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

Hamel, E and Day, BW and Miller, JH and Jung, MK and Northcote, PT and Ghosh, AK and Curran, DP and Cushman, M and Nicolaou, KC and Paterson, I and Sorensen, EJ (2006) Synergistic effects of peloruside A and laulimalide with taxoid site drugs, but not with each other, on tubulin assembly. Molecular Pharmacology, 70 (5). 1555 - 1564. ISSN 0026-895X

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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 17β-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.

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Details

Item Type: Article
Status: Published
Creators/Authors:
CreatorsEmailPitt UsernameORCID
Hamel, E
Day, BW
Miller, JH
Jung, MK
Northcote, PT
Ghosh, AK
Curran, DPcurran@pitt.eduCURRAN
Cushman, M
Nicolaou, KC
Paterson, I
Sorensen, EJ
Date: 24 November 2006
Date Type: Publication
Journal or Publication Title: Molecular Pharmacology
Volume: 70
Number: 5
Page Range: 1555 - 1564
DOI or Unique Handle: 10.1124/mol.106.027847
Schools and Programs: Dietrich School of Arts and Sciences > Chemistry
Refereed: Yes
ISSN: 0026-895X
MeSH Headings: Bicyclo Compounds, Heterocyclic--chemistry; Bicyclo Compounds, Heterocyclic--pharmacology; Drug Synergism; Glutamic Acid--metabolism; Guanosine Triphosphate--metabolism; Humans; Lactones--chemistry; Lactones--pharmacology; Macrolides; Microtubule-Associated Proteins--metabolism; Models, Molecular; Paclitaxel--pharmacology; Taxoids--chemistry; Taxoids--pharmacology; Temperature; Tubulin--metabolism; Tumor Cells, Cultured
PubMed ID: 16887932
Date Deposited: 14 May 2013 14:21
Last Modified: 02 Feb 2019 15:58
URI: http://d-scholarship.pitt.edu/id/eprint/18689

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