Limits...
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.

Show MeSH

Related in: MedlinePlus

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

License
getmorefigures.php?uid=PMC4126874&req=5

sch26: Uenishi's retrosynthetic analysis of (–)-zampanolide.

Mentions: Uenishi's retrosynthetic strategy is illustrated in Scheme 26.11 The side chain of 1 could be introduced by acid-catalyzed N-hemiacetalization of 3 with amide 123. The macrolactone ring could be constructed using HWE reaction and macrolactonization as critical reactions. As shown in Scheme 27, the synthesis of the C9–C20 fragment commenced from ring opening of PMB protected (R)-glycidol with vinyllithium 126 (prepared from the corresponding stannane67 and BuLi). The subsequent product was protected as its pivaloate ether and converted to enal 128 by a two-step procedure. Allylsilane 129 was prepared from aldehyde 92 through the three-step sequence of dibromomethylenation, Kumada–Tamao–Corriu coupling with TMSCH2MgCl, and protodesilylation. The Hosomi–Sakurai reaction of 128 with 129 promoted by SnCl4 afforded the desired 131 (15S) in 47% yield as well as its isomer 130 (15R) in 42% yield; the latter could be converted to 131 in 65% yield by Mitsunobu reaction followed by methanolysis. Transformation of 131 to 132 proceeded through an efficient five-step sequence in 76% overall yield. The THP ring in 124 was built by intramolecular O-Michael reaction; the subsequent ester was reduced with DIBALH, with concomitant removal of the pivaloate group, to provide the C9–C20 fragment (124). The preparation of the C1–C8 fragment (125) started with dibromomethylenation of aldehyde 133 followed by stereoselective Sonogashira coupling with TMS-acetylene (Scheme 28). Introduction of a methyl group to alkyne 134via the Kumada–Tamao–Corriu coupling proceeded with the anticipated inversion of olefin geometry.68 Transformation of the terminal TMS-acetylene to ester 136 proceeded through a two-step sequence. Another four-step sequence including TIPS ether removal, diethyl methylphosphonate introduction, and oxidations completed the synthesis of 125. The syntheses of 3 and 1 were completed as shown in Scheme 28. The HWE reaction of aldehyde 124 and β-ketophosponate 125 provided seco acid 137, which was subjected to cyclization using the Trost–Kita method to generate a macrolactone. Dactylolide (3) was readily prepared from the macrolactone via a two-step sequence. Treatment of 3 with hexadienoylamide 123 catalyzed by CSA afforded 1 in 12% yield.


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

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

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

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

sch26: Uenishi's retrosynthetic analysis of (–)-zampanolide.
Mentions: Uenishi's retrosynthetic strategy is illustrated in Scheme 26.11 The side chain of 1 could be introduced by acid-catalyzed N-hemiacetalization of 3 with amide 123. The macrolactone ring could be constructed using HWE reaction and macrolactonization as critical reactions. As shown in Scheme 27, the synthesis of the C9–C20 fragment commenced from ring opening of PMB protected (R)-glycidol with vinyllithium 126 (prepared from the corresponding stannane67 and BuLi). The subsequent product was protected as its pivaloate ether and converted to enal 128 by a two-step procedure. Allylsilane 129 was prepared from aldehyde 92 through the three-step sequence of dibromomethylenation, Kumada–Tamao–Corriu coupling with TMSCH2MgCl, and protodesilylation. The Hosomi–Sakurai reaction of 128 with 129 promoted by SnCl4 afforded the desired 131 (15S) in 47% yield as well as its isomer 130 (15R) in 42% yield; the latter could be converted to 131 in 65% yield by Mitsunobu reaction followed by methanolysis. Transformation of 131 to 132 proceeded through an efficient five-step sequence in 76% overall yield. The THP ring in 124 was built by intramolecular O-Michael reaction; the subsequent ester was reduced with DIBALH, with concomitant removal of the pivaloate group, to provide the C9–C20 fragment (124). The preparation of the C1–C8 fragment (125) started with dibromomethylenation of aldehyde 133 followed by stereoselective Sonogashira coupling with TMS-acetylene (Scheme 28). Introduction of a methyl group to alkyne 134via the Kumada–Tamao–Corriu coupling proceeded with the anticipated inversion of olefin geometry.68 Transformation of the terminal TMS-acetylene to ester 136 proceeded through a two-step sequence. Another four-step sequence including TIPS ether removal, diethyl methylphosphonate introduction, and oxidations completed the synthesis of 125. The syntheses of 3 and 1 were completed as shown in Scheme 28. The HWE reaction of aldehyde 124 and β-ketophosponate 125 provided seco acid 137, which was subjected to cyclization using the Trost–Kita method to generate a macrolactone. Dactylolide (3) was readily prepared from the macrolactone via a two-step sequence. Treatment of 3 with hexadienoylamide 123 catalyzed by CSA afforded 1 in 12% 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