1boz | pdb_00001boz
STRUCTURE-BASED DESIGN AND SYNTHESIS OF LIPOPHILIC 2,4-DIAMINO-6-SUBSTITUTED QUINAZOLINES AND THEIR EVALUATION AS INHIBITORS OF DIHYDROFOLATE REDUCTASE AND POTENTIAL ANTITUMOR AGENTS
Structural highlights
Disease[DYR_HUMAN] Defects in DHFR are the cause of megaloblastic anemia due to dihydrofolate reductase deficiency (DHFRD) [MIM:613839]. DHFRD is an inborn error of metabolism, characterized by megaloblastic anemia and/or pancytopenia, severe cerebral folate deficiency, and cerebral tetrahydrobiopterin deficiency. Clinical features include variable neurologic symptoms, ranging from severe developmental delay and generalized seizures in infancy, to childhood absence epilepsy with learning difficulties, to lack of symptoms.[1] [2] Function[DYR_HUMAN] Key enzyme in folate metabolism. Contributes to the de novo mitochondrial thymidylate biosynthesis pathway. Catalyzes an essential reaction for de novo glycine and purine synthesis, and for DNA precursor synthesis. Binds its own mRNA and that of DHFRL1.[3] [4] Evolutionary Conservation Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf. Publication Abstract from PubMedThe synthesis and biological activities of 14 6-substituted 2,4-diaminoquinazolines are reported. These compounds were designed to improve the cell penetration of a previously reported series of 2,4-diamino-6-substituted-pyrido[2,3-d]pyrimidines which had shown significant potency and remarkable selectivity for Toxoplasma gondii dihydrofolate reductase (DHFR), but had much lower inhibitory effects on the growth of T. gondii cells in culture. The target N9-H analogues were obtained via regiospecific reductive amination of the appropriate benzaldehydes with 2,4,6-triaminoquinazoline, which, in turn, was synthesized from 2,4-diamino-6-nitroquinazoline. The N9-CH3 analogues were synthesized via a regiospecific reductive methylation of the corresponding N9-H precursors. The compounds were evaluated as inhibitors of DHFR from human, Pneumocystis carinii, T. gondii, rat liver, Lactobacillus casei, and Escherichia coli, and selected analogues were evaluated as inhibitors of the growth of tumor cells in culture. These analogues displayed potent T. gondii DHFR inhibition as well as inhibition of the growth of T. gondii cells in culture. Further, selected analogues were potent inhibitors of the growth of tumor cells in culture in the in vitro screening program of the National Cancer Institute with GI50s in the nanomolar and subnanomolar range. Crystallographic data for the ternary complex of hDHFR-NADPH and 2,4-diamino-6-[N-(2', 5'-dimethoxybenzyl)-N-methylamino]pyrido[2,3-d]pyrimidine, 1c, reveal the first structural details for a reversed N9-C10 folate bridge geometry as well as the first conformational details of a hybrid piritrexim-trimetrexate analogue. Structure-based design and synthesis of lipophilic 2,4-diamino-6-substituted quinazolines and their evaluation as inhibitors of dihydrofolate reductases and potential antitumor agents.,Gangjee A, Vidwans AP, Vasudevan A, Queener SF, Kisliuk RL, Cody V, Li R, Galitsky N, Luft JR, Pangborn W J Med Chem. 1998 Aug 27;41(18):3426-34. PMID:9719595[5] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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