Syntheses and Structure−Activity Relationships of Novel Nor-seco Taxoids

Abstract

A series of novel nor-seco taxoids (4a−b, 5a−d, 6), including either a C-13 ester linkage or a C-13 amide linkage, was synthesized by means of the β-lactam synthon method using the coupling of (3R,4S)-1-acyl-β-lactams with properly protected nor-seco baccatin III derivatives (1, 2, 3) as the key step. Nor-seco baccatin III derivatives were prepared through oxidative cleavage of the A ring of 14β-hydroxy-10-deacetylbaccatin III followed by reduction, amination using Mitsunobu conditions, or reductive amination. Nor-seco taxoids with a C-13 ester linkage (4a−b) or a C-13 N-Me amide linkage (6) show reduced cytotoxicity against human cancer cell lines as compared with paclitaxel, but still retain a certain level of activity despite the destruction of the taxane A ring. However, none of the analogues with a C-13 N-H amide linkage (5a−d) exhibit appreciable activity (IC50 > 1.0 μM). A restrained molecular dynamics study reveals the inability of 5a−d to attain the proposed bioactive conformation, which accounts for the loss of activity.