Specific inhibition of Type II inosine monophosphate dehydrogenase activity of Tmolt(4) T cell human leukaemia cells by 3-methoxy and di-benzohydroxamic acids, maleic hydrazide and malonic acids

Small-molecular-weight benzohydroxamic and malonic acids and maleic hydrazi de proved to be potent inhibitors of the activity of human Tmolt(4) leukaem ia Type II IMP (inosine monophosphate) dehydrogenase (IMPDH) activity. They were competitive inhibitors with respect to IMPDH demonstrating K-i values in the range 2.57-41.3 muM. less than half the values of the IC50 (muM) fo r the inhibition of Type II IMPDH. The IC50 muM values positively correlate d with the ability of each compound to inhibit crude IMPDH activity, de-nov o purine and DNA syntheses and growth of the T leukaemia cell line. Compoun ds were not inhibitors of Type 1 IMPDH. Type I IMPDH predominates in normal resting cells compared with Type II which is found in rapidly proliferatin g cells. Discovery of agents which would selectivity target IMPDH found in proliferating cells should eliminate any antineoplastic therapeutic toxic e ffects in normal cells of the body.