Synthesis and biological evaluation of novel 3′-difluorovinyl taxoids

Larissa Kuznetsova, Liang Sun, Jin Chen, Xianrui Zhao, Joshua Seitz, Manisha Das, Yuan Li, Jean M. Veith, Paula Pera, Ralph J. Bernacki, Shujun Xia, Susan B. Horwitz, Iwao Ojima

Research output: Contribution to journalArticle

17 Scopus citations

Abstract

A series of 3′-difluorovinyl taxoids with C10 modifications, as well as those with C2 and C10 modifications, were strategically designed to block the metabolism by cytochrome P-450 3A4 enzyme and synthesized. These novel difluorovinyl taxoids were evaluated for their cytotoxicity against drug-sensitive human breast (MCF7), multidrug-resistant (MDR) human ovarian (NCI/ADR), human colon (HT-29) and human pancreatic (PANC-1) cancer cell lines. 3′-Difluorovinyl taxoids exhibit several to 16 times better activity against MCF7, HT-29 and PANC-1 cell lines and up to three orders of magnitude higher potency against NCI/ADR cell line as compared to paclitaxel. Structure-activity relationship study shows the critical importance of the C2 modifications on the activity against MDR cancer cell line, while the C10 modifications have a rather minor effect on the potency with some exceptions. The effect of the C2 modifications on potency against MCF7 cell line increases in the following order: H < F < Cl < N 3. Among the twenty five 3′-difluorovinyl taxoids evaluated, eight taxoids exhibited less than 100 pM IC 50 values against MCF7 cell line. Difluorovinyl taxoids induced GTP-independent tubulin polymerization much faster than paclitaxel. Then, the resulting microtubules were stable to Ca 2+-induced depolymerization, indicating strong stabilization of microtubules. Molecular modeling study indicated that a difluorovinyl taxoid binds to β-tubulin in a manner that is consistent with the REDOR-Taxol structure. The difluorovinyl group appears to mimic the isobutenyl group to some extent, but with very different electronic property, which may account for the unique activities of difluorovinyl taxoids.

Original languageEnglish (US)
Pages (from-to)177-188
Number of pages12
JournalJournal of Fluorine Chemistry
Volume143
DOIs
StatePublished - Nov 1 2012

Keywords

  • Anticancer agent
  • Baccatin
  • Difluorovinyl
  • Fluoro-taxoid
  • Microtubules
  • Structure-activity relationship
  • Taxoid
  • β-Lactam Synthon Method

ASJC Scopus subject areas

  • Biochemistry
  • Environmental Chemistry
  • Physical and Theoretical Chemistry
  • Organic Chemistry
  • Inorganic Chemistry

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  • Cite this

    Kuznetsova, L., Sun, L., Chen, J., Zhao, X., Seitz, J., Das, M., Li, Y., Veith, J. M., Pera, P., Bernacki, R. J., Xia, S., Horwitz, S. B., & Ojima, I. (2012). Synthesis and biological evaluation of novel 3′-difluorovinyl taxoids. Journal of Fluorine Chemistry, 143, 177-188. https://doi.org/10.1016/j.jfluchem.2012.07.007