Scripps VIVO scripps research logo

  • Index
  • Log in
  • Home
  • People
  • Organizations
  • Research
  • Events
Search form
As of April 1st VIVO Scientific Profiles will no longer updated for faculty, and the link to VIVO will be removed from the library website. Faculty profile pages will continue to be updated via Interfolio. VIVO will continue being used behind the scenes to update graduate student profiles. Please contact helplib@scripps.edu if you have questions.
How to download citations from VIVO | Alternative profile options

Synergistic effects of peloruside a and laulimalide with taxoid site drugs, but not with each other, on tubulin assembly

Academic Article
uri icon
  • Overview
  • Identity
  • Additional Document Info
  • View All
scroll to property group menus

Overview

authors

  • Hamel, E.
  • Day, B. W.
  • Miller, J. H.
  • Jung, M. K.
  • Northcote, P. T.
  • Ghosh, A. K.
  • Curran, D. P.
  • Cushman, M.
  • Nicolaou, K.C.
  • Paterson, I.
  • Sorensen, Erik J.

publication date

  • 2006

journal

  • Molecular Pharmacology  Journal

abstract

  • Previous studies on the drug content of pelleted tubulin polymers suggest that peloruside A binds in the laulimalide site, which is distinct from the taxoid site. In a tubulin assembly system containing microtubule-associated proteins and GTP, however, peloruside A was significantly less active than laulimalide, inducing assembly in a manner that was most similar to sarcodictyins A and B. Because peloruside A thus far seems to be the only compound that mimics the action of laulimalide, we examined combinations of microtubule-stabilizing agents for synergistic effects on tubulin assembly. We found that peloruside A and laulimalide showed no synergism but that both compounds could act synergistically with a number of taxoid site agents [paclitaxel, epothilones A/B, discodermolide, dictyostatin, eleutherobin, the steroid derivative 17beta-acetoxy-2-ethoxy-6-oxo-B-homo-estra-1,3,5(10)-trien-3-ol, and cyclostreptin]. None of the taxoid site compounds showed any synergism with each other. From an initial study with peloruside A and cyclostreptin, we conclude that the synergism phenomenon derives, at least in part, from an apparent lowering of the tubulin critical concentration with drug combinations compared with single drugs. The apparent binding of peloruside A in the laulimalide site led us to attempt construction of a pharmacophore model based on superposition of an energy-minimized structure of peloruside A on the crystal structure of laulimalide. Although the different sizes of the macrocycles limited our ability to superimpose the two molecules, atom correspondences that were observed were consistent with the difficulty so far experienced in creation of fully active analogs of laulimalide.

subject areas

  • Bicyclo Compounds, Heterocyclic
  • Drug Synergism
  • Glutamic Acid
  • Guanosine Triphosphate
  • Humans
  • Lactones
  • Macrolides
  • Microtubule-Associated Proteins
  • Models, Molecular
  • Paclitaxel
  • Taxoids
  • Temperature
  • Tubulin
  • Tumor Cells, Cultured
scroll to property group menus

Identity

International Standard Serial Number (ISSN)

  • 0026-895X

Digital Object Identifier (DOI)

  • 10.1124/mol.106.027847

PubMed ID

  • 16887932
scroll to property group menus

Additional Document Info

start page

  • 1555

end page

  • 1564

volume

  • 70

issue

  • 5

©2022 The Scripps Research Institute | Terms of Use | Powered by VIVO

  • About
  • Contact Us
  • Support