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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

Reddy's synthesis of fragment C8–C20 of (–)-zampanolide.
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sch43: Reddy's synthesis of fragment C8–C20 of (–)-zampanolide.

Mentions: Reddy and co-workers reported a new synthetic route for the known pyran-containing subunit 38 (ref. 85) that had been synthesized by Hoye and co-workers.18 The synthesis began with the known Weinreb amide 201 (Scheme 43), which was obtained in four steps from l-malic acid following a reported protocol.86 The initial four-carbon extension was achieved by the addition of homopropargyl benzyl ether (202) to Weinreb amide 201, which gave the desired alkynone 203. Key cyclization of the alkynone gave pyranone 204. THP 205 was obtained from 204via sequential reduction, DDQ benzyl removal, oxidation, and Wittig olefination. Conversion of 205 to ester 206 was achieved by a deprotection–oxidation–Wittig reaction sequence. Bromide 207 was achieved by reduction of ester 206 and subsequent treatment with CBr4 and PPh3. A three-carbon unit was introduced to compound 207 through a CuI/K2CO3/NaI-mediated coupling reaction to give 208. Reduction of the alkyne to the desired trans-olefin followed by Sharpless asymmetric epoxidation gave target compound 38.


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

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

Reddy's synthesis of fragment C8–C20 of (–)-zampanolide.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

sch43: Reddy's synthesis of fragment C8–C20 of (–)-zampanolide.
Mentions: Reddy and co-workers reported a new synthetic route for the known pyran-containing subunit 38 (ref. 85) that had been synthesized by Hoye and co-workers.18 The synthesis began with the known Weinreb amide 201 (Scheme 43), which was obtained in four steps from l-malic acid following a reported protocol.86 The initial four-carbon extension was achieved by the addition of homopropargyl benzyl ether (202) to Weinreb amide 201, which gave the desired alkynone 203. Key cyclization of the alkynone gave pyranone 204. THP 205 was obtained from 204via sequential reduction, DDQ benzyl removal, oxidation, and Wittig olefination. Conversion of 205 to ester 206 was achieved by a deprotection–oxidation–Wittig reaction sequence. Bromide 207 was achieved by reduction of ester 206 and subsequent treatment with CBr4 and PPh3. A three-carbon unit was introduced to compound 207 through a CuI/K2CO3/NaI-mediated coupling reaction to give 208. Reduction of the alkyne to the desired trans-olefin followed by Sharpless asymmetric epoxidation gave target compound 38.

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