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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

Hoye's alternative total synthesis of (–)-dactylolide and (–)-zampanolide.
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sch8: Hoye's alternative total synthesis of (–)-dactylolide and (–)-zampanolide.

Mentions: Hoye and co-workers completed their syntheses of (–)-dactylolide (3)18 using two strategies: (i) a novel Ti(iv)-mediated macrolactonization of an epoxy-acid (route A); and (ii) a complementary ring-closing metathesis (RCM) macrocyclization (route B) (Scheme 5). The fragment C9–C20 was constructed using Hosomi–Sakurai–Prins (HSP) cyclization as a key reaction (Scheme 6).49 The 2,6-cis-THP 42, which was readily converted into aldehyde 43, was exclusively generated by the HSP cyclization reaction49 of enal 40 with allyl silane 41 (ref. 50) catalyzed by a protic acid. As shown in Scheme 7, aldehyde 43 was converted to epoxide 36 through a three-step sequence including Takai iodoalkenylation, desilylation, and Sharpless asymmetric epoxidation. Reaction of the alkenyllithium, prepared from epoxide 36 by protection followed by halogen–lithium exchange reaction, with aldehyde 37 generated fragment C1–C20 (44), which was converted into epoxy-carboxylic acid 45 in a five-step sequence. Macrolactone 46 was achieved by treating 45 with Ti(Oi-Pr)4 under high dilution conditions. Sequential desilylation, oxidation of allylic alcohol, and oxidative cleavage of the C20–C21 diol generated 3. Hoye's alternative and more convergent synthesis of 3 as well as its subsequent conversion to 1 is shown in Scheme 8. Olefin 38, prepared from aldehyde 43, was coupled with trienoic acid 39 catalyzed by Ti(Ot-Bu)4 to give diene precursor 49. After protection of the vicinal diol in situ with excess bis-trimethylsilylacetamide, Grubbs RCM generated macrolactone 46 with an E-geometry of the C8–C9 alkene.


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

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

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

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

sch8: Hoye's alternative total synthesis of (–)-dactylolide and (–)-zampanolide.
Mentions: Hoye and co-workers completed their syntheses of (–)-dactylolide (3)18 using two strategies: (i) a novel Ti(iv)-mediated macrolactonization of an epoxy-acid (route A); and (ii) a complementary ring-closing metathesis (RCM) macrocyclization (route B) (Scheme 5). The fragment C9–C20 was constructed using Hosomi–Sakurai–Prins (HSP) cyclization as a key reaction (Scheme 6).49 The 2,6-cis-THP 42, which was readily converted into aldehyde 43, was exclusively generated by the HSP cyclization reaction49 of enal 40 with allyl silane 41 (ref. 50) catalyzed by a protic acid. As shown in Scheme 7, aldehyde 43 was converted to epoxide 36 through a three-step sequence including Takai iodoalkenylation, desilylation, and Sharpless asymmetric epoxidation. Reaction of the alkenyllithium, prepared from epoxide 36 by protection followed by halogen–lithium exchange reaction, with aldehyde 37 generated fragment C1–C20 (44), which was converted into epoxy-carboxylic acid 45 in a five-step sequence. Macrolactone 46 was achieved by treating 45 with Ti(Oi-Pr)4 under high dilution conditions. Sequential desilylation, oxidation of allylic alcohol, and oxidative cleavage of the C20–C21 diol generated 3. Hoye's alternative and more convergent synthesis of 3 as well as its subsequent conversion to 1 is shown in Scheme 8. Olefin 38, prepared from aldehyde 43, was coupled with trienoic acid 39 catalyzed by Ti(Ot-Bu)4 to give diene precursor 49. After protection of the vicinal diol in situ with excess bis-trimethylsilylacetamide, Grubbs RCM generated macrolactone 46 with an E-geometry of the C8–C9 alkene.

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