilstein J. Org. Chem. 2015, 11, 1475–1485, doi:10.3762/bjoc.11.160

• -(trifluoromethyl)phenyl)azole 1f or 2f (Figure 5) could be in relation with a reaction temperature (too high) not suitable to discriminate between similarly acidified positions. Antiproliferative activity in A2058 melanoma cells The N-arylated pyrroles and indoles exerted low to moderate antiproliferative activity

• antiproliferative activity, with no significant difference between the pyrrole and indole derivatives. Conclusion Unlike other azoles such as pyrazole and triazoles [37][38][40], pyrrole and indole do not possess any atom capable of coordinating metals. As a consequence, the corresponding CH acidities in THF

• substrates. Consequently, the Gibbs energy of the homodesmic reaction (ΔGr,sol) and the pKa value are related by the following equation: Biological evaluation. The antiproliferative activity of N-arylated pyrrole and indole derivatives was studied in the A2058 (ATCC® CRL-11147) cell line as described

Antioxidant potential of curcumin-related compounds studied by chemiluminescence kinetics, chain-breaking efficiencies, scavenging activity (ORAC) and DFT calculations

• Adriana K. Slavova-Kazakova,
• Silvia E. Angelova,
• Timur L. Veprintsev,
• Petko Denev,
• Davide Fabbri,
• Maria Antonietta Dettori,
• Maria Kratchanova,
• Vladimir V. Naumov,
• Aleksei V. Trofimov,
• Rostislav F. Vasil’ev,
• Giovanna Delogu and
• Vessela D. Kancheva

Beilstein J. Org. Chem. 2015, 11, 1398–1411, doi:10.3762/bjoc.11.151

• , dimers 6 and 7 are nontoxic to PC12 cells at a concentration of 40 μM and, contrary to curcumin, dimer 7 protects PC12 cells against MnCl2 damage [11]. When the phenol OH groups of dimer 8 were protected with methyl or phenyl groups, antiproliferative activity against malignant melanoma cells was

C-5’-Triazolyl-2’-oxa-3’-aza-4’a-carbanucleosides: Synthesis and biological evaluation

• Roberto Romeo,
• Caterina Carnovale,
• Salvatore V. Giofrè,
• Maria A. Chiacchio,
• Adriana Garozzo,
• Emanuele Amata,
• Giovanni Romeo and
• Ugo Chiacchio

Beilstein J. Org. Chem. 2015, 11, 328–334, doi:10.3762/bjoc.11.38

• 4.50–5.10 and 4.25–4.75 ppm, respectively in 13 and 14, as a doublet of doublets, for the methylene group at C-4’ position. Biological tests The antiproliferative effect of the obtained derivatives was tested on a panel of cell lines: african green monkey kidney cells (Vero and BS-C-1), human

Selective methylation of kaempferol via benzylation and deacetylation of kaempferol acetates

• Qinggang Mei,
• Chun Wang,
• Weicheng Yuan and
• Guolin Zhang

Beilstein J. Org. Chem. 2015, 11, 288–293, doi:10.3762/bjoc.11.33

• hypoxia-inducible factor (HIF)-1-dependent luciferase expression [15], and possess potent antiproliferative effects on the human colon cancer cell line Caco-2 [16]. 3,7-Di-O-methylkaempferol (kumatakenin) demonstrates high inhibitory activity against porcine pancreas α-amylase [7]. 4′,7-Di-O

Natural phenolic metabolites with anti-angiogenic properties – a review from the chemical point of view

• Qiu Sun,
• Jörg Heilmann and
• Burkhard König

Beilstein J. Org. Chem. 2015, 11, 249–264, doi:10.3762/bjoc.11.28

• antiproliferative effects [55] that strongly inhibit angiogenesis in both in vitro and in vivo models. Mechanistically, it interferes with MMP-2 and a urokinase plasminogen activator (uPA) [56]. However, due to its instability in aqueous solution, complex structure and limited availability, hyperforin is neither a

• drug candidate nor a good model compound. The finding that structurally simpler, natural, acylphloroglucinol derivatives also showed antiproliferative effects against endothelial cells with inhibitory effects in a tube-formation assay on Matrigel catalyzed the search for simple acylphloroglucinols with

• anti-angiogenic activity. Within this group, some geranylated monocyclic and bicyclic acylphloroglucinol derivatives have been identified that are structurally much more simple than hyperforin. However, they exhibiting potent antiproliferative activity for a human microvascular endothelial cell line