The novel silatecan 7-tert-butyldimethylsilyl-10-hydroxycamptothecin displays high lipophilicity, improved human blood stability, and potent anticancer activity
D. Bom et al., The novel silatecan 7-tert-butyldimethylsilyl-10-hydroxycamptothecin displays high lipophilicity, improved human blood stability, and potent anticancer activity, J MED CHEM, 43(21), 2000, pp. 3970-3980
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.