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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

Hong's retrosynthetic analysis of (+)-dactylolide.
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sch32: Hong's retrosynthetic analysis of (+)-dactylolide.

Mentions: (+)-Dactylolide (4) was synthesized by the Hong group from 1,3-dithiane, featuring the 1,6-oxa conjugate addition reaction of a 2,4-dienal for the facile synthesis of the 2,6-cis-THP subunit, the umpolung alkylation reaction of a cyanohydrin, and the N-heterocyclic carbene (NHC)-catalyzed oxidative macrolactonization reaction.75 Hong's retrosynthetic plan for 4 is outlined in Scheme 32. The macrolactone core could be constructed from the C1–C6 fragment (152) and the C7–C20 fragment (151) by intramolecular oxidative macrolactonization of ω-hydroxy aldehyde catalyzed by an NHC and umpolung alkylation of cyanohydrin. The synthesis of the C7–C20 fragment is shown in Scheme 33. The coupling of the dithiane 155, prepared from dithiane 153,76 with dienyl chloride 157 (ref. 77) mediated by nBuLi–nBu2Mg provided 158, which was converted to aldehyde 159 through a deprotection–oxidation sequence. Stereoselective installation of the C15 secondary carbinol by an asymmetric organozinc addition, avoiding the possible chelation of the oxygen atoms to zinc, required slow addition of 159 to a mixture of the corresponding bromozinc reagent of 160 and lithiated (1S, 2R)-NME. This procedure provided 161 in good stereoselectivity (dr = 7.7 : 1), and this was subjected to organocatalytic 1,6-oxa conjugate addition reaction catalyzed by (S)-162 to provide the desired 2,6-cis-THP 151 with excellent stereoselectivity and yield, representing the first successful example of THP construction through an intramolecular 1,6-oxa conjugate addition reaction. Hong and co-workers proceeded to install the C1–C6 fragment using an acyl anion equivalent (Scheme 34). The TBS-protected cyanohydrin 163, prepared from 151, was coupled with dienyl chloride 152 followed by concomitant PMB removal and oxidation at C1 to generate ω-hydroxy aldehyde 164. NHC-catalyzed oxidative macrolactonization of 164 provided macrolactone 165. This represents the first example of NHC-catalyzed oxidative macrolactonization of a ω-hydroxy aldehyde. The synthesis of 4 was completed by elaborating the C13 exo-methylene group, unveiling the C7 carbonyl group, and oxidizing the C20 hydroxyl group.


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

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

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

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

sch32: Hong's retrosynthetic analysis of (+)-dactylolide.
Mentions: (+)-Dactylolide (4) was synthesized by the Hong group from 1,3-dithiane, featuring the 1,6-oxa conjugate addition reaction of a 2,4-dienal for the facile synthesis of the 2,6-cis-THP subunit, the umpolung alkylation reaction of a cyanohydrin, and the N-heterocyclic carbene (NHC)-catalyzed oxidative macrolactonization reaction.75 Hong's retrosynthetic plan for 4 is outlined in Scheme 32. The macrolactone core could be constructed from the C1–C6 fragment (152) and the C7–C20 fragment (151) by intramolecular oxidative macrolactonization of ω-hydroxy aldehyde catalyzed by an NHC and umpolung alkylation of cyanohydrin. The synthesis of the C7–C20 fragment is shown in Scheme 33. The coupling of the dithiane 155, prepared from dithiane 153,76 with dienyl chloride 157 (ref. 77) mediated by nBuLi–nBu2Mg provided 158, which was converted to aldehyde 159 through a deprotection–oxidation sequence. Stereoselective installation of the C15 secondary carbinol by an asymmetric organozinc addition, avoiding the possible chelation of the oxygen atoms to zinc, required slow addition of 159 to a mixture of the corresponding bromozinc reagent of 160 and lithiated (1S, 2R)-NME. This procedure provided 161 in good stereoselectivity (dr = 7.7 : 1), and this was subjected to organocatalytic 1,6-oxa conjugate addition reaction catalyzed by (S)-162 to provide the desired 2,6-cis-THP 151 with excellent stereoselectivity and yield, representing the first successful example of THP construction through an intramolecular 1,6-oxa conjugate addition reaction. Hong and co-workers proceeded to install the C1–C6 fragment using an acyl anion equivalent (Scheme 34). The TBS-protected cyanohydrin 163, prepared from 151, was coupled with dienyl chloride 152 followed by concomitant PMB removal and oxidation at C1 to generate ω-hydroxy aldehyde 164. NHC-catalyzed oxidative macrolactonization of 164 provided macrolactone 165. This represents the first example of NHC-catalyzed oxidative macrolactonization of a ω-hydroxy aldehyde. The synthesis of 4 was completed by elaborating the C13 exo-methylene group, unveiling the C7 carbonyl group, and oxidizing the C20 hydroxyl group.

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