A Novel Approach to the Study of Solution Structures and Dynamic Behavior of Paclitaxel and Docetaxel Using Fluorine-Containing Analogs as Probes

Abstract

Three fluorine-containing paclitaxel and docetaxel analogs, 3‘-dephenyl-3‘-(4-fluorophenyl)-3‘N-debenzoyl-3‘N-(4-fluorobenzoyl)paclitaxel (3), 3‘-dephenyl-3‘-(4-fluorophenyl)docetaxel (4), and 2‘,10-diacetyl-3‘-dephenyl-3‘-(4-fluorophenyl)docetaxel (5), are prepared and used as probes for the conformational analysis of paclitaxel and docetaxel in aqueous and nonaqueous solvent systems. The dependence of the 19F chemical shifts and the JH2‘-H3‘ values of these fluorinated analogs is examined through 19F and 1H variable temperature (VT) NMR measurements. The experiments clearly indicate highly dynamic behavior of these molecules and the existence of equilibrium between conformers, especially in protic solvents, i.e., DMSO-d6/D2O, CH3OD/D2O, and CH3OD, which have not clearly been recognized by the previous studies. The analysis of the VT NMR data in combination with molecular modeling including restrained molecular dynamics (RMD) has identified three key conformers, A, B, and C, in which conformer C possesse...