Syntheses and structure–activity relationships of novel 3′-difluoromethyl and 3′-trifluoromethyl-taxoids

• Published in: Journal of fluorine chemistry 2008-09, Vol.129 (9), p.817-828
• Main Authors: Kuznetsova, Larissa V., Pepe, Antonella, Ungureanu, Ioana M., Pera, Paula, Bernacki, Ralph J., Ojima, Iwao
• Format: Article
• Language: English
• Subjects: Anticancer agent; Baccatin; Difluoromethyl; Fluoro-taxoid; Structure–activity relationship; Taxoid; Trifluoromethyl; β-Lactam synthon method
• ISSN: 0022-1139; 1873-3328
• DOI: 10.1016/j.jfluchem.2008.05.013

Novel 3′-difluoromethyl-taxoids and 3′-trifluoromethyl-taxoids were synthesized and evaluated for their in vitro cytotoxicities against human breast, non-small cell lung, and colon cancer cell lines. These second-generation fluoro-taxoids exhibit two orders of magnitude higher potency than paclitaxel against multidrug-resistant cancer cell lines. Structure–activity relationship of these highly potent fluoro-taxoids is discussed. ▪ A series of novel 3′-difluoromethyl-taxoids and 3′-trifluoromethyl-taxoids with modifications at the C2 and C10 positions were synthesized and evaluated for their in vitro cytotoxicities against human breast carcinoma (MCF7-S, MCF7-R, LCC6-WT, LCC6-MDR), non-small cell lung carcinoma (H460) and colon adenocarcinoma (HT-29) cell lines. These second-generation fluoro-taxoids exhibited several times to more than 20 times better potency than paclitaxel against drug-sensitive cancer cell lines, MCF7-S, LCC6-WT, H460, and HT-29. These fluoro-taxoids also possess two orders of magnitude higher potency than paclitaxel against drug-resistant cancer cell lines, MCF7-R and LCC6-MDR. Structure–activity relationship study shows the importance of the C10 modification for increasing the activity against multidrug-resistant cancer cell lines. Effects of the C2-benzoate modifications on the potency in the 3′-difluoromethyl-taxoid series are very clear (i.e., F < MeO < Cl < N 3), while those in the 3′-trifluoromethyl-taxoid series are less obvious. Also, different trends in the sensitivity to the C2-substitution are observed between drug-sensitive cell lines and drug-resistant cancer cell lines that overexpress efflux pumps.