1BOZ

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

1BOZ の概要

• エントリーDOI: 10.2210/pdb1boz/pdb
• 分子名称: PROTEIN (DIHYDROFOLATE REDUCTASE), NADPH DIHYDRO-NICOTINAMIDE-ADENINE-DINUCLEOTIDE PHOSPHATE, N6-(2,5-DIMETHOXY-BENZYL)-N6-METHYL-PYRIDO[2,3-D]PYRIMIDINE-2,4,6-TRIAMINE, ... (4 entities in total)
• 機能のキーワード: oxidoreductase
• 由来する生物種: Homo sapiens (human)
• 細胞内の位置: Mitochondrion : P00374
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 22345.20

構造登録者

Gangjee, A.,Vidwans, A.P.,Vasudevan, A.,Queener, S.F.,Kisliuk, R.L.,Cody, V.,Li, R.,Galitsky, N.,Luft, J.R.,Pangborn, W. (登録日: 1998-08-06, 公開日: 1998-08-12, 最終更新日: 2024-05-22)

主引用文献

Gangjee, A.,Vidwans, A.P.,Vasudevan, A.,Queener, S.F.,Kisliuk, R.L.,Cody, V.,Li, R.,Galitsky, N.,Luft, J.R.,Pangborn, W.
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.
J.Med.Chem., 41:3426-3434, 1998

PubMed Abstract: The 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.

PubMed: 9719595
DOI: 10.1021/jm980081y

実験手法

X-RAY DIFFRACTION (2.1 Å)