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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

Two views of the tubulin–zampanolide complex at 1.8 Å resolution. Adapted from Science, 2013, 339, 587–590 with permission.
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fig3: Two views of the tubulin–zampanolide complex at 1.8 Å resolution. Adapted from Science, 2013, 339, 587–590 with permission.

Mentions: In an important publication Steinmetz et al. reported the structure of α,β-tubulin complexed with the stathmin-like protein RB3, tubulin–tyrosine ligase, and zampanolide at 1.8 Å resolution (Fig. 3).38 This structure clearly showed that zampanolide was deeply buried in the taxane luminal binding pocket formed by hydrophobic residues of helix H7, β strand S7, and the M-loop, and that its C9 atom was covalently bound to the NE2 atom of His229 of β-tubulin, consistent with the major fragment ion in the mass spectrometric results described above.23


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

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

Two views of the tubulin–zampanolide complex at 1.8 Å resolution. Adapted from Science, 2013, 339, 587–590 with permission.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

fig3: Two views of the tubulin–zampanolide complex at 1.8 Å resolution. Adapted from Science, 2013, 339, 587–590 with permission.
Mentions: In an important publication Steinmetz et al. reported the structure of α,β-tubulin complexed with the stathmin-like protein RB3, tubulin–tyrosine ligase, and zampanolide at 1.8 Å resolution (Fig. 3).38 This structure clearly showed that zampanolide was deeply buried in the taxane luminal binding pocket formed by hydrophobic residues of helix H7, β strand S7, and the M-loop, and that its C9 atom was covalently bound to the NE2 atom of His229 of β-tubulin, consistent with the major fragment ion in the mass spectrometric results described above.23

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