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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

Smith's total synthesis of (+)-zampanolide.
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sch4: Smith's total synthesis of (+)-zampanolide.

Mentions: Smith's retrosynthetic analysis is outlined in Scheme 1.10,12,13 A stereoselective Curtius rearrangement44 was used to install the N-acyl hemiaminal side chain and Horner–Emmons macrocyclization45 was employed to close the macrolactone ring at C2–C3. The macrocyclization precursor was constructed using nucleophilic epoxide ring-opening and Kocienski–Julia olefination as key reactions. The Petasis–Ferrier rearrangement was developed by Smith as a powerful and stereoselective approach to cis-2,6-disubstituted THP groups, and it was elegantly applied to the construction of the same unit in Smith's synthesis of zampanolide.46 As shown in Scheme 2, fragment C3–C8 (16) was prepared from known alkynolate 20 (ref. 47) via a Michael-type carbometallation followed by four sequential reactions: reduction, protection, deprotection, and oxidation. The Smith synthesis of fragment C9–C20 is shown in Scheme 3. The aldehyde 23 was prepared via Brown asymmetric allylation of aldehyde 22,48 followed by silylation and oxidative cleavage of the terminal alkene. The aldehyde was readily converted to β-hydroxy ester 24 in two steps, and this was condensed with aldehyde 25 mediated by TMSOTf to give a mixture of dioxanones 26 (10 : 1 at C-5). This cyclization was presumed to proceed via a transition state wherein the aldehyde side chain adopts a pseudoequatorial orientation. A mixture of the cyclic acetals 27 (6 : 1 at C-15) was achieved via the Petasis–Tebbe methylenation of 26, which was subjected to the Petasis-Ferrier rearrangement with Me2AlCl to yield 2,6-cis-pyranone 28. Wittig methylenation of ketone 28 followed by desilylation gave alkene 29. Sulfone 17 was achieved by incorporation of the thiotetrazole via the Mitsunobu protocol and oxidation. Fragment C18–C21 (18) was prepared using (+)-diethyl tartrate as starting material through a seven-step sequence. As shown in Scheme 4, the trans-C8–C9 double bond in 30 was built by treating aldehyde 16 with sulfone 17 through the Kocienske–Julia olefination reaction. Fragment C3–C21 (31) was achieved by reaction of the mixed cyano-Gilman cuprate, derived from vinyl bromide 30 and lithium 2-thienylcyanocuprate, with epoxide 18. Phosphonoacetate 32, prepared by condensing diethylphosphonoacetic acid with 31, was subjected to Horner–Emmons macrocyclization reaction and a following three-step sequence to provide carboxylic acid 33. Carbamate 34 was prepared via Curtius rearrangement followed by treatment with trimethylsilylethanol. Transformation of carbamate 34 to (+)-zampanolide (2) was achieved by acylation with acid chloride 15 followed by a four-step, deprotection–oxidation sequence.


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

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

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

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

sch4: Smith's total synthesis of (+)-zampanolide.
Mentions: Smith's retrosynthetic analysis is outlined in Scheme 1.10,12,13 A stereoselective Curtius rearrangement44 was used to install the N-acyl hemiaminal side chain and Horner–Emmons macrocyclization45 was employed to close the macrolactone ring at C2–C3. The macrocyclization precursor was constructed using nucleophilic epoxide ring-opening and Kocienski–Julia olefination as key reactions. The Petasis–Ferrier rearrangement was developed by Smith as a powerful and stereoselective approach to cis-2,6-disubstituted THP groups, and it was elegantly applied to the construction of the same unit in Smith's synthesis of zampanolide.46 As shown in Scheme 2, fragment C3–C8 (16) was prepared from known alkynolate 20 (ref. 47) via a Michael-type carbometallation followed by four sequential reactions: reduction, protection, deprotection, and oxidation. The Smith synthesis of fragment C9–C20 is shown in Scheme 3. The aldehyde 23 was prepared via Brown asymmetric allylation of aldehyde 22,48 followed by silylation and oxidative cleavage of the terminal alkene. The aldehyde was readily converted to β-hydroxy ester 24 in two steps, and this was condensed with aldehyde 25 mediated by TMSOTf to give a mixture of dioxanones 26 (10 : 1 at C-5). This cyclization was presumed to proceed via a transition state wherein the aldehyde side chain adopts a pseudoequatorial orientation. A mixture of the cyclic acetals 27 (6 : 1 at C-15) was achieved via the Petasis–Tebbe methylenation of 26, which was subjected to the Petasis-Ferrier rearrangement with Me2AlCl to yield 2,6-cis-pyranone 28. Wittig methylenation of ketone 28 followed by desilylation gave alkene 29. Sulfone 17 was achieved by incorporation of the thiotetrazole via the Mitsunobu protocol and oxidation. Fragment C18–C21 (18) was prepared using (+)-diethyl tartrate as starting material through a seven-step sequence. As shown in Scheme 4, the trans-C8–C9 double bond in 30 was built by treating aldehyde 16 with sulfone 17 through the Kocienske–Julia olefination reaction. Fragment C3–C21 (31) was achieved by reaction of the mixed cyano-Gilman cuprate, derived from vinyl bromide 30 and lithium 2-thienylcyanocuprate, with epoxide 18. Phosphonoacetate 32, prepared by condensing diethylphosphonoacetic acid with 31, was subjected to Horner–Emmons macrocyclization reaction and a following three-step sequence to provide carboxylic acid 33. Carbamate 34 was prepared via Curtius rearrangement followed by treatment with trimethylsilylethanol. Transformation of carbamate 34 to (+)-zampanolide (2) was achieved by acylation with acid chloride 15 followed by a four-step, deprotection–oxidation sequence.

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