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

  1. Author:
    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, E. J.
  2. Author Address

    NCI, Toxicol & Pharmacol Branch, Dev Therapeut Program, Div Canc Treatment & Diagnosis,NIH, Frederick, MD 21702 USA. Univ Pittsburgh, Dept Pharmaceut Sci, Pittsburgh, PA USA. Univ Pittsburgh, Dept Chem, Pittsburgh, PA USA. Victoria Univ Wellington, Sch Biol Sci, Wellington, New Zealand. Victoria Univ Wellington, Sch Chem & Phys Sci, Wellington, New Zealand. NCI, SAIC Frederick Inc, NIH, Frederick, MD 21701 USA. Purdue Univ, Dept Med Chem & Mol Pharmacol, W Lafayette, IN 47907 USA. Purdue Univ, Purdue Canc Ctr, Sch Pharm & Pharmaceut Sci, W Lafayette, IN 47907 USA. Purdue Univ, Dept Chem, W Lafayette, IN 47907 USA. Scripps Res Inst, Dept Chem, La Jolla, CA USA. Scripps Res Inst, Skaggs Inst Chem Biol, La Jolla, CA USA. Univ Calif San Diego, Dept Chem & Biochem, La Jolla, CA 92093 USA. Univ Cambridge, Dept Chem, Cambridge CB2 1EW, England. Princeton Univ, Dept Chem, Princeton, NJ 08544 USA.;Hamel, E, NCI, Toxicol & Pharmacol Branch, Dev Therapeut Program, Div Canc Treatment & Diagnosis,NIH, Bldg 469,Room 104, Frederick, MD 21702 USA.;hamele@mail.nih.gov
    1. Year: 2006
    2. Date: Nov
  1. Journal: Molecular Pharmacology
    1. 70
    2. 5
    3. Pages: 1555-1564
  2. Type of Article: Article
  3. ISSN: 0026-895X
  1. 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 17 beta-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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External Sources

  1. DOI: 10.1124/mol.106.027847
  2. WOS: 000241436100010

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