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 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

• cytotoxic and antiproliferative activity on three human cancer cell lines, the neuroblastoma SH-SY5Y, the HT-29 colorectal adenocarcinoma and the HepG2 hepatocellular carcinoma cells. In particular, the most active compound 6e shows an IC50 in the range of 9–22 μM: biological tests suggest that the

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

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

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

• activity. Aplysinin B (3) was not subjected to any biological activity test due to the minute amount and its existence as the minor compound of a mixture. The results showed that 1 and 2 exhibited mild cytotoxic activity against KB-31 epidermoid carcinoma cells (IC50 = 69 and 26 µM, respectively). Only 2

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

• 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

• 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

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

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

• 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

• , which were subsequently demethylated using BBr3 to give compounds 47–51 in 48 to 78% yield. Compound 47 (R1 = H, R2 = OH, R3 = OH) showed antiproliferative activity with an IC50 of 0.88 ± 0.08 µM in vitro. Compound 38 (alkyl = CH(CH3)CH2CH3) exhibited a moderate antiproliferative effect (IC50 = 11.0 ± 1

• antiproliferative activity of these acylphloroglucinols in HMEC-1 increases with increasing log P. Increasing the number of carbon atoms in the acyl group provides higher lipophilicity, which allows the compound to better penetrate across cellular membranes in the in vitro assay. In contrast, the activity of the

Come-back of phenanthridine and phenanthridinium derivatives in the 21st century

• Lidija-Marija Tumir,
• Marijana Radić Stojković and
• Ivo Piantanida

Beilstein J. Org. Chem. 2014, 10, 2930–2954, doi:10.3762/bjoc.10.312

• within the polynucleotide binding site. All 4,9-DAP derivatives also showed considerable antiproliferative activity, interestingly only 19 having strong, micromolar activity in vitro but negligible in vivo toxic effects in mice [97]. Strong fluorescence of 19 allowed monitoring of the very efficient

• analogue, dihydroimidazophenanthridinium cation characterised by cyclic structure connecting positions 5 and 6, showed promising antiproliferative activity [3][98][99]. Molecular modelling results and some preliminary experiments suggest intercalative binding mode, however up till now interactions with

Synthesis of isoprenoid bisphosphonate ethers through C–P bond formations: Potential inhibitors of geranylgeranyl diphosphate synthase

• Xiang Zhou,
• Jacqueline E. Reilly,
• Kathleen A. Loerch,
• Raymond J. Hohl and
• David F. Wiemer

Beilstein J. Org. Chem. 2014, 10, 1645–1650, doi:10.3762/bjoc.10.171

• should reduce cellular levels of GGPP and thus diminish protein geranylgeranylation, one might expect that inhibitors of this enzyme would interfere with essential cell signaling pathways and demonstrate antiproliferative activity. Several years ago we reported the synthesis of digeranyl bisphosphonate

New sesquiterpene hydroquinones from the Caribbean sponge Aka coralliphagum

• Qun Göthel and
• Matthias Köck

Beilstein J. Org. Chem. 2014, 10, 613–621, doi:10.3762/bjoc.10.52

• -positive and Gram-negative bacteria, fungi, and for antiproliferative activity. The results given in Table 4 show that siphonodictyal E3 (3) and cyclosiphonodictyol A (5) exhibited mild activity against the Gram-positive bacteria Staphylococcus aureus and Micrococcus luteus, while siphonodictyal E4 (4

Preparation of new alkyne-modified ansamitocins by mutasynthesis

• Kirsten Harmrolfs,
• Lena Mancuso,
• Binia Drung,
• Florenz Sasse and
• Andreas Kirschning

Beilstein J. Org. Chem. 2014, 10, 535–543, doi:10.3762/bjoc.10.49

• introduce a thiol linker by Huisgen-type cycloaddition which can principally be utilized to create tumor targeting conjugates. In bioactivity tests, only those new ansamitocin derivatives showed strong antiproliferative activity that bear an ester side chain at C-3. Keywords: ansamitocins; antibiotics

