Nancy Krauss

NMR and molecular modeling study of the conformations of taxol and of its side chain methylester in aqueous and non-aqueous solution.

Abstract The conformations of the antimitotic agent taxol and its side chain methyl ester have been studied by NMR-spectroscopy and molecular modeling in hydrophobic (CDCl3) and hydrophilic (water, d6-DMSO) solvents. For the side chain methyl ester (4), the coupling constant JH2′-H3′ changes from ≈2 Hz in chloroform to ≈5 Hz in d6-DMSO or water : d6-DMSO, 1 : 1 (v/v). The conformational equilibrium for 4 thus shifts from one favoring conformers with a gauche torsion angle (chloroform), to one predominantly of conformers having this torsion angle anti. In the case of taxol, JH2′-H3′ changes from 2.7 Hz in CDCl3 to ≈8 Hz in water, water - sodium dodecyl sulfate (SDS) and/or d6-DMSO. Again, gauche conformations are implicated in chloroform, but molecular modeling suggests the anti conformer 27 to be dominant in aqueous media and in d6-DMSO. No nuclear Overhauser effects (nOes) between the side chain and the taxane ring-system are observed in chloroform solution. In water and/or d6-DMSO, however, nOes between the side chain (Ph3′ and H2′) and the OAc4 methyl group are detected.

Characterization of the taxol structure-activity profile for the locus of the A-ring side chain

Abstract Two series of taxol analogs with various N -acyl groups on 3′-phenylisoserine and isoserine A-ring side chains, respectively, were prepared, and their microtubule assembly acitivities and cytotoxicities toward J774.2 cells were evaluated. Biological activities were adversely affected by the structural modifications investigated, although the 3′-phenylisoserine series was significantly more active than the isoserine series.