Isolation and structure of combretastatin

Pettit, George R.; Cragg, Gordon M.; Herald, Delbert L.; Schmidt, Jean M.; Lohavanijaya, Prasert

doi:10.1139/v82-202

Cited by 235 publications

(182 citation statements)

References 6 publications

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“…3) was isolated from the root bark of the South African willow tree Combretum caffrum Kuntze [2]. Initially, the isolation was based on bioassay techniques that used the astrocyte reversal system.…”

Section: Stilbene Derivatives As Tubulin-interactive Agentsmentioning

confidence: 99%

“…This review focuses on the anti-carcinogenic properties of natural and modified stilbenes with respect to their interaction with the cellular protein tubulin. The interest in stilbenes as tubulin-interactive agents was inspired by the work of Pettit, who first isolated combretastatins and determined their anti-mitotic activity in the 1980s [2]. Combretastatins are natural cis-stilbenes that are isolated from the bark of the African willow tree (Combretum caffrum).…”

Section: Introductionmentioning

confidence: 99%

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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%

Section: Introductionmentioning

confidence: 99%

Tubulin-interactive stilbene derivatives as anticancer agents

Mikstacka

Stefański

Różański

2013

Cellular and Molecular Biology Letters

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“…A variety of small molecules with diverse molecular scaffolds have been shown to bind tubulin at the colchicine site [6][7][8][9]. One class of these compounds receiving particular attention has been that based on the natural product combretastatin A-4 discovered by Pettit [10,11]. Despite some successes, the discovery of new, more efficacious inhibitors is becoming increasingly important because of multi-drug resistance to tubulin-binding antimitotic agents [12].…”

Section: Introductionmentioning

confidence: 99%

Docking and hydropathic scoring of polysubstituted pyrrole compounds with antitubulin activity

Tripathi

Fornabaio

Kellogg

et al. 2008

Bioorganic & Medicinal Chemistry

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Compounds that bind at the colchicine site of tubulin have drawn considerable attention with studies indicating that these agents suppress microtubule dynamics and inhibit tubulin polymerization. Data for eighteen polysubstituted pyrrole compounds are reported, including antiproliferative activity against human MDA-MB-435 cells and calculated free energies of binding following docking the compounds into models of αβ-tubulin. These docking calculations coupled with HINT interaction analyses are able to represent the complex structures and the binding modes of inhibitors such that calculated and measured free energies of binding correlate with an r 2 of 0.76. Structural analysis of the binding pocket identifies important intermolecular contacts that mediate binding. As seen experimentally, the complex with JG-03-14 (3,5-dibromo-4-(3,4-dimethoxyphenyl)-1H-pyrrole-2-carboxylic acid ethyl ester) is the most stable. These results illuminate the binding process and should be valuable in the design of new pyrrole-based colchicine site inhibitors as these compounds have very accessible syntheses.

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“…and Zeyh) Kuntze (or as Salicifolium E. Mey), a valuable lead uncovered in the U.S. National Cancer Institute's (NCI) world-wide explorations (5). Eventually we succeeded in isolating combretastatin (I), which was found to significantly cause astrocyte reversal in the NCI astrocytoma bioassay (6) and inhibition of tubulin polymerization (7). Isolation of diphenylethanol 1 was followed by discovery of the principal PS in vivo active constituent of Combretum caffrum fractions, the powerful tubulin polymerization inhibitor combretastatin A-1 (2, ref.…”

mentioning

confidence: 99%

Isolation, structure, and synthesis of combretastatin A-2, A-3, and B-2

Pettit¹,

Singh²

1987

Can. J. Chem.

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Further investigation of the South African tree Combretumcaffrum (Combretaceae) for murine P388 lymphocytic leukemia (PS) cell-growth inhibitory substances has led to discovery of three new active constituents designated combretastatins A-2 (5a, PS ED50 0.027 μg/mL), A-3 (5b, PS ED50 0.026 μg/mL), and B-2 (3b, PS ED50 0.32 μg/mL). Both combretastatins A-2 and A-3 were found to markedly inhibit tubulin polymerization. The structure of each combretastatin was firmly established by a combination of high resolution (400 MHz) 1H and 13C nuclear magnetic resonance and mass spectral analyses followed by total syntheses. The conversion of methyl gallate (7b) to combretastatin A-2 via intermediates 7c → 7d → 7e → 7a and 6a → 5a illustrates the practical synthetic route utilized for obtaining these substances. The Wittig reaction employed as the penultimate step in obtaining combretastatins A-3, afforded predominantly the natural Z isomer.

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Isolation and structure of combretastatin

Cited by 235 publications

References 6 publications

Tubulin-interactive stilbene derivatives as anticancer agents

Tubulin-interactive stilbene derivatives as anticancer agents

Docking and hydropathic scoring of polysubstituted pyrrole compounds with antitubulin activity

Isolation, structure, and synthesis of combretastatin A-2, A-3, and B-2

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