2. Academic Validation
  3. Design, synthesis, and biological evaluation of new-generation taxoids

Design, synthesis, and biological evaluation of new-generation taxoids

  • J Med Chem. 2008 Jun 12;51(11):3203-21. doi: 10.1021/jm800086e.
Iwao Ojima 1,  Jin Chen,  Liang Sun,  Christopher P Borella,  Tao Wang,  Michael L Miller,  Songnian Lin,  Xudong Geng,  Larisa Kuznetsova,  Chuanxing Qu,  David Gallager,  Xianrui Zhao,  Ilaria Zanardi,  Shujun Xia,  Susan B Horwitz,  Jon Mallen-St Clair,  Jennifer L Guerriero,  Dafna Bar-Sagi,  Jean M Veith,  Paula Pera,  Ralph J Bernacki
Affiliations

Affiliation

  • 1 Department of Chemistry, State University of New York at Stony Brook, Stony Brook, NY 11794-3400, USA. iojima@notes.cc.sunysb.edu
PMID: 18465846 DOI: 10.1021/jm800086e
Abstract

Novel second-generation taxoids with systematic modifications at the C2, C10, and C3'N positions were synthesized and their structure-activity relationships studied. A number of these taxoids exhibited exceptionally high potency against multidrug-resistant cell lines, and several taxoids exhibited virtually no difference in potency against the drug-sensitive and drug-resistant cell lines. These exceptionally potent taxoids were termed "third-generation taxoids". 19 (SB-T-1214), 14g (SB-T-121303), and 14i (SB-T-1213031) exhibited excellent activity against paclitaxel-resistant ovarian Cancer cell lines with mutations in beta-tubulin as well, wherein the drug resistance is mediated by the beta-tubulin mutation. These taxoids were found to possess exceptional activity in promoting tubulin assembly, forming numerous very short microtubules similar to those formed by discodermolide. Taxoids 19 and 14g also showed excellent cytotoxicity against four pancreatic Cancer cell lines, expressing three to four multidrug-resistant genes. Moreover, taxoid 19 exhibited excellent in vivo efficacy against highly drug-resistant CFPAC-1 pancreatic as well as DLD-1 human colon tumor xenografts in mice.

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