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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

Lee's total synthesis of (–)-dactylolide.
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sch31: Lee's total synthesis of (–)-dactylolide.

Mentions: Lee's retrosynthetic analysis, as shown in Scheme 29, features the construction of C–C and C–O bonds by transition-metal-catalyzed reactions in the hope of minimizing the need for functional group transformations and protection–deprotection steps.69,70 They envisioned closing the macrolactone ring through a late-stage RCM reaction at C16–C17. The C3–C4 bond was planned to be synthesized through a Suzuki–Miyaura coupling of iodoacylate 138 and a cyclic boronic acid half ester 139. This could be accessed through the ruthenium-catalyzed Alder-ene reaction (RCAER)71 and allylic [1,3]-transposition.72 The pyran subunit in 139 would be installed using a tandem RCAER and palladium-catalyzed ring closure. The synthesis of the C4–C16 fragment 139 commenced with the RCAER between ethyl carbonate 140 and homopropargylic alcohol 141 (Scheme 30).73 The product was treated with palladium catalyst in the presence of Trost's chiral (+)-DPPBA ligand to afford 2,6-cis-disubstituted THP 142, which was readily converted to aldehyde 143 through a deprotection–oxidation sequence. Leighton allylation followed by TBS protection afforded homoallyl silyl ether 144. The RCAER of alkynyl boronate 145 occurred selectively with the least hindered double bond at C7 of 144, and afforded vinyl boronate 146. Cyclic boronic acid half ester 139 was obtained by the 1,3-transposition of the allyl alcohol of 146 with rhenium oxide.74 2-Iodoacrylate 138, the Suzuki coupling partner, was prepared from TBS-protected (S)-glycidol 147 through the sequence shown in Scheme 31. Ester 138 was synthesized by ring opening with 2-propenylmagnesium chloride followed by Mitsunobu reaction of 148 with 2-iodoacrylic acid 149. Suzuki coupling between 138 and 139 followed by a four-step sequence delivered (–)-dactylolide.


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

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

Lee's total synthesis of (–)-dactylolide.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

sch31: Lee's total synthesis of (–)-dactylolide.
Mentions: Lee's retrosynthetic analysis, as shown in Scheme 29, features the construction of C–C and C–O bonds by transition-metal-catalyzed reactions in the hope of minimizing the need for functional group transformations and protection–deprotection steps.69,70 They envisioned closing the macrolactone ring through a late-stage RCM reaction at C16–C17. The C3–C4 bond was planned to be synthesized through a Suzuki–Miyaura coupling of iodoacylate 138 and a cyclic boronic acid half ester 139. This could be accessed through the ruthenium-catalyzed Alder-ene reaction (RCAER)71 and allylic [1,3]-transposition.72 The pyran subunit in 139 would be installed using a tandem RCAER and palladium-catalyzed ring closure. The synthesis of the C4–C16 fragment 139 commenced with the RCAER between ethyl carbonate 140 and homopropargylic alcohol 141 (Scheme 30).73 The product was treated with palladium catalyst in the presence of Trost's chiral (+)-DPPBA ligand to afford 2,6-cis-disubstituted THP 142, which was readily converted to aldehyde 143 through a deprotection–oxidation sequence. Leighton allylation followed by TBS protection afforded homoallyl silyl ether 144. The RCAER of alkynyl boronate 145 occurred selectively with the least hindered double bond at C7 of 144, and afforded vinyl boronate 146. Cyclic boronic acid half ester 139 was obtained by the 1,3-transposition of the allyl alcohol of 146 with rhenium oxide.74 2-Iodoacrylate 138, the Suzuki coupling partner, was prepared from TBS-protected (S)-glycidol 147 through the sequence shown in Scheme 31. Ester 138 was synthesized by ring opening with 2-propenylmagnesium chloride followed by Mitsunobu reaction of 148 with 2-iodoacrylic acid 149. Suzuki coupling between 138 and 139 followed by a four-step sequence delivered (–)-dactylolide.

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