The highly lipophilic DNA topoisomerase I inhibitor DB-67 displays elevated lactone levels in human blood and potent anticancer activity

Abstract The novel silatecan 7-t-butyldimethylsilyl-10-hydroxycamptothecin (DB-67) is 25- to 50-times more lipophilic than camptothecin and readily incorporates into lipid bilayers. Using the method of fluorescence anisotropy titration, we determined that DB-67 bound to small unilamellar vesicles composed of dilaurylphosphatidylcholine (DLPC) with an association constant ( K value) of 5000 M −1 . This association constant is significantly higher than the K DLPC value observed for camptothecin ( K DLPC value of 110 M −1 ). Using HPLC methods, we demonstrated that the presence of liposomal membranes readily stabilize the lactone form of DB-67. At drug and lipid concentrations of 10 μM and 0.3 mM, respectively, the lactone form of DB-67 persisted in liposome suspension after 3 h of incubation at 37°C. Thus an advantage of a liposomal formulation of DB-67 is that the presence of lipid bilayers assists with stabilizing the key pharmacophore of the agent. The highly lipophilic character of DB-67, in combination with its 10-hydroxy moiety (which functions to enhance lactone stability in the presence of human serum albumin), results in DB-67 having superior stability in human blood with a percent lactone at equilibrium value of 30 [Cancer Res. 59 (1999) 4898; J. Med. Chem. 43 (2000) 3970]. Potent cytotoxicities against a broad range of cancer cells were observed for DB-67, indicating that DB-67 is of comparable potency to camptothecin. The impressive human blood stability and cytotoxicity profiles for DB-67 indicate it is an excellent candidate for comprehensive in vivo pharmacological and efficacy studies. Based on these promising attributes, DB-67 is currently being developed under the NCI RAID program. Due to its potent anti-topoisomerase I activity and its intrinsic blood stability, DB-67 appears as an attractive novel camptothecin for clinical development.