• , we demonstrated that the ansamitocins (maytansinoids) 3–5 are an ideal showcase for creating small libraries by mutasynthesis [8][9][10]. These secondary metabolites exert strong antiproliferative activity towards different leukemia cell lines as well as human solid tumors. Inhibitory concentrations

• still strong antiproliferative activity (IC50 < 10 nM) for different cancer cell lines. Importantly, the intact conjugate showed strong antiproliferative activity for a FR+ cancer cell line but was inactive against a FR− cell line. Indeed, despite the substantial size of the substituent remaining at C19

Total synthesis of (+)-grandiamide D, dasyclamide and gigantamide A from a Baylis–Hillman adduct: A unified biomimetic approach

• Andivelu Ilangovan and
• Shanmugasundar Saravanakumar

Beilstein J. Org. Chem. 2014, 10, 127–133, doi:10.3762/bjoc.10.9

• aglaforbesin A (1) and pyramidatin (4) for pyramidaglain (3) as shown in Figure 1 [3]. The benzopyran and benzoxepine containing flavaglins showed insecticidal, antifungal and antiproliferative activity against various cancer cell lines [4]. Apart from acting as precursors for flavaglins, some of the cyclic

IBD-mediated oxidative cyclization of pyrimidinylhydrazones and concurrent Dimroth rearrangement: Synthesis of [1,2,4]triazolo[1,5-c]pyrimidine derivatives

• Caifei Tang,
• Zhiming Li and
• Quanrui Wang

Beilstein J. Org. Chem. 2013, 9, 2629–2634, doi:10.3762/bjoc.9.298

• pyrazolo[4,3-d]pyrimidine sildenafil. In addition, trapidil is a [1,2,4]triazolo[1,5-a]pyrimidine compound, which is the first triazolopyrimidine registered as a drug possessing antiproliferative activity in glioma cells and vascular smooth muscle cells (VSMCs) and used as a coronary vasodilator in the

New tridecapeptides of the theonellapeptolide family from the Indonesian sponge Theonella swinhoei

• Annamaria Sinisi,
• Barbara Calcinai,
• Carlo Cerrano,
• Henny A. Dien,
• Angela Zampella,
• Claudio D’Amore,
• Barbara Renga,
• Stefano Fiorucci and
• Orazio Taglialatela-Scafati

Beilstein J. Org. Chem. 2013, 9, 1643–1651, doi:10.3762/bjoc.9.188

• show four valine residues. The structures of the compounds, isolated along with the known theonellapeptolide Id, were determined by extensive 2D NMR and MS/MS analyses followed by application of Marfey’s method. The isolated peptides exhibited moderate antiproliferative activity against HepG2 cells, a

• hepatic carcinoma cell line. Keywords: antiproliferative activity; cyclic peptides; marine metabolites; theonellapeptolides; 2D NMR; Introduction Three decades of extensive chemical investigation [1] have clearly evidenced that marine sponges of the genus Theonella (Lithistida, Theonellidae) are

• during the present investigation (1–3) have been evaluated for their antiproliferative activity against HepG2 cells, a hepatic carcinoma cell line. As reported in Figure 4, all tested compounds showed antiproliferative activity at low micromolar doses, with a similar pattern of potency. At the dose 10 μM

Chemical modification allows phallotoxins and amatoxins to be used as tools in cell biology

• Jan Anderl,
• Hartmut Echner and
• Heinz Faulstich

Beilstein J. Org. Chem. 2012, 8, 2072–2084, doi:10.3762/bjoc.8.233

• incubation time (Table 1). Phalloidin displayed no antiproliferative activity up to a concentration of 10−3 M in the culture medium. In contrast, the most lipophilic ester derivative, phalloidin oleate (1e), showed an IC50 value of proliferation inhibition of 2.5 × 10−6 M, and was thus ca. 1000 times more

