A common pharmacophore for cytotoxic natural products that stabilize microtubules

Iwao Ojima, Subrata Chakravarty, Tadashi Inoue, Songnian Lin, Lifeng He, Susan Band Horwitz, Scott D. Kuduk, Samuel J. Danishefsky

Research output: Contribution to journalArticle

269 Scopus citations

Abstract

Taxol (paclitaxel), a complex diterpene obtained from the Pacific yew, Taxus brevifolia, is arguably the most important new drug in cancer chemotherapy. The mechanism of cytotoxic action for paclitaxel - i.e., the stabilization of microtubules leading to mitotic arrest - is now shared by four recently identified natural products, eleutherobin, epothilones A and B, and discodermolide. Their ability to competitively inhibit [3H]paclitaxel binding to microtubules strongly suggests the existence of a common binding site. Recently, we have developed nonaromatic analogues of paclitaxel that maintain high cytotoxicity and tubulin binding (e.g., nonataxel). We now propose a common pharmacophore that unites paclitaxel, nonataxel, the epothilones, eleutherobin, and discodermolide, and rationalizes the extensive structure-activity relationship data pertinent to these compounds. Insights from the common pharmacophore have enabled the development of a hybrid construct with demonstrated cytotoxic and tubulin-binding activity.

Original languageEnglish (US)
Pages (from-to)4256-4261
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume96
Issue number8
DOIs
Publication statusPublished - Apr 13 1999

    Fingerprint

ASJC Scopus subject areas

  • General

Cite this