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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

Ghosh's total synthesis of (–)-zampanolide.
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sch38: Ghosh's total synthesis of (–)-zampanolide.

Mentions: The Ghosh group accomplished an enantioselective total synthesis of 1 using a novel DDQ/Bronsted acid promoted cyclization as the key reaction.78 Their retrosynthetic analysis is shown in Scheme 35.16,24 The strategic bond disconnection of the side chain at C20 provides macrolactone 167, which can be constructed from the C9–C20 fragment 169 and the C1–C8 fragment 168 by Yamaguchi esterification followed by RCM. A similar RCM strategy was first employed by Hoye.18 The double bond at C16–C17 in the C9–C20 fragment 169 could be installed by a cross metathesis reaction, and the THP ring could be constructed by an oxidative cyclization reaction. Fragment C1–C8 (168) could be built by Reformatsky reaction followed by Wittig olefination. As shown in Scheme 36, the synthesis commenced with known ester 170.79 Selective protection followed by esterification with tert-butyl cinnamyl carbonate (171) catalyzed by Pd(PPh3)4 afforded cinnamyl ether 172, which was converted to allylsilane 173 employing the procedure modified by Narayanan and Bunnelle.80 Oxidative cyclization of 173 with DDQ catalyzed by PPTS constructed the 4-methylene-THP ring in 174 stereoselectively and efficiently, presumably due to the Zimmerman–Traxler transition state where all substituents are equatorially oriented. Disubstituted olefin 174 was converted to monosubstituted olefin 175via a three-step sequence. Olefin 176 was obtained by opening PMB-protected glycidol with isopropenylmagnesium bromide followed by alcohol protection as TES ether. Grubbs cross-metathesis of 175 with 176 provided an E/Z olefin mixture (1.7 : 1). Removal of all silyl groups followed by chromatographic purification provided trisubstituted olefin 177. Selective oxidation followed by Wittig olefination generated 169. The synthesis of the C1–C8 fragment (Scheme 37) began with the preparation of allyl bromide 178,81 which was subjected to Reformatsky reaction with acrolein to give unsaturated δ-lactone 179. DIBAL-H reduction followed by Wittig reaction afforded allylic alcohol 180. Fragment C1–C8 (168) was prepared from 180 through a protection-saponification sequence. The completion of the synthesis (Scheme 38) started with Yamaguchi esterification of acid 168 with alcohol 169 to furnish 181, which was subjected to Grubbs RCM reaction. The subsequent macrolactone was converted to 3 by a deprotection–oxidation sequence. The conversion of 3 to 1 was completed by treatment of aldehyde 3 with amide 123 in the presence of (S)-TRIP (182) in 51% yield.


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

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

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

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

sch38: Ghosh's total synthesis of (–)-zampanolide.
Mentions: The Ghosh group accomplished an enantioselective total synthesis of 1 using a novel DDQ/Bronsted acid promoted cyclization as the key reaction.78 Their retrosynthetic analysis is shown in Scheme 35.16,24 The strategic bond disconnection of the side chain at C20 provides macrolactone 167, which can be constructed from the C9–C20 fragment 169 and the C1–C8 fragment 168 by Yamaguchi esterification followed by RCM. A similar RCM strategy was first employed by Hoye.18 The double bond at C16–C17 in the C9–C20 fragment 169 could be installed by a cross metathesis reaction, and the THP ring could be constructed by an oxidative cyclization reaction. Fragment C1–C8 (168) could be built by Reformatsky reaction followed by Wittig olefination. As shown in Scheme 36, the synthesis commenced with known ester 170.79 Selective protection followed by esterification with tert-butyl cinnamyl carbonate (171) catalyzed by Pd(PPh3)4 afforded cinnamyl ether 172, which was converted to allylsilane 173 employing the procedure modified by Narayanan and Bunnelle.80 Oxidative cyclization of 173 with DDQ catalyzed by PPTS constructed the 4-methylene-THP ring in 174 stereoselectively and efficiently, presumably due to the Zimmerman–Traxler transition state where all substituents are equatorially oriented. Disubstituted olefin 174 was converted to monosubstituted olefin 175via a three-step sequence. Olefin 176 was obtained by opening PMB-protected glycidol with isopropenylmagnesium bromide followed by alcohol protection as TES ether. Grubbs cross-metathesis of 175 with 176 provided an E/Z olefin mixture (1.7 : 1). Removal of all silyl groups followed by chromatographic purification provided trisubstituted olefin 177. Selective oxidation followed by Wittig olefination generated 169. The synthesis of the C1–C8 fragment (Scheme 37) began with the preparation of allyl bromide 178,81 which was subjected to Reformatsky reaction with acrolein to give unsaturated δ-lactone 179. DIBAL-H reduction followed by Wittig reaction afforded allylic alcohol 180. Fragment C1–C8 (168) was prepared from 180 through a protection-saponification sequence. The completion of the synthesis (Scheme 38) started with Yamaguchi esterification of acid 168 with alcohol 169 to furnish 181, which was subjected to Grubbs RCM reaction. The subsequent macrolactone was converted to 3 by a deprotection–oxidation sequence. The conversion of 3 to 1 was completed by treatment of aldehyde 3 with amide 123 in the presence of (S)-TRIP (182) in 51% yield.

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