Syntheses and antifolate activity of 5-methyl-5-deaza analogs of aminopterin, methotrexate, folic acid, and N10-methylfolic acid

Abstract

Evidence indicating that modifications at the 5- and 10-positions of classical folic acid antimetabolites lead to compounds with favorable differential membrane transport in tumor vs. normal proliferative tissue prompted an investigation of 5-alkyl-5-deaza analogues. 2-Amino-4-methyl-3,5-pyridinedicarbonitrile, prepared by hydrogenolysis of its known 6-chloro precursor, was treated with guanidine to give 2,4-diamino-5-methylpyrido[2,3-d]pyrimidine-6-carbonitrile which was converted via the corresponding aldehyde and hydroxymethyl compound to 6-(bromomethyl)-2,4-diamino-5-methylpyrido[2,3-d]pyrimidine. Reductive condensation of the nitrile 8 with diethyl N-(4-amino-benzoyl)-L-glutamate followed by ester hydrolysis gave 5-methyl-5-deazaaminopterin. Treatment of 12 with formaldehyde and Na(CN)BH3 afforded 5-methyl-5-deazamethotrexate, which was also prepared from 15 and dimethyl N-[(4-methylamino)benzoyl]-L-glutamate followed by ester hydrolysis. 5-Methyl-10-ethyl-5-deazaaminopterin was similarly prepared from 15. Biological evaluation of the 5-methyl-5-deaza analogues together with previously reported 5-deazaaminopterin and 5-deazamethotrexate for inhibition of dihydrofolate reductase (DHFR) isolated from L1210 cells and for their effect on cell growth inhibition, transport characteristics, and net accumulation of polyglutamate forms in L1210 cells revealed the analogues to have essentially the same properties as the appropriate parent compound, aminopterin or methotrexate (MTX), except that 20 and 21 were approximately 10 times more growth inhibitory than MTX. In in vivo tests against P388/0 and P388/MTX leukemia in mice, the analogues showed activity comparable to that of MTX, with the more potent 20 producing the same response in the P388/0 test as MTX but at one-fourth the dose; none showed activity against P388/MTX. Hydrolytic deamination of 12 and 20 produced 5-methyl-5-deazafolic acid and 5,10-dimethyl-5-deazafolic acid, respectively. In bacterial studies on the 2-amino-4-oxo analogues, 5-deazafolic acid proved to be a potent inhibitor of Lactobacillus casei DHFR and also the growth of both L. casei ATCC 7469 and Streptococcus faecium ATCC 8043. Its 5-methyl congener 22 is also inhibitory toward L. casei, but its IC50 for growth inhibition is much lower than its IC50 values for inhibition of DHFR or thymidylate synthase from L. casei, suggesting an alternate site of action.

Design and Synthesis of Classical and Nonclassical 6-Arylthio-2,4-diamino-5-ethylpyrrolo[2,3-d]pyrimidines as Antifolates

“…Molecular modeling (Sybyl 7.0) 6 suggested that an extension of the 5-methyl group to an ethyl group might enhance the potency and selectivity against some pathogenic DHFR. Thus, a series of nonclassical 5-ethyl-6-[(substituted-phenyl)-sulfanyl]-7H-pyrrolo [2,3-d]pyrimidine-2,4-diamines (3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17) were also synthesized.…”

Base-Catalyzed Synthesis of Pyridopyrimidinone Derivatives

“…Pyrazolopyrimidine heterocyclic compounds have excellent biological medicine activity in the aspects of anticancer [1], diminishing inflammation [2], disinfecting [3], resisting allergy [4], resisting convulsion [5], relieving pain [6], bringing down fever [7] and calmative [8]. Some compounds containing pyrazolopyrimidine fused ring have been applied in clinical treatment, such as pirenperone used as calmative, Barmastine used as antiallergic agent.…”

Green and Efficient Synthesis of Some Pyrido[2,3-D]Pyrimidin-4(3h)-One Derivatives Via Iodine Catalyst in Aqueous Media and Evaluation the Synthesized Compounds as Anticancer

“…The pyrido [2,3-d]pyrimidine nucleus represents in many biologically active compounds which includes antitumour [1][2][3][4][5][6][7], antibacterial [8], anticonvulsant [9], antipyretic [10], analgesic [11], and CNS depressant activity [12]. Specifically pyrido [2,3-d]pyrimidines known to inhibit Pneumocystis carinii(pc), Toxoplasma gondii(tg) of tumor cell lines in culture [13] and the activity is attributed to inhibition of dihydrofolate reductase (DHFR) [14,15].…”