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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

Jenning's synthesis of fragment C1–C8 of (–)-dactylolide.
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sch14: Jenning's synthesis of fragment C1–C8 of (–)-dactylolide.

Mentions: Jennings and co-workers constructed the macrolactone core structure by reaction of fragment C9–C20 (65) and fragment C1–C8 (66) by Yamaguchi esterification and RCM (Scheme 12).19,52 Fragment C9–C20 (65) was constructed via diastereoselective axial reduction of an oxonium cation, RCM of a divinyl ester, and introduction of an asymmetric centre by Brown's asymmetric allylation. As delineated in Scheme 13, the α,β-alkynyl ester 68, prepared from glycidol 67 in four steps, was converted to enal 69 through a 4-step sequence: Michael addition of thiolate, copper-mediated 1,4-addition–elimination, reduction, and oxidation. Brown's asymmetric allylation of 69 followed by esterification furnished acrylate ester 70. RCM of 70 followed by oxidation and reduction with PhSeH provided lactone 71. 2,6-cis-THP 72 was prepared by the nucleophilic addition of ester 71 followed by diastereoselective reduction of oxonium cation. Fragment C9–C20 (65) was obtained in a four-step sequence: oxidation, methylenation, deprotection, and protection. Jennings' approach to fragment C1–C8 features a diastereoselective HWE, as shown in Scheme 14. The diene precursor 76 was made by Yamaguchi esterification of alcohol 65 with carboxylic acid 66 (Scheme 15). After removal of the protecting groups at C7 and C20, the corresponding diene was subjected to Grubbs' RCM to generate the desired macrolactone. Finally, (–)-dactylolide was obtained by oxidation with Dess–Martin reagent.


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

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

Jenning's synthesis of fragment C1–C8 of (–)-dactylolide.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

sch14: Jenning's synthesis of fragment C1–C8 of (–)-dactylolide.
Mentions: Jennings and co-workers constructed the macrolactone core structure by reaction of fragment C9–C20 (65) and fragment C1–C8 (66) by Yamaguchi esterification and RCM (Scheme 12).19,52 Fragment C9–C20 (65) was constructed via diastereoselective axial reduction of an oxonium cation, RCM of a divinyl ester, and introduction of an asymmetric centre by Brown's asymmetric allylation. As delineated in Scheme 13, the α,β-alkynyl ester 68, prepared from glycidol 67 in four steps, was converted to enal 69 through a 4-step sequence: Michael addition of thiolate, copper-mediated 1,4-addition–elimination, reduction, and oxidation. Brown's asymmetric allylation of 69 followed by esterification furnished acrylate ester 70. RCM of 70 followed by oxidation and reduction with PhSeH provided lactone 71. 2,6-cis-THP 72 was prepared by the nucleophilic addition of ester 71 followed by diastereoselective reduction of oxonium cation. Fragment C9–C20 (65) was obtained in a four-step sequence: oxidation, methylenation, deprotection, and protection. Jennings' approach to fragment C1–C8 features a diastereoselective HWE, as shown in Scheme 14. The diene precursor 76 was made by Yamaguchi esterification of alcohol 65 with carboxylic acid 66 (Scheme 15). After removal of the protecting groups at C7 and C20, the corresponding diene was subjected to Grubbs' RCM to generate the desired macrolactone. Finally, (–)-dactylolide was obtained by oxidation with Dess–Martin reagent.

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