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Zampanolide and dactylolide: cytotoxic tubulin-assembly agents and promising anticancer leads.

Chen QH, Kingston DG - Nat Prod Rep (2014)

Bottom Line: Zampanolide is a marine natural macrolide and a recent addition to the family of microtubule-stabilizing cytotoxic agents.Zampanolide exhibits unique effects on tubulin assembly and is more potent than paclitaxel against several multi-drug resistant cancer cell lines.A high-resolution crystal structure of αβ-tubulin in complex with zampanolide explains how taxane-site microtubule-stabilizing agents promote microtubule assemble and stability.

View Article: PubMed Central - PubMed

Affiliation: Department of Chemistry, California State University, Fresno, 2555 E. San Ramon Avenue, M/S SB70, Fresno, CA 93740, USA. qchen@csufresno.edu.

ABSTRACT
Zampanolide is a marine natural macrolide and a recent addition to the family of microtubule-stabilizing cytotoxic agents. Zampanolide exhibits unique effects on tubulin assembly and is more potent than paclitaxel against several multi-drug resistant cancer cell lines. A high-resolution crystal structure of αβ-tubulin in complex with zampanolide explains how taxane-site microtubule-stabilizing agents promote microtubule assemble and stability. This review provides an overview of current developments of zampanolide and its related but less potent analogue dactylolide, covering their natural sources and isolation, structure and conformation, cytotoxic potential, structure-activity studies, mechanism of action, and syntheses.

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Related in: MedlinePlus

Taylor's synthesis of fragment C9–C20 of (–)-zampanolide.
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sch44: Taylor's synthesis of fragment C9–C20 of (–)-zampanolide.

Mentions: Taylor and co-workers applied their recently developed methodology87 to assemble the 4-alkoxy-2,6-cis-THP 217 from an advanced sulfonyl pyran fragment. The synthesis commenced with preparation of 210 as illustrated in Scheme 44. The epoxide 209 was prepared from (R)-aspartic acid via modification of the literature's procedure.88 Regioselective epoxide opening with vinyl magnesium bromide in the presence of catalytic CuI followed by p-bromobenzyloxy methyl ether alkylation gave the PBB ether 210. Electrophilic activation of the resulting ether with ICl at low temperature provided exclusively 1,3-syn diol monoether. PBu3-catalyzed conjugate addition of alcohol 211 to methyl propiolate yielded β-alkoxyacrylate 212. Intramolecular radical cyclization promoted by Et3B in the presence of 1-ethylpiperidinium hypophosphate gave THP 213 in good diastereoselectivity (>20 : 1). Reduction followed by Grieco–Sharpless olefination provided 214. Exposure of terminal olefin 214 to excess methacrolein mediated by Hoveyda–Grubbs' second-generation catalyst followed by HWE olefination gave dienonate 215. Reduction of the dienoate with DIBAL-H followed by Sharpless epoxidation and in situ silyl protecting gave alcohol 216. Completion of the C9–C20 fragment was accomplished via regioselective opening of the vinyl epoxide with DIBAL-H at low temperature. Desilylation followed by acetonide formation provided 217.


Zampanolide and dactylolide: cytotoxic tubulin-assembly agents and promising anticancer leads.

Chen QH, Kingston DG - Nat Prod Rep (2014)

Taylor's synthesis of fragment C9–C20 of (–)-zampanolide.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4126874&req=5

sch44: Taylor's synthesis of fragment C9–C20 of (–)-zampanolide.
Mentions: Taylor and co-workers applied their recently developed methodology87 to assemble the 4-alkoxy-2,6-cis-THP 217 from an advanced sulfonyl pyran fragment. The synthesis commenced with preparation of 210 as illustrated in Scheme 44. The epoxide 209 was prepared from (R)-aspartic acid via modification of the literature's procedure.88 Regioselective epoxide opening with vinyl magnesium bromide in the presence of catalytic CuI followed by p-bromobenzyloxy methyl ether alkylation gave the PBB ether 210. Electrophilic activation of the resulting ether with ICl at low temperature provided exclusively 1,3-syn diol monoether. PBu3-catalyzed conjugate addition of alcohol 211 to methyl propiolate yielded β-alkoxyacrylate 212. Intramolecular radical cyclization promoted by Et3B in the presence of 1-ethylpiperidinium hypophosphate gave THP 213 in good diastereoselectivity (>20 : 1). Reduction followed by Grieco–Sharpless olefination provided 214. Exposure of terminal olefin 214 to excess methacrolein mediated by Hoveyda–Grubbs' second-generation catalyst followed by HWE olefination gave dienonate 215. Reduction of the dienoate with DIBAL-H followed by Sharpless epoxidation and in situ silyl protecting gave alcohol 216. Completion of the C9–C20 fragment was accomplished via regioselective opening of the vinyl epoxide with DIBAL-H at low temperature. Desilylation followed by acetonide formation provided 217.

Bottom Line: Zampanolide is a marine natural macrolide and a recent addition to the family of microtubule-stabilizing cytotoxic agents.Zampanolide exhibits unique effects on tubulin assembly and is more potent than paclitaxel against several multi-drug resistant cancer cell lines.A high-resolution crystal structure of αβ-tubulin in complex with zampanolide explains how taxane-site microtubule-stabilizing agents promote microtubule assemble and stability.

View Article: PubMed Central - PubMed

Affiliation: Department of Chemistry, California State University, Fresno, 2555 E. San Ramon Avenue, M/S SB70, Fresno, CA 93740, USA. qchen@csufresno.edu.

ABSTRACT
Zampanolide is a marine natural macrolide and a recent addition to the family of microtubule-stabilizing cytotoxic agents. Zampanolide exhibits unique effects on tubulin assembly and is more potent than paclitaxel against several multi-drug resistant cancer cell lines. A high-resolution crystal structure of αβ-tubulin in complex with zampanolide explains how taxane-site microtubule-stabilizing agents promote microtubule assemble and stability. This review provides an overview of current developments of zampanolide and its related but less potent analogue dactylolide, covering their natural sources and isolation, structure and conformation, cytotoxic potential, structure-activity studies, mechanism of action, and syntheses.

Show MeSH
Related in: MedlinePlus