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Proton-mediated Liberation of Aldophosphamide from a Nontoxic Prodrug: A Strategy for Tumor-selective Activation of Cytocidal Drugs¹

Institute für Organische Chemie der Georg-August-Universität, Tammannstrasse 2, D-3400 Göttingen [L. F. T., M. N., T. M., R. F.]; Medizinische Universitätsklinik, Abteilung Innere Medizin II, Otfried-Müller-Strasse 10, D-7400 Tübingen [E. J.]; and Institut für Zellbiologie (Tumorforschung), Universität Essen (GH), Hufelandstrasse 55, D-4300 Essen [M. F. R., K-H. G., E. J.]; Federal Republic of Germany

Based on the findings that the pH in malignant tumors can be preferentially decreased by stimulation of their aerobic glycolysis, acid-sensible prodrugs, which are nearly nontoxic at physiological pH, were synthesized. At lower pH, however, these compounds are cleaved with liberation of a cytotoxic species. The prototypic drug compound 2-hexenopyranoside of aldophosphamide was prepared, which releases aldophosphamide by acid-catalyzed hydrolysis. Exposure of cultured M1R rat mammary carcinoma cells to this agent at pH 7.4 only resulted in slight toxicity. However, when drug treatment was performed at pH 6.2, the mean pH in malignant tumors of hyperglycemic hosts, the colony-forming fraction of M1R cells decreased to 0.05 and 0.0001 of controls treated at pH 7.4 after exposure for 24 h and 48 h, respectively. The synthesis of the 2-hexenopyranoside of aldophosphamide is described in detail.

¹ Glucosidation Part 11. For Part 10 see Ref. 18. This research was supported by Grant 03189-52A9 from the Bundesministerium für Forschung und Technologie, by Grant 85-003-1 from the Wilhelm Sander-Stiftung, and by the Fonds der Chemischen Industrie.

² To whom requests for reprints should be addressed.

Received 12/15/88. Revised 4/10/89. Accepted 4/19/89.