Antineoplastic Agents. 410. Asymmetric Hydroxylation of <i>trans</i>-Combretastatin A-4

Pettit, George R.; Toki, Brian E.; Herald, Delbert L.; Boyd, Michael R.; Hamel, Ernest; Pettit, Robin K.; Chapuis, Jean Charles

doi:10.1021/jm9807149

Cited by 74 publications

(52 citation statements)

References 17 publications

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“…CA-4 exerts a potent cytotoxicity against many human cancer cell lines, including multi-drug resistant (MDR) cancer cells [35]. However, CA-4 does not display the expected activity in vivo due to its poor bioavailability caused by its low solubility and the instability of its cis conformation, which easily changes to form the trans-isomer [41]. Phosphates as prodrugs of combretastatins show better aqueous solubility and importantly, they are metabolized to their active forms by phosphatase, which exerts high activity in the tumor environment.…”

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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“…While others have shown that CA4P possesses antivascular effects against proliferating, nonneoplastic tissue (11), CA4P has also been shown to possess direct antineoplastic activity against different tumor cell lines (12). Other derivatives of combretastatin, as well as the most potent member, CA4P, have also been shown to possess direct antineoplastic properties (13)(14)(15)(16). In order to evaluate the potential role of CA4P as a component of the therapy of ATC, we undertook an in vitro analysis of its cytotoxic activity using human ATC cell lines.…”

Section: Introductionmentioning

confidence: 99%

Combretastatin A4 Phosphate Has Primary Antineoplastic Activity Against Human Anaplastic Thyroid Carcinoma Cell Lines and Xenograft Tumors

Dziba

Marcinek²,

Venkataraman³

et al. 2002

Thyroid

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Anaplastic thyroid carcinoma (ATC) is a fatal malignancy the clinical outcome of which is unaltered by current therapeutic modalities. A recent phase 1 clinical trial of combretastatin A4 phosphate (CA4P) produced a long-lasting total remission in a patient with ATC. CA4P is a tubulin-binding agent derived from the African bush willow, Combretum caffrum, which possesses tumor vascular-targeting activity. In order to discriminate primary antineoplastic effects from tumor antivascular activity, we evaluated CA4P cytotoxicity in eight human ATC cell lines and compared it to paclitaxel, another tubulin-binding agent with significant clinical activity. CA4P displayed significant cytotoxicity against the ATC cell lines, comparable to that of paclitaxel, and these effects were longer lasting in two cell lines compared to the duration of paclitaxel. We further investigated the effects of CA4P on xenograft tumors from four ATC cell lines injected in athymic nude mice. Significantly lower tumor weights were observed in animals treated with CA4P compared to those treated with vehicle alone. Continuous monitoring of xenograft tumor volumes from one of the ATC cell lines also revealed a significantly lower rate of tumor growth in the CA4P-treated mice compared to those receiving vehicle alone. These results suggest that antitumoral effects of CA4P can be consequent to a combination of primary antineoplastic effects as well as the potential destruction of tumor vasculature.

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“…The E-isomers display dramatically reduced inhibition of cancer cell growth and tubulin assembly [29]. In our efforts to discover novel tubulin assembly inhibitors [30e32], we recently found that isocombretastatin A-4 (isoCA-4), the third and "forgotten" structural isomer of the natural product, displayed biological activities comparable to that of CA-4 [33,34].…”

Section: Introductionmentioning

confidence: 99%