An Approach Towards More Selective Anticancer Agents

A promising approach towards better targeted anticancer drug therapy takes advantage of enhanced expression of proteases associated with human malignancies. Especially plasminogen activator activity has been found to be substantially increased, leading to an enhanced activity of the serine protease plasmin. Bifunctional alkylating agents, such as N-(2-chloroethyl)-N-nitrosoureas, display broad spectrum anticancer activity, but also exhibit considerable systemic toxicity. We describe here the synthesis of new N-nitrosourea-based prodrugs designed to become activated by tumor-associated proteases, to provide for enhanced antitumor activity and reduced systemic toxicity. Tripeptides representing substrates for plasmin were linked by an amide bond to N’-(2-aminoethyl)-N-(2-chloroethyl)-N-nitrosourea and the corresponding N’-methyl derivative. Synthesis and plasmin-triggered decomposition of these new tripeptide conjugates is described. Cancer cells expressing high plasminogen activator activity are highly sensitive to the new prodrugs in the presence of plasminogen, but not in its absence.

tumor-associated proteases - plasminogen activators - proteolytic prodrug activation - tripeptide conjugates - N-(2-chloroethyl)-N-nitrosoureas