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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

Keck's synthesis of fragment C9–C20 of (+)-dactylolide.
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sch17: Keck's synthesis of fragment C9–C20 of (+)-dactylolide.

Mentions: Keck constructed the macrolactone core using HWE macrocyclization and the HSP reaction, featuring construction of two asymmetric centres via his catalytic asymmetric allylation reaction and a diastereoselective pyran annulation (Scheme 16).53 The preparation of fragment C9–C20 (77) is shown in Scheme 17. Asymmetric allylation of aldehyde 79 with allylstannane 80 catalyzed by BINOL titanium tetraisopropoxide (BITIP) gave (R)-homoallylic alcohol 81 in 93% ee. Isomerization to the (E)-unsaturated aldehyde 82 (32 : 1) was achieved by protection of the hydroxyl group, treatment with NaH, and a two-step reduction (Scheme 17). Keck and co-workers believed that the observed high stereoselectivity is a kinetic phenomenon associated with a preferred pathway for formation of the U shaped internally chelated enolate anion with sodium as counterion. Fragment C9–C14 (85) was prepared by asymmetric allylation of aldehyde 83 and allyl stannane 84 catalyzed by (S)-BITIP in 95% ee (Scheme 17). Fragment C9–C20 (77) was prepared by the HSP reaction between 82 and 85 followed by a deprotection–oxidation procedure. The synthesis of fragment C3–C8 (78) began with intermediate 86 (ref. 54) (Scheme 18). Transformation of ester 86 to silyl ether 87 was carried out via a three-step sequence. The desired β-ketophosphonate 78 was achieved via another three-step sequence including oxidation, addition of the lithiate of methyl dimethyl phosphonate into this aldehyde, and oxidation of the resulting alcohol. HWE olefination of 77 with 78 under Peterson's conditions provided (E)-enone 88. To avoid the possibility that the acidity of C6–H might cause C7 enolization, the ketone at C7 was converted to its PMB ether, which was selected by Keck because both PMB groups (at C7 and C20) could be deprotected and both alcohols oxidized in the same operation at the later stage. Next, phosphonoacetate 89 was prepared by selective deprotection and modified Keck–Boden macrolactonization.55 A polymer-bound DCC (PS-DCC) rather than DCC itself was used to simplify the workup and purification due to the polarity of the phosphonate. Intramolecular HWE macrolactonization followed by PMB deprotection and double oxidation afforded 4 (Scheme 18).


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

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

Keck's synthesis of fragment C9–C20 of (+)-dactylolide.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

sch17: Keck's synthesis of fragment C9–C20 of (+)-dactylolide.
Mentions: Keck constructed the macrolactone core using HWE macrocyclization and the HSP reaction, featuring construction of two asymmetric centres via his catalytic asymmetric allylation reaction and a diastereoselective pyran annulation (Scheme 16).53 The preparation of fragment C9–C20 (77) is shown in Scheme 17. Asymmetric allylation of aldehyde 79 with allylstannane 80 catalyzed by BINOL titanium tetraisopropoxide (BITIP) gave (R)-homoallylic alcohol 81 in 93% ee. Isomerization to the (E)-unsaturated aldehyde 82 (32 : 1) was achieved by protection of the hydroxyl group, treatment with NaH, and a two-step reduction (Scheme 17). Keck and co-workers believed that the observed high stereoselectivity is a kinetic phenomenon associated with a preferred pathway for formation of the U shaped internally chelated enolate anion with sodium as counterion. Fragment C9–C14 (85) was prepared by asymmetric allylation of aldehyde 83 and allyl stannane 84 catalyzed by (S)-BITIP in 95% ee (Scheme 17). Fragment C9–C20 (77) was prepared by the HSP reaction between 82 and 85 followed by a deprotection–oxidation procedure. The synthesis of fragment C3–C8 (78) began with intermediate 86 (ref. 54) (Scheme 18). Transformation of ester 86 to silyl ether 87 was carried out via a three-step sequence. The desired β-ketophosphonate 78 was achieved via another three-step sequence including oxidation, addition of the lithiate of methyl dimethyl phosphonate into this aldehyde, and oxidation of the resulting alcohol. HWE olefination of 77 with 78 under Peterson's conditions provided (E)-enone 88. To avoid the possibility that the acidity of C6–H might cause C7 enolization, the ketone at C7 was converted to its PMB ether, which was selected by Keck because both PMB groups (at C7 and C20) could be deprotected and both alcohols oxidized in the same operation at the later stage. Next, phosphonoacetate 89 was prepared by selective deprotection and modified Keck–Boden macrolactonization.55 A polymer-bound DCC (PS-DCC) rather than DCC itself was used to simplify the workup and purification due to the polarity of the phosphonate. Intramolecular HWE macrolactonization followed by PMB deprotection and double oxidation afforded 4 (Scheme 18).

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