A number of water-soluble natural camptothecins containing a polyamine linked to the carboxylate function of the opened lactone ring has been identified. To investigate the therapeutic interest of these hydrophilic camptothecins, a series of analogs containing a polyamine moiety has been synthesized, and IDN5174 was selected for further development. In the NCI-H460 human lung carcinoma cell line the molecule was cytotoxic, even though less potent than topotecan or SN38, in short-term and long-term exposure assays (1 and 72 h). The analysis of topoisomerase-mediated DNA cleavage using purified enzyme indicated that IDN5174 was an efficient topoisomerase I poison and displayed the same cleavage pattern of SN38. Persistence of the DNA cleavage after NaCl-mediated disruption of the ternary complex was comparable to that of SN38. Stabilization of the cleavable complex was not the result of hydrolysis of the N-C bond between polyamine and the drug, because less than 1% of camptothecin was formed during the enzymatic reaction. Against the NCI-H460 human tumor xenograft, IDN5174 exhibited an activity comparable to that of topotecan or irinotecan (TWI% ∼ 90%) when given i.v. or per os. Preliminary evaluation of IDN5174 pharmacokinetics in CD1 mice, after i.v. administration of 15 mg/kg, showed rapid plasmatic clearance with elimination half-life of 20 minutes. In plasma the camptothecin level were 50-fold lower than that of IDN5174. In conclusion, such results were unexpected, since a closed α-lactone ring has been considered for long time a critical requirement for effective camptothecins. In spite of presenting a polyamine linked through a stable N-C bond to the carboxilate function of the opened lactone ring, the novel camptothecin analog IDN5174 maintained the biological and antitumor properties of the established camptotecins. The contribution of closed-ring camptothecins in determining the effects of IDN5174 appeared marginal.

[Proc Amer Assoc Cancer Res, Volume 47, 2006]