75822-12-7Relevant academic research and scientific papers
Nonclassical 2,4-diamino-8-deazafolate analogues as inhibitors of dihydrofolate reductases from rat liver, Pneumocystis carinii, and Toxoplasma gondii
Gangjee, Aleem,Zhu, Yuanming,Queener, Sherry F.,Francom, Paula,Broom, Arthur D.
, p. 1836 - 1845 (2007/10/03)
The synthesis and biological activity of 42 6-substituted-2,4- diaminopyrido[3,2-d]pyrimidines (2,4-diamino-8-deazafolate analogues) are reported. The compounds were synthesized in improved yields compared to previous classical analogues using modifications of procedures reported previously by us. Specifically, the S-phenyl-; mono-, di-, and trimethoxyphenyl-; and mono-, di-, and trichlorophenyl-substituted analogues with H or CH3 at the N10 position and methyl and trifluoromethyl phenyl ketone analogues with H, C0H3, and CH2C≡CH at the N10 position were synthesized. The S10 and N10 α- and β-naphthyl analogues along with the N10 CH3 analogues were also synthesized. These compounds were evaluated as inhibitors of dihydrofolate reductases (DHFR) from Pneumocystis carinii (pc) and Toxoplasma gondii (tg); selectivity ratios were determined against rat liver (rl) DHFR as the mammalian reference enzyme. Against pcDHFR the IC50 values ranged from 0.038 x 10-6 M for 2,4-diamino-6-[(N-methyl-2'- naphthylamino)methyl]pyrido[3,2-d]pyrimidine (28) to 5.5 x 10-6 M for 2,4- diamino-6-[(2',4'-dimethoxyanilino)methyl]pyrido[3,2-d]pyrimidine (15). N10 methylation in all instances increased potency. None of the analogues were selective for pcDHFR. Against tgDHFR the most potent analogue was 2,4- diamino-6-[(N-methylanilino)methyl]pyrido[3,2-d]pyrimidine (5) (IC50 0.0084 x 10-6 M) and the least potent was 2,4-diamino-6-[(2'- naphthylamino)methyl]-pyrido[3,2-d]pyrimidine (37) (IC50 0.16 x 10-6 M). N10 methylation afforded an increase in potency up to 10-fold. In contrast to pcDHFR, several of the 8-deaza analogues were significantly selective for tgDHFR, most notably 2,4-diamino-6-[(2'-chloro-N- methylanilino)methyl]pyrido[3,2-d]pyrimidine (13), 2,4-diamino-6-[(3',4',5'- trimethoxyanilino)methyl]pyrido-[3,2-d]pyrimidine (29), and 2,4-diamino-6- [(2',4',6'-trichloroanilino)methyl]pyrido[3,2-d]pyrimidine (32) which combined high potency at 10-8 M along with selectivities of 8.0, 5.0, and 12.4, respectively. The potency of these three analogues are comparable to the clinically used agent trimetrexate while their selectivities for tgDHFR are 17-43-fold better than trimetrexate.
The reduction of aryl trifluoromethyl ketones by sodium borohydride. The hydride transfer process
Stewart, Ross,Teo, K. C.
, p. 2491 - 2496 (2007/10/02)
The rates of reduction of 17 aryl trifluoromethyl ketones by sodium borohydride in 2-propanol have been measured.The rho (ρ) value is 3.12, excluding the 4-amino and 4-dimethylamino groups, which both lower the rate to a greater extent than their ? values predict.The close correspondence between substituent effects for hydride addition in the methyl and trifluoromethyl series (excluding the amino groups) suggests that normal substituent effects are to be expected for oxidation processes involving hydride removal in trifluoromethyl compounds.The present results are consistent with the oxidation of aryl trifluoromethyl carbi ols by permanganate taking place by hydrogen atom abstraction.The effect of substituents on the rate of reduction of the trifluoromethyl ketones is almost identical to that on the equilibrium constant for formation of the ketone hydrates.The application of the reactivity-selectivity principle to the reduction reaction is also considered.Reduction of the 4-ethyl compound has ΔH = 2.7 kcal mol-1 and ΔS = -38 cal deg-1 mol-1.
