Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:1.5.1.3 (dihydrofolate reductase)
 5,819 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

2-Carbomethoxy-4-(p-carbomethoxyphenyl)cyclohexanone was prepared in a four-step process and thermally condensed with 2,4,6-triaminopyrimidine to afford methyl 2,4-diamino-4-deoxy-7-hydroxy-5,10-ethano-5,10-dideazapteroate+ ++. Reduction of the 7-oxo function with borane gave the 7,8-dihydro pterin which was subsequently oxidized to the fully aromatic pteroate ester with dicyanodichlorobenzoquinone. Saponification of the benzoate ester, coupling with diethyl glutamate and final ester hydrolysis afforded the title compound. This novel deazaaminopterin analogue was approximately as potent as methotrexate in vitro in terms of DHFR and L1210 cell growth inhibition. There are indications of diastereomeric differences in the enzyme inhibition measurements. A significant transport advantage over MTX for influx into L1210 cells was observed. The compound was active against the E 0771 murine mammary solid tumor, but further investigation with individual diastereomers is required to define the ED50.
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PMID:Synthesis and antifolate properties of 5,10-ethano-5,10-dideazaaminopterin. 173 49

Twenty 6-substituted 2,4-diaminotetrahydroquinazolines were designed, synthesized, and biologically evaluated as novel nonclassical inhibitors of dihydrofolate reductase (DHFR) from Pneumocystis carinii and Toxoplasma gondii and as antitumor agents. The 6-substituents included substituted anilinomethyls, with alkoxy (OCH3, and OCH2CH3) and halogen (Cl and Br) moieties on the phenyl ring; an indolinomethyl; and 1-naphthylaminomethyls. The compounds were synthesized from a protected key intermediate 2,4-bis(acetamido)-5,6,7, 8-tetrahydroquinazoline-6-carboxaldehyde (26) by reductive amination with the appropriate amine. Compound 26 was obtained via a Diels--Alder reaction of 2-(trimethylsiloxy) -1,3-butadiene with acrolein to afford cyclohexanone-4-carboxaldehyde dimethyl acetal (23) after deprotection of the silyloxy group and protection of the aldehyde in a single step. Cyclocondensation of 23 with dicyandiamide followed by protection of the 2,4-diamino groups and deprotection of the 6-acetal gave 26. The compounds were significantly potent ((7-330) x 10(-9) M) and selective against T. gondii (versus rat liver DHFR). The most selective analogue against T. gondii DHFR was 2,4-diamino-6-[[(2',5'-dimethoxyphenyl) methylamino]methyl]-5,6,7,8-tetrahydroquinazoline (5) which showed exceptionally high inhibitory activity against the growth of T. gondii cells in culture (IC50 = 5.4 x 10(-8) M). Selected analogues were evaluated as inhibitors of the growth of tumor cells in culture. The most active analogues inhibited the growth of tumor cells at GI50 = 10(-8) M.
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PMID:Nonclassical 2,4-diamino-6-(aminomethyl)-5,6,7,8-tetrahydroquinazoline antifolates: synthesis and biological activities. 765 54