Novel 8-deaza-5,6,7,8-tetrahydroaminopterin derivatives as dihydrofolate inhibitor: design, synthesis and antifolate activity.
ABSTRACT We report, for the first time, the synthesis and biological activities of 8-deaza-5,6,7,8-tetrahydroaminopterin 9, and the 5-substituted and 5,10-disubstituted analogues 11, 13, 15, and 17. The analogues were obtained from key compound diethyl 8-deaza-5,6,7,8-tetrahydroaminopterin 8 following the catalytic reduction of the pyridine ring of diethyl 8-deaza aminopterin 5. The five novel 8-deaza-5,6,7,8-tetrahydroaminopterin derivatives were assayed in vitro for their cytotoxicity on BGC-823, HL-60, Bel-7402 and Hela tumor cell lines, and inhibition on recombinant human dihydrofolate reductase (DHFR), among which the most potent molecule (compound 9) was about 4- to 10-fold poorer than MTX on the four kinds of tumor cell lines, and its effect on DHFR was about 17-fold poorer than MTX. The docking studies were followed to explain the biological testing results.
- Journal of Heterocyclic Chemistry - J HETEROCYCL CHEM. 01/2009; 46(6):1151-1153.
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ABSTRACT: A direct new synthetic method on the chemistry of benzo[g]pteridines is reported. Reactions between 5,8-dichloro-2,3-dicyanoquinoxaline and benzamidines gave 4-amino-2-aryl-6,9-dichlorobenzo[g]pteridines in high to quantitative yields. The molecular structure of an N-acetyl derivative of a member of this family of compounds, 4-acetamido-6,9-dichloro-2-phenylbenzo[g]pteridine, was determined by X-ray crystallography. The synthesized compounds were evaluated for their potential anti-inflammatory activity as inhibitors of the pro-inflammatory cytokines TNF-α and IL-6. Compounds 5b, 5d and 5i showed the highest level of inhibition of both cytokines. The rest of the compounds into the series (5a, 5f, 5g and 5h), with the only exceptions of compounds 5c and 5e, which were unable to inhibit TNF-α and were the two compounds with the lower effect upon IL-6, were also able to reach good levels of inhibition of TNF-α and even higher levels of inhibition of IL-6.European journal of medicinal chemistry 05/2013; 66C:269-275. · 3.27 Impact Factor