Hydrolyzable hydrophobic taxanes: synthesis and anti-cancer activities

A series of taxane prodrugs with 2-bromoacyl chains attached at the 2'-posi tion of the paclitaxel side chain, varying from six, eight, 12, 14 to 16 ca rbons in length, were synthesized, characterized and evaluated against huma n breast MCF-7 cancer cell line for their growth inhibitory (GI(50)) activi ties. The GI(50) is the drug concentration required to inhibit cell growth by 50%. For comparison, hydrophobic taxanes varying in acyl chain lengths f rom six to 16 carbons were also synthesized and compared for their GO(50)s with taxanes having equivalent bromoacyl chain lengths. The bromoacyl taxan es bearing six, eight and 12 carbon acyl chain lengths had GI(50) values ve ry similar to parent paclitaxel. The GI(50) was 3 nM for three taxanes vers us 1 nM for paclitaxel on the MCF7 cell line. Increasing the acyl chain len gth to 14 or 16 carbons resulted in a significant decrease in cytotoxicity and an increase in the GI(50) to 20 or 70 nM, respectively. In general, the GI(50) values were directly related to the bromoacyl chain lengths in cult ured tumor cells. Unlike bromoacyl taxanes, the taxanes lacking bromine in their acyl chain composition were 50- to 250-fold less active, suggesting t hat the heteroatom facilitated the hydrolysis of acyl chains to yield free paclitaxel. These differences in growth inhibitory activities may indirectl y reflect differences in the susceptibility of the acyl chain to bromine-in duced hydrolysis after association of the derivative with cell membranes. L iposome formulations of 5-bromoacyl taxanes bearing six, eight, 12 and 16 c arbons were prepared and tested in SCID mice against a xenografted human ov car-3 ovarian tumor. In vivo results showed that bromoacyl taxanes with a l onger chain were therapeutically more efficacious than those with a short c hain, presumably due to slow hydrolysis of the prodrug followed by sustaine d delivery of paclitaxel to the tumor. [(C) 2001 Lippincott Williams & Wilk ins.].