Irreversible enzyme inhibitors. CXI. Candidate active‐site‐directed irreversible inhibitors of dihydrofolic reductase derived from 4,6‐diamino‐1,2‐dihydro‐l‐phenyl‐s‐triazines. V.

Abstract

AbstractCondensation of 5‐(p‐nitrophenyl)‐2‐pentanone with phenylbiguanide hydrochloride (V) gave a 2‐methyl‐2‐(p‐nitrophenylpropyl)‐1,2‐dihydro‐s‐triazine (IX); hydrogenation of the nitro group to amino followed by bromoacetylation afforded the candidate irreversible inhibitor of dihydrofolic reductase, namely, 2‐(p‐bromoacetamidophenylpropyl)‐4,6‐diamino‐1,2‐dihydro‐2‐methyl‐s‐triazine hydrochloride (VIII). Similarly, the o, m, and p‐isomers of 5‐nitrophenoxy‐2‐pentanone were converted to the corresponding 2‐(bromoacetamidophenoxypropyl)‐1,2‐dihydro‐s‐triazines (XI). The four candidate irreversible inhibitors were evaluated on the dihydrofolic reductases from pigeon liver, Walker‐256 rat tumor, and L‐1210/FR8 mouse leukemia. Only VIII was an irreversible inhibitor; VIII slowly inactivated the L‐121‐/FR8 mouse leukemia enzyme with a half‐life of 2–3 hours at 37°, but VIII showed no inactivation of the other two dihydrofolic reductases—a species specific inactivation.