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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.
Author(s) -
Baker B. R.,
Johnson Morris A.
Publication year - 1967
Publication title -
journal of heterocyclic chemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.321
H-Index - 59
eISSN - 1943-5193
pISSN - 0022-152X
DOI - 10.1002/jhet.5570040408
Subject(s) - chemistry , hydrochloride , enzyme , reductase , triazine , stereochemistry , active site , biochemistry , organic chemistry
Condensation 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.