SYNTHESES AND STRUCTURE-ACTIVITY-RELATIONSHIPS OF NOVEL NOR-SECO TAXOIDS

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 p-lactam synthon method using the coupling of (3R,4S)-1-acyl-be ta-lactams with properly protected nor-seco baccatin III derivatives ( 1, 2, 3) as the key step. Nor-seco baccatin III derivatives were prepa red through oxidative cleavage of the A ring of 14 beta-hydroxy-10-dea cetylbaccatin III followed by reduction, amination using Mitsunobu con ditions, or reductive amination. Nor-seco taxoids with a C-13 ester li nkage (4a-b) or a C-13 N-Me amide linkage (6) show reduced cytotoxicit y against human cancer cell lines as compared with paclitaxel, but sti ll retain a certain level of activity despite the destruction of the t axane A ring. However, none of the analogues with a C-13 N-H amide lin kage (5a-d) exhibit appreciable activity (IC50 > 1.0 mu M). A restrain ed molecular dynamics study reveals the inability of 5a-d to attain th e proposed bioactive conformation, which accounts for the loss of acti vity.