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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

McLeod's synthesis of fragment C9–C20 of (–)-dactylolide.
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sch20: McLeod's synthesis of fragment C9–C20 of (–)-dactylolide.

Mentions: McLeod reported an enantioselective synthesis of (–)-dactylolide, featuring the construction of the 2,6-cis-THP by catalytic asymmetric Jacobsen hetero-Diels–Alder reaction,56 and the remote C19 chiral centre by a sequence of chelation-controlled Grignard addition and Ireland–Claisen rearrangement.20 As shown in the retrosynthetic analysis (Scheme 19), the macrolactone core was constructed by convergent coupling of fragment C1–C8 (90) and fragment C9–C20 (91) using a sequence of Mitsunobu esterification followed by Grubbs' RCM. The synthesis of 1 (Scheme 20) began with the linkage of aldehyde 92 and silyl enol ether 93 mediated by Jacobsen's chiral tridentate chromium(iii) catalyst 94. THP 95 can be synthesized on a multigram scale by careful workup followed by PMB removal. Diene 96 was synthesized through a three-step procedure including oxidation, Wittig methylenation, and silyl ether deprotection. Nucleophilic addition of isopropenyl Grignard to the aldehyde obtained by oxidation of 96 proceeded with chelation control to favour formation of 97 with the 16S-configuration. Alcohol 97 was then converted to ester 99via esterification with PMB protected glycolic acid 98. Direct reduction of a crude product of the polar carboxylic acid derived from the Ireland–Claisen [3,3] sigmatropic rearrangement of ester 99 gave alcohol 100 as a single diastereomer. Alcohol 100 was converted to alcohol 91 through a simple protection–deprotection procedure. Synthesis of trienoic acid 90 was completed (Scheme 21) in seven steps from acrylate ester 101 (ref. 57) with trisubstituted Z-alkene established via a six-membered lactone intermediate 102. Direct Wittig reaction of the lactol derived from partial reduction of lactone 102 with ylide 103 afforded (2E, 4Z)-diene ester 104. The aldehyde, derived from 104, reacted with vinylcerium reagent, followed by a protection–hydrolysis procedure, to afford fragment C1–C8 (90). The final stage synthesis is shown in Scheme 22. Mitsunobu esterification provided ester 105. The diene precursor, derived from 105, was subjected to a Grubbs RCM reaction to afford macrocyclic diols 106, which were subjected to global oxidation to give (–)-dactylolide 3.


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

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

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

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

sch20: McLeod's synthesis of fragment C9–C20 of (–)-dactylolide.
Mentions: McLeod reported an enantioselective synthesis of (–)-dactylolide, featuring the construction of the 2,6-cis-THP by catalytic asymmetric Jacobsen hetero-Diels–Alder reaction,56 and the remote C19 chiral centre by a sequence of chelation-controlled Grignard addition and Ireland–Claisen rearrangement.20 As shown in the retrosynthetic analysis (Scheme 19), the macrolactone core was constructed by convergent coupling of fragment C1–C8 (90) and fragment C9–C20 (91) using a sequence of Mitsunobu esterification followed by Grubbs' RCM. The synthesis of 1 (Scheme 20) began with the linkage of aldehyde 92 and silyl enol ether 93 mediated by Jacobsen's chiral tridentate chromium(iii) catalyst 94. THP 95 can be synthesized on a multigram scale by careful workup followed by PMB removal. Diene 96 was synthesized through a three-step procedure including oxidation, Wittig methylenation, and silyl ether deprotection. Nucleophilic addition of isopropenyl Grignard to the aldehyde obtained by oxidation of 96 proceeded with chelation control to favour formation of 97 with the 16S-configuration. Alcohol 97 was then converted to ester 99via esterification with PMB protected glycolic acid 98. Direct reduction of a crude product of the polar carboxylic acid derived from the Ireland–Claisen [3,3] sigmatropic rearrangement of ester 99 gave alcohol 100 as a single diastereomer. Alcohol 100 was converted to alcohol 91 through a simple protection–deprotection procedure. Synthesis of trienoic acid 90 was completed (Scheme 21) in seven steps from acrylate ester 101 (ref. 57) with trisubstituted Z-alkene established via a six-membered lactone intermediate 102. Direct Wittig reaction of the lactol derived from partial reduction of lactone 102 with ylide 103 afforded (2E, 4Z)-diene ester 104. The aldehyde, derived from 104, reacted with vinylcerium reagent, followed by a protection–hydrolysis procedure, to afford fragment C1–C8 (90). The final stage synthesis is shown in Scheme 22. Mitsunobu esterification provided ester 105. The diene precursor, derived from 105, was subjected to a Grubbs RCM reaction to afford macrocyclic diols 106, which were subjected to global oxidation to give (–)-dactylolide 3.

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