Potential antitumor agents. 11. Inhibitors of alkaline phosphatase, an enzyme involved in the resistance of neoplastic cells to 6 thiopurines

Article abstract of DOI:10.1021/jm00255a005

A series of 4' substituted derivatives of 5 hydroxy 2 formylpyridine thiosemicarbazone (5 HP) has been synthesized and evaluated as inhibitors of alkaline phosphatase partially purified from a murine ascitic cell line of Sarcoma 180 resistant to the antileukemic agents 6 mercaptopurine and 6 thioguanine. These agents were also tested as inhibitors of ribonucleoside diphosphate reductase from rat Novikoff hepatoma and for antineoplastic activity in mice bearing either 6 thiopurine sensitive or resistant cells of Sarcoma 180. Structure activity relationship studies have delineated the bulk requirement for a 5 membered ring at the 4' position for optimum phosphatase inhibitor interaction. Similar bulk produced loss of activity by α (N) heterocyclic carboxaldehyde thiosemicarbazones as inhibitors of ribonucleoside diphosphate reductase. Some of these agents were found to possess potent tumor inhibitory potential.