The novel silatecan 7-tert-butyldimethylsilyl-10-hydroxycamptothecin displays high lipophilicity, improved human blood stability, and potent anticancer activity

We describe the rational design and synthesis of B- and A,B-ring-modified c amptothecins. The key alpha -hydroxy-delta -lactone pharmacophore in 7-tert -butyldimethylsilyl-10-hydroxycamptothecin (DB-67, 14) displays superior st ability in human blood when compared with clinically relevant camptothecin analogues. In human blood 14 displayed a t(1/2) of 130 min and a percent la ctone at equilibrium value of 30%. The tert-butyldimethylsilyl group render s the new agent 25-times more lipophilic than camptothecin, and 14 is readi ly incorporated, as its active lactone form, into cellular and liposomal bi layers. In addition, the dual 7-alkylsilyl and 10-hydroxy substitution in 1 4 enhances drug stability in the presence of human serum albumin. Thus, the net lipophilicity and the altered human serum albumin interactions togethe r function to promote the enhanced blood stability. In vitro cytotoxicity a ssays using multiple different cell lines derived from eight distinct tumor types indicate that 14 is of comparable potency to camptothecin and 10-hyd roxycamptothecin, as well as the FDA-approved camptothecin analogues topote can and CPT-11. In addition, cell-free cleavage assays reveal that 14 is hi ghly active and forms more stable top1 cleavage complexes than camptothecin or SN-38. The impressive blood stability and cytotoxicity profiles for 14 strongly suggest that it is an excellent candidate for additional in vivo p harmacological and efficacy studies.