• , were highly toxic for mouse fibroblasts, and their antiproliferative activity was comparable to the most lipophilic derivative, phalloidin oleate (Figure 4a). Their toxicity was found to be dependent on the configuration of the polymer, since phalloidin bound to D-configurated polylysine was about 10

Unprecedented deoxygenation at C-7 of the ansamitocin core during mutasynthetic biotransformations

• Tobias Knobloch,
• Gerald Dräger,
• Wera Collisi,
• Florenz Sasse and
• Andreas Kirschning

Beilstein J. Org. Chem. 2012, 8, 861–869, doi:10.3762/bjoc.8.96

• mutants and mutasynthetic approaches. We suggest that the formation of these derivatives is based on elimination at C-7/C-8 followed by reduction(s) of the intermediate enone. In bioactivity tests, only ansamitocin derivatives bearing an ester side chain at C-3 showed strong antiproliferative activity

• -proansamitocin 8 (3.5 mg/L) and two diastereomeric byproducts 9a and 9b (7.6 mg/L; 1:1 ratio) from the fermentation broth of A. pretiosum Δasm12/21 (Figure 1). We also showed that none of these proansamitocin derivatives exhibit antiproliferative activity. Herein, we describe the unprecedented formation of

• )ansamitocin derivatives lacking the ester side chain at C-3 (11b, 11g–h, 12–16) do not show any antiproliferative activity (IC50 > 800 nM) for at least two of the cell lines listed in Table 1. Compounds 11c–e, bearing the ester side chain at C-3, predominantly showed activities in the pM range. As seen also

Marilones A–C, phthalides from the sponge-derived fungus Stachylidium sp.

• Celso Almeida,
• Stefan Kehraus,
• Miguel Prudêncio and
• Gabriele M. König

Beilstein J. Org. Chem. 2011, 7, 1636–1642, doi:10.3762/bjoc.7.192

• activity towards three cancer cell lines (NCI-H460, MCF7 and SF268). Marilone A and C (1, 3) showed weak antiproliferative activity with an average GI50 of 36.7 and 26.6 µM, respectively (see Supporting Information File 1). Marilone B (2) was assayed in a panel of 44 psychoactive receptors, including 11

Efficient syntheses of 25,26-dihydrodictyostatin and 25,26-dihydro-6-epi-dictyostatin, two potent new microtubule-stabilizing agents

• María Jiménez,
• Wei Zhu,
• Andreas Vogt,
• Billy W. Day and
• Dennis P. Curran

Beilstein J. Org. Chem. 2011, 7, 1372–1378, doi:10.3762/bjoc.7.161

• , PA 15260, USA Department of Pharmaceutical Sciences, School of Pharmacy, 3501 Terrace Street, University of Pittsburgh, Pittsburgh, PA 15261 USA 10.3762/bjoc.7.161 Abstract The dictyostatins are powerful microtubule-stabilizing agents that have shown antiproliferative activity against a variety of

• microtubule-stabilizing agents include taxanes, epothilones, and discodermolides, among others [3][4]. Dictyostatin (1a) is an exceptionally potent microtubule-stabilizing agent that has shown antiproliferative activity in a variety of human cancer cell lines in the low nanomolar range. Isolated first in 1994

Colchitaxel, a coupled compound made from microtubule inhibitors colchicine and paclitaxel

• Karunananda Bombuwala,
• Thomas Kinstle,
• Vladimir Popik,
• Sonal O. Uppal,
• James B. Olesen,
• Jose Viña and
• Carol A. Heckman

Beilstein J. Org. Chem. 2006, 2, No. 13, doi:10.1186/1860-5397-2-13

• , for antiproliferative activity of paclitaxel and vinorelbine individually, but synergy with concentrations as low as 3 nM and 0.01 nM respectively [51]. Thus, differing model systems yielded results variously suggesting antagonistic, non-additive, or synergistic effects. However, there is evidence