133446-60-3Relevant academic research and scientific papers
Synthesis and biological evaluation of 9-thia-5,10-dideazafolic acid
Wall, Mark,Benkovic, Stephen J.
, p. 1097 - 1099 (2002)
The folate analogue, 9-thia-5,10-dideazafolic acid (3b), was obtained in an efficient two-step procedure in an overall yield of 60%. The previously unknown intermediate dimethyl-thiocarbamic acid S-(2-amino-3,4-dihydo-4-oxo-pyrido[2,3-d] pyrimidin-6-yl) e
Synthesis and biological activities of tricyclic conformationally restricted tetrahydropyrido annulated furo[2,3-d]pyrimidines as inhibitors of dihydrofolate reductases
Gangjee, Aleem,Elzein, Elfatih,Queener, Sherry F.,McGuire, John J.
, p. 1409 - 1416 (2007/10/03)
The synthesis of seven 2,4-diamino-5,6,7,8-tetrahydro-7-substituted pyrido[4',3':4,5]furo[2,3-d]pyrimidines 1-6 are reported as nonclassical antifolate inhibitors of dihydrofolate reductase (DHFR) and compound 7 as a classical antifolate inhibitor of tumor cells in culture. The compounds were designed as conformationally restricted analogues of trimetrexate. The synthesis was accomplished from the cyclocondensation of 3-bromo-4-piperidone with 2,4-diamino-6-hydroxypyrimidine to afford regiospecifically 2,4-diamino- 5,6,7,8-tetrahydropyrido-[4',3':4,5]furo[2,3-d]pyrimidine-7-hydrobromide (16). This in turn was alkylated with the appropriate benzyl halide to afford the target compounds 1-6. The classical antifolate 7 utilized 4- (chloromethyl)benzoyl-L-glutamic acid diethyl ester (17) instead of the benzyl halide for alkylation, followed by saponification to afford 7. Compounds 1-6 showed moderate inhibitory potency against DHFR from Pneumocystis carinii, Toxoplasma gondii, Mycobacterium avium, and rat liver. The classical analogue 7 was 88-fold more potent against M. avium DHFR than against rat liver DHFR. The classical analogue was also inhibitory against the growth of tumor cells, CCRF-CEM, and FaDu, in culture.
Quinