Contraction of the Tropolonic Ring of Colchicine by Hydrogen Peroxide Oxidation

Iorio, M. A.

doi:10.3987/r-1984-10-2207

Cited by 27 publications

(17 citation statements)

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“…Allo compound 1, prepared here by Iorio's procedure 4 , has the same αS,7S absolute configuration as natural colchicine 5 , and has been proven to be a valuable internal standard because of its potent activity in assays measuring interactions with tubulin [6][7][8] .…”

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confidence: 99%

“…It seemed, therefore, of interest to prepare C(7)-oxygenated analogs of 1 and to measure their effects on tubulin and the growth of several human tumor cell lines. Compound 1, used as the starting material to prepare the desired compounds, was prepared from colchicine by a modification of Iorio's procedure 4 . In an attempt to resolve the separation problem, we removed impurities and isolated 1 and 2 as a mixture.…”

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confidence: 99%

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Antitumor Agents. 192. Antitubulin Effect and Cytotoxicity of C(7)-Oxygenated Allocolchicinoids

Guan

Zhu

Brossi

et al. 1999

Collect. Czech. Chem. Commun.

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Two allocolchicinoids 6 and 8, prepared from colchicine, together with allo compounds 9-11, made from 6 by reduction and regiodemethylation, were evaluated for antitubulin and antitumor activities. Structures of 6, 8, and 10 were confirmed by X-ray crystallographic analysis. Compounds 6, 8, and 9 have high tubulin binding affinity and display potent inhibitory activities against tubulin polymerization and solid human tumor cell lines. Particularly, drug-resistant KB cell lines, including KB-7d, KB-VCR, and KB-CPT, do not show marked resistance to these compounds.

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confidence: 99%

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Antitumor Agents. 192. Antitubulin Effect and Cytotoxicity of C(7)-Oxygenated Allocolchicinoids

Guan

Zhu

Brossi

et al. 1999

Collect. Czech. Chem. Commun.

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“…Taking another tack, Miller et al (1997) prepared seven-member tropolonic A ring analogs of 2ME to enhance the analogy to the C ring of colchicine and found several of these to be highly active inhibitors of tubulin assembly. Because allocolchicinoids, with a seven-member B ring but six-member C ring, such as compound 1 (Iorio, 1984), are often more active than the corresponding colchicinoids (Kang et al, 1990), we decided to synthesize steroid derivatives with an expanded B ring, with the two isomers of compound 2 being our ultimate target. We were encouraged to find the intermediate compound 5 (see reaction scheme in Fig.…”

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A Steroid Derivative with Paclitaxel-Like Effects on Tubulin Polymerization

et al. 2000

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The endogenous estrogen metabolite 2-methoxyestradiol has modest antimitotic activity that may result from a weak interaction at the colchicine binding site of tubulin, but it nevertheless has in vivo antitumor activity. Synthetic efforts to improve activity led to compounds that increased inhibitory effects on cell growth, tubulin polymerization, and binding of colchicine to tubulin. This earlier work was directed at modifications in the steroid A ring, which is probably analogous to the colchicine tropolonic C ring. One of the most active analogs prepared was 2-ethoxyestradiol (2EE). We report here that different modifications in the steroid B ring of 2EE yield compounds with two apparently distinct modes of action. Simple expansion of the B ring to seven members resulted in a compound comparable to 2EE in its ability to inhibit tubulin polymerization and colchicine binding to tubulin. Acetylation of the hydroxyl groups in this analog and in 2EE essentially abolished these inhibitory properties. The introduction of a ketone functionality at C6, together with acetylation of the hydroxyls at positions 3 and 17, produced a compound with activity similar to that of paclitaxel, in that the agent enhanced tubulin polymerization into polymers that were partially stable at 0 degrees C. The acetyl group at C17, but not that at C3, was essential for this paclitaxel-like activity.

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“…Most natural analogues are modified in the C-7 side chain substituent except allocolchicine (43), with an aromatic 6-member ring and a COOCH 3 substituent at C-10, and cornigerine (44) with an OCH 3 substituent at C-10 which have both been obtained from Colchicum cornigerum [136]. Allocolcichine (43) which has also been isolated from C. autumnale [137] and N-acetylcolchinol O-methylether, a semisynthetic analogue obtained by reaction of colchicine with hydrogen peroxide [138] , are both more potent inhibitors than colchicine in ITP and ICB assays [139,140].…”

Section: Colchicine and Its Analoguesmentioning

confidence: 99%

Microtubulin Binding Sites as Target for Developing Anticancer Agents

Islam¹,

Iskander²

2004

MRMC

134

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Microtubules (MTs) play important and diverse roles in eukaryotic cells. Their function and biophysical properties have made alpha-and beta-tubulin, the main components of MTs, the subject of intense study. Interfering with normal MT dynamics, for example, by the addition of tubulin ligands, can cause the cell great distress and affect MT stability and functions, including mitosis, cell motion and intracellular organelle transport. It has been shown in the literature that tubulin is an important target molecule for developing anticancer drugs. Tubulin binding molecules have generated considerable interest after the successful introduction of the taxanes into clinical oncology and the widespread use of the vinca alkaloids vincristine and vinblastine. These compounds inhibit cell mitosis by binding to the protein tubulin in the mitotic spindle and preventing polymerization into the MTs. This mode of action is also shared with other natural agents eg colchicine and podophyllotoxin. However various tubulin isotypes have shown resistance to taxanes and other MT agents. Therefore, there is a strong need to design and develop new natural analogs as antimitotic agents to interact with tubulin at sites different from those of vinca alkaloids and taxanes. This minireview provides SAR on several classes of antimitotic agents reported in the literature. The structures and data given are essential to the scientists who are involved in drug design and development in the field of anticancer drugs.

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Contraction of the Tropolonic Ring of Colchicine by Hydrogen Peroxide Oxidation

Cited by 27 publications

References 0 publications

Antitumor Agents. 192. Antitubulin Effect and Cytotoxicity of C(7)-Oxygenated Allocolchicinoids

Antitumor Agents. 192. Antitubulin Effect and Cytotoxicity of C(7)-Oxygenated Allocolchicinoids

A Steroid Derivative with Paclitaxel-Like Effects on Tubulin Polymerization

Microtubulin Binding Sites as Target for Developing Anticancer Agents

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