Design, synthesis and biological evaluation of dihydronaphthalene and benzosuberene analogs of the combretastatins as inhibitors of tubulin polymerization in cancer chemotherapy

Sriram, Madhavi; Hall, John J.; Grohmann, Nathan C.; Strecker, Tracy E.; Wootton, Taylor; Franken, Andreas; Trawick, Mary Lynn; Pinney, Kevin G.

doi:10.1016/j.bmc.2008.07.050

Cited by 79 publications

(90 citation statements)

References 46 publications

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“…CA-4 binds to tubulin at the colchicine-binding site, leading to the formation of abnormal mitotic spindles as a result of the disturbance of the dynamic equilibrium of microtubule formation [35]. The IC 50 value (concentration that inhibits tubulin polymerization to 50%) of CA-4 was determined in several laboratories and ranged from 0.53 to 2.4 M [33,[38][39][40]. CA-4 exerts a potent cytotoxicity against many human cancer cell lines, including multi-drug resistant (MDR) cancer cells [35].…”

Section: Stilbene Derivatives As Tubulin-interactive Agentsmentioning

confidence: 99%

Tubulin-interactive stilbene derivatives as anticancer agents

Mikstacka

Stefański

Różański

2013

Cellular and Molecular Biology Letters

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Microtubules are dynamic polymers that occur in eukaryotic cells and play important roles in cell division, motility, transport and signaling. They form during the process of polymerization of α- and β-tubulin dimers. Tubulin is a significant and heavily researched molecular target for anticancer drugs. Combretastatins are natural cis-stilbenes that exhibit cytotoxic properties in cultured cancer cells in vitro. Combretastatin A-4 (3′-hydroxy-3,4,4′, 5-tetramethoxy-cis-stilbene; CA-4) is a potent cytotoxic cis-stilbene that binds to β-tubulin at the colchicine-binding site and inhibits tubulin polymerization. The prodrug CA-4 phosphate is currently in clinical trials as a chemotherapeutic agent for cancer treatment. Numerous series of stilbene analogs have been studied in search of potent cytotoxic agents with the requisite tubulin-interactive properties. Microtubule-interfering agents include numerous CA-4 and transresveratrol analogs and other synthetic stilbene derivatives. Importantly, these agents are active in both tumor cells and immature endothelial cells of tumor blood vessels, where they inhibit the process of angiogenesis. Recently, computer-aided virtual screening was used to select potent tubulin-interactive compounds. This review covers the role of stilbene derivatives as a class of antitumor agents that act by targeting microtubule assembly dynamics. Additionally, we present the results of molecular modeling of their binding to specific sites on the α- and β-tubulin heterodimer. This has enabled the elucidation of the mechanism of stilbene cytotoxicity and is useful in the design of novel agents with improved anti-mitotic activity. Tubulin-interactive agents are believed to have the potential to play a significant role in the fight against cancer.

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Section: Stilbene Derivatives As Tubulin-interactive Agentsmentioning

confidence: 99%

Tubulin-interactive stilbene derivatives as anticancer agents

Mikstacka

Stefański

Różański

2013

Cellular and Molecular Biology Letters

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“…An early initial molecular design paradigm led us to utilize clinically relevant non-steroidal, selective estrogen receptor modulators (SERMs) and related compounds as molecular templates modified to mimic colchicine and CA4 . 37–39 This led us to the discovery and establishment of benzo[ b ]thiophene, 40–42 benzofuran, 42–43 dihydronaphthalene, 30–32 benzosuberene, 30–34 and indole-based 35 analogues as potent inhibitors of tubulin polymerization (Fig. 1).…”

Section: Introductionmentioning

confidence: 99%

Structural interrogation of benzosuberene-based inhibitors of tubulin polymerization

Herdman

Devkota

Lin

et al. 2015

Bioorganic & Medicinal Chemistry

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The discovery of 3-methoxy-9-(3′,4′,5′-trimethoxyphenyl)-6,7-dihydro-5H-benzo[7]annulen-4-ol (a benzosuberene-based analogue referred to as KGP18) was originally inspired by the natural products colchicine and combretastatin A-4 (CA4). The relative structural simplicity and ease of synthesis of KGP18, coupled with its potent biological activity as an inhibitor of tubulin polymerization and its cytotoxicity (in vitro) against human cancer cell lines, has resulted in studies focused on new analogue design and synthesis. Our goal was to probe the relationship of structure to function in this class of anticancer agents. A series of twenty-two new benzosuberene-based analogues of KGP18 was designed and synthesized. These compounds vary in their methoxylation pattern and separately incorporate trifluoromethyl groups around the pendant aryl ring for the evaluation of the effect of functional group modifications on the fused six-membered aromatic ring. In addition, the 8,9-saturated congener of KGP18 has been synthesized to assess the necessity of unsaturation at the carbon atom bearing the pendant aryl ring. Six of the molecules from this benzosuberene-series of compounds were active (IC50 < 5 μM) as inhibitors of tubulin polymerization while four analogues were comparable (IC50 approximately 1 μM) in their tubulin inhibitory activity to CA4 and KGP18. The potency of a bis-trifluoromethyl analogue 74 and the unsaturated KGP18 derivative 73 as inhibitors of tubulin assembly along with their moderate cytotoxicity suggested the potential utility of these compounds as vascular disrupting agents (VDAs) to selectively target microvessels feeding tumors. Accordingly, water-soluble and DMSO-soluble phosphate prodrug salts of each were synthesized for preliminary in vivo studies to assess their potential efficacy as VDAs.

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“…3 The replacement of the olefinic bridge of CA-4 with a carbonyl group yields phenstatin, 4 which has similar potency and mechanism of actions with CA-4. BPR0L075 5 and Oxi-6196 6 are 2-aroylindole and dihydronaphthalene analogues of CA-4, which show strong inhibition on tubulin polymerization. Methylated chalcone SD400, which has an IC 50 value of 0.21 nM against K562 human leukemia cells, is a potent tubulin inhibitor.…”

Section: Introductionmentioning

confidence: 99%

Design, Synthesis, and Biological Evaluation of Stable Colchicine Binding Site Tubulin Inhibitors as Potential Anticancer Agents

et al. 2014

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To block the metabolically labile sites of novel tubulin inhibitors targeting the colchicine binding site based on SMART, ABI, and PAT templates, we have designed, synthesized, and biologically tested three focused sets of new derivatives with modifications at the carbonyl linker, the para-position in the C ring of SMART template, and modification of A ring of the PAT template. Structure–activity relationships of these compounds led to the identification of new benzimidazole and imidazo[4,5-c]pyridine-fused ring templates, represented by compounds 4 and 7, respectively, which showed enhanced antitumor activity and substantially improved the metabolic stability in liver microsomes compared to SMART. MOM group replaced TMP C ring and generated a potent analogue 15, which showed comparable potency to the parent SMART compound. Further modification of PAT template yielded another potent analogue 33 with 5-indolyl substituent at A ring.

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Design, synthesis and biological evaluation of dihydronaphthalene and benzosuberene analogs of the combretastatins as inhibitors of tubulin polymerization in cancer chemotherapy

Cited by 79 publications

References 46 publications

Tubulin-interactive stilbene derivatives as anticancer agents

Tubulin-interactive stilbene derivatives as anticancer agents

Structural interrogation of benzosuberene-based inhibitors of tubulin polymerization

Design, Synthesis, and Biological Evaluation of Stable Colchicine Binding Site Tubulin Inhibitors as Potential Anticancer Agents

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