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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

Floreancig's total synthesis of (+)-dactylolide.
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sch11: Floreancig's total synthesis of (+)-dactylolide.

Mentions: Two key objectives to Floreancig's total synthesis of dactylolide were to maximize convergency and to minimize the number of carbon–carbon bond-forming reactions.21 They postulated that the former objective could be achieved through the union of two advanced fragments by an acetal linkage. They envisioned asymmetric vinylogous Mukaiyama aldol reactions to be effective vehicles for achieving the latter objective. As shown in Floreancig's retrosynthetic analysis (Scheme 9), macrocyclization could be achieved by a Horner–Wadsworth–Emmons (HWE) reaction, the same strategy used in Smith's synthesis.10,12,13 2,6-cis-THP in fragment C3–C20 (51) could be constructed via the sequential cyclization starting from acetal 52. Fragment C15–C20 (61) was prepared using the same procedure as described by Evans.51 Fragment C3–C13 (60) was synthesized using the procedure as illustrated in Scheme 10. The (Z)-vinyl stannane 54 was prepared from hydroalumination of alkyne 53 followed by stannylation. Coupling of stannane 54 with bromide 55 followed by hydrolysis generated enal 56. Ketal 59 was achieved in 93% ee through the asymmetric Mukaiyama aldol reaction of enal 56 with acetal 57 catalysed by Denmark's catalyst 58 and SiCl4. Fragment C3–C13 (60) was readily obtained by esterification of 59 followed by stereoselective reduction. Treatment of bis-TMS ether of 60 with aldehyde 61 mediated by TMSOTf provided the key acetal 62. 2,6-cis-THP 51 was prepared by Peterson olefination of 62 with excess TMSMgCl and CeCl3 followed by HSP cyclization catalysed by pyridinium triflate and MgSO4. The observed selectivity of kinetically facile 6-endo pathway over 8-endo pathway suggested that cyclization instead of ionization might be the product-determining step. Rearrangement of the C9 hydroxy group to C7 was achieved by a selenium variant of the Mislow–Evans rearrangement. Transformation from 51 to 63 was achieved in four steps. The corresponding phosphonoacetate, prepared by selective oxidation of allylic alcohol in 63 followed by esterification of C19 hydroxy group with phosphono acetic acid, underwent intramolecular HWE reaction mediated by NaHMDS to generate macrolactone 64. Finally, (+)-dactylolide was obtained through a deprotection–oxidation procedure (Scheme 11).


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

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

Floreancig's total synthesis of (+)-dactylolide.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

sch11: Floreancig's total synthesis of (+)-dactylolide.
Mentions: Two key objectives to Floreancig's total synthesis of dactylolide were to maximize convergency and to minimize the number of carbon–carbon bond-forming reactions.21 They postulated that the former objective could be achieved through the union of two advanced fragments by an acetal linkage. They envisioned asymmetric vinylogous Mukaiyama aldol reactions to be effective vehicles for achieving the latter objective. As shown in Floreancig's retrosynthetic analysis (Scheme 9), macrocyclization could be achieved by a Horner–Wadsworth–Emmons (HWE) reaction, the same strategy used in Smith's synthesis.10,12,13 2,6-cis-THP in fragment C3–C20 (51) could be constructed via the sequential cyclization starting from acetal 52. Fragment C15–C20 (61) was prepared using the same procedure as described by Evans.51 Fragment C3–C13 (60) was synthesized using the procedure as illustrated in Scheme 10. The (Z)-vinyl stannane 54 was prepared from hydroalumination of alkyne 53 followed by stannylation. Coupling of stannane 54 with bromide 55 followed by hydrolysis generated enal 56. Ketal 59 was achieved in 93% ee through the asymmetric Mukaiyama aldol reaction of enal 56 with acetal 57 catalysed by Denmark's catalyst 58 and SiCl4. Fragment C3–C13 (60) was readily obtained by esterification of 59 followed by stereoselective reduction. Treatment of bis-TMS ether of 60 with aldehyde 61 mediated by TMSOTf provided the key acetal 62. 2,6-cis-THP 51 was prepared by Peterson olefination of 62 with excess TMSMgCl and CeCl3 followed by HSP cyclization catalysed by pyridinium triflate and MgSO4. The observed selectivity of kinetically facile 6-endo pathway over 8-endo pathway suggested that cyclization instead of ionization might be the product-determining step. Rearrangement of the C9 hydroxy group to C7 was achieved by a selenium variant of the Mislow–Evans rearrangement. Transformation from 51 to 63 was achieved in four steps. The corresponding phosphonoacetate, prepared by selective oxidation of allylic alcohol in 63 followed by esterification of C19 hydroxy group with phosphono acetic acid, underwent intramolecular HWE reaction mediated by NaHMDS to generate macrolactone 64. Finally, (+)-dactylolide was obtained through a deprotection–oxidation procedure (Scheme 11).

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