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.
SourceAvailable from: Antonio J Ruiz Alcaraz[Show abstract] [Hide abstract]
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. DOI:10.1016/j.ejmech.2013.05.020 · 3.43 Impact Factor
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ABSTRACT: A number of 8-deazatetrahydrofolates bearing electrophilic groups on N(5) were designed and synthesized based on the action mechanism of methionine synthase, and their biological activities were investigated as well. Compounds (11b, 12b and 16) showed the most active against methionine synthase (IC(50): 8.11 μM, 1.73 μM, 1.43 μM). In addition, the cytotoxicity to human tumor cell lines and dihydrofolate reductase (DHFR) inhibition by target compounds were evaluated.European Journal of Medicinal Chemistry 10/2012; 58C:228-236. DOI:10.1016/j.ejmech.2012.09.027 · 3.43 Impact Factor
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ABSTRACT: The synthesis of 2-amino-4-hydroxyl-6-hydroxymethyl-5,6,7,8-tetrahydropyrido[3,2-d]pyrimidine 3 is described from 2-amino-6-methyluracil 4 through the crucial step of 2-pivaloyl protecting and cyclization. The assignment of the structure of 3 was performed by its spectral data, the (1)H NMR, (13)C NMR, gHMQC, and HRMS spectra.Journal of Heterocyclic Chemistry 11/2009; 46(6):1151-1153. DOI:10.1002/jhet.197 · 1.22 Impact Factor