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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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Altmann's retrosynthetic analysis of (–)-dactylolide.
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sch39: Altmann's retrosynthetic analysis of (–)-dactylolide.

Mentions: Altmann's retrosynthetic analysis for 3 (Scheme 39) is centred on HWE macrocyclization involving the formation of the C8–C9 double bond.17,82 The requisite precursor would be obtained via ester formation between the C1–C8 fragment (183) and the C9–C20 fragment (184). The synthesis of the C9–C20 fragment 184 started with the Cu-mediated regioselective epoxide opening of 185, prepared from (R)-aspartic acid in three steps, with vinyl-MgBr (Scheme 40). Alcohol 186 was then elaborated into THP 188 in a highly stereoselective Prins-type reaction employing a segment coupling approach as developed by Rychnovsky.83 In a first step, this involved esterification of 186 with 2-butynoic acid, which was followed by DIBAL-H reduction of the ester and trapping of the aluminated intermediate at –78 °C with Ac2O to furnish 187. Treatment of 187 with TMSI gave substituted THP 188 with the desired 2,6-syn relationship and the iodine located anti to the substituents in the 2- and 6-positions. This is in line with previous observations by Rychnovsky for related transformations. Conversion of 188 to 189 was achieved by a four-step sequence: iodide displacement with CsOAc/18-crown-6, hydrolysis, Swern oxidation, and Wittig reaction. Conversion of 189 to the desired E-vinyl iodide 190 was achieved with Bu3Sn(Bu)CuCNLi2 generated in situ followed by Sn–I exchange with NIS. Reaction of vinyl iodide 190 with PMB-protected (R)-glycidol 191 generated fragment C9–C20 (184). Unsaturated acid 183 was prepared by coupling of lithiated Z-vinyl iodide 192 (obtained in two steps from 2-butynol) and epichlorohydrin mediated by BF3·OEt2 (Scheme 41). Treatment of 193 with base followed by BF3-mediated epoxide opening with lithiated diethylphosphite gave β-hydroxyphosphonate 194, which was converted to aldehyde 195 through a protection–deprotection–oxidation sequence. HWE reaction followed by basic hydrolysis then afforded the desired acid 183. The final assembly of (–)-dactylolide commenced with esterification of alcohol 184 with acid 183 (Scheme 41) under Yamaguchi conditions to give an ester which was converted to HWE precursor 196 through a global desilylation–oxidation sequence. Ring-closure step was achieved with Ba(OH)2 as an optimized base and the synthesis of 3 was completed by PMB removal and DMP oxidation.


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

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

Altmann's retrosynthetic analysis of (–)-dactylolide.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

sch39: Altmann's retrosynthetic analysis of (–)-dactylolide.
Mentions: Altmann's retrosynthetic analysis for 3 (Scheme 39) is centred on HWE macrocyclization involving the formation of the C8–C9 double bond.17,82 The requisite precursor would be obtained via ester formation between the C1–C8 fragment (183) and the C9–C20 fragment (184). The synthesis of the C9–C20 fragment 184 started with the Cu-mediated regioselective epoxide opening of 185, prepared from (R)-aspartic acid in three steps, with vinyl-MgBr (Scheme 40). Alcohol 186 was then elaborated into THP 188 in a highly stereoselective Prins-type reaction employing a segment coupling approach as developed by Rychnovsky.83 In a first step, this involved esterification of 186 with 2-butynoic acid, which was followed by DIBAL-H reduction of the ester and trapping of the aluminated intermediate at –78 °C with Ac2O to furnish 187. Treatment of 187 with TMSI gave substituted THP 188 with the desired 2,6-syn relationship and the iodine located anti to the substituents in the 2- and 6-positions. This is in line with previous observations by Rychnovsky for related transformations. Conversion of 188 to 189 was achieved by a four-step sequence: iodide displacement with CsOAc/18-crown-6, hydrolysis, Swern oxidation, and Wittig reaction. Conversion of 189 to the desired E-vinyl iodide 190 was achieved with Bu3Sn(Bu)CuCNLi2 generated in situ followed by Sn–I exchange with NIS. Reaction of vinyl iodide 190 with PMB-protected (R)-glycidol 191 generated fragment C9–C20 (184). Unsaturated acid 183 was prepared by coupling of lithiated Z-vinyl iodide 192 (obtained in two steps from 2-butynol) and epichlorohydrin mediated by BF3·OEt2 (Scheme 41). Treatment of 193 with base followed by BF3-mediated epoxide opening with lithiated diethylphosphite gave β-hydroxyphosphonate 194, which was converted to aldehyde 195 through a protection–deprotection–oxidation sequence. HWE reaction followed by basic hydrolysis then afforded the desired acid 183. The final assembly of (–)-dactylolide commenced with esterification of alcohol 184 with acid 183 (Scheme 41) under Yamaguchi conditions to give an ester which was converted to HWE precursor 196 through a global desilylation–oxidation sequence. Ring-closure step was achieved with Ba(OH)2 as an optimized base and the synthesis of 3 was completed by PMB removal and DMP oxidation.

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