title: Syntheses and Structure-Activity Relationships of Novel 3'-Difluoromethyl and 3'-Trifluoromethyl-Taxoids.
abstract: 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.
authors.affiliation: Department of Chemistry, State University of New York at Stony Brook, Stony Brook, NY 11794-3400.
authors.forename: Larissa V
authors.initials: LV
authors.lastname: Kuznetsova
authors.forename: Antonella
authors.initials: A
authors.lastname: Pepe
authors.forename: Ioana M
authors.initials: IM
authors.lastname: Ungureanu
authors.forename: Paula
authors.initials: P
authors.lastname: Pera
authors.forename: Ralph J
authors.initials: RJ
authors.lastname: Bernacki
authors.forename: Iwao
authors.initials: I
authors.lastname: Ojima