Synthesis and antitumor activity of CBI-bearing ester and carbamate prodrugs of CC-1065 analogue

Prodrugs of a CBI-bearing CC-1065 analogue were synthesized. Antitumor activity of the compounds was evaluated against tumor cells in vitro and in mouse tumor models. Compounds 1 and 7, bearing methylpiperazine and DHA moieties, respectively, showed significant antitumor activity in both the L1210 leukemia and Lewis lung carcinoma mouse tumor models. For the carbamate prodrugs 1–4 and 6, there is a good correlation between the drug’s potency both in vitro and in animal tumor models; however, there is no correlation between the prodrug’s antitumor activity and the type of bonds linking the free drug. There are no significant differences between the antitumor activities of those that can or cannot be protonated at physiological pH. Compounds 6 and 7, each bearing a DHA moiety, did not show significantly improved antitumor activity compared to other prodrugs bearing DHA moieties, suggesting that DHA may not be used universally to significantly improve a drug’s antitumor efficacy.

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