Synthesis, Dihydrofolate Reductase Inhibition, Anti-proliferative Testing, and Saturation Transfer Difference 1H-NMR Study of Some New 2-Substituted-4,6-diaminopyrimidine Derivatives

Abstract

A series of 2-substituted-4,6-diaminipyrimidine derivatives were synthesized and evaluated for their dihydrofolate reductase (DHFR) inhibitory activity. Saturation transfer difference (STD) 1 H-NMR experiments were used to probe the binding characteristics of the compounds with human DHFR enzyme. The most potent molecules, 12 and 15, in enzyme assay study showed the best results in STD experiments indicating their intimate interaction with the receptor. The docking studies were followed to explain the structural basis for the observed interaction between the ligands and DHFR. All the compounds were also assayed in vitro for their growth inhibitory activity on MCF-7, HepG2, SKHep1, and Hela tumor cell lines. Compounds 16, 17, and 22 demonstrated the most potent in vitro anti-proliferative activity among the others.Key words diaminopyrimidine; dihydrofolate reductase inhibitory activity; synthesis Interfering with folate metabolism in cancerous cells could provide a useful mean in cancer chemotherapy as a result of the inhibition of the biosynthesis of nucleic acid precursors.

Na2CO3-Mediated [3+3] Annulation Reaction of Substituted Benzamidines with 2-Benzylidenemalononitriles: Access to Substituted Pyrimidine-4,6-diamines

“…17 A similar synthetic strategy also was reported by the Kobarfard group via the reaction of thiourea and malononitrile in absolute ethanol as solvent. 5b El-Sayed and Mohamed described the condensation of N -(2,3-dihydro-1 H -inden-5-yl)carbonohydrazonoyl dicyanide with guanidine hydrochloride in refluxing ethanol to furnish the 4,6-diaminopyrimidine framework with an azo group (Scheme 1 ). 18 In 2012, Wilson and co-workers reported the synthesis of 4,6-diamino-2,5-diphenylpyrimidine by reacting phenylmalononitrile with benzamidine in a flow system (Scheme 1 ).…”

Antiproliferative Activity of (−)‐Isopulegol‐based 1,3‐Oxazine, 1,3‐Thiazine and 2,4‐Diaminopyrimidine Derivatives

“…[ 16 , 17 , 18 ] Among the existing large numbers of structurally diverse pyrimidine derivatives, 2,4‐diaminopyrimidines have attracted considerable attention due to their important chemopreventive and chemotherapeutic effects. [ 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 ] This structural motif is involved in numerous biological activities – mainly concerning cancer – with action mechanisms related to folate metabolism inhibition, [38] kinase inhibitor activity[ 26 , 39 , 40 , 41 , 42 , 43 , 44 ] and apoptosis induction. [ 22 , 45 , 46 ] For example, Ceritinib (Zykadia™), [47] Alectinib (Alecensa TM ), [48] Brigatinib (Alunbrig™), [49] Lorlatinib, (Lorbrena TM ), [50] small‐molecule antineoplastic anaplastic lymphoma kinase (ALK) inhibitors, and others are used for the treatment of patients with non‐small cell lung cancer.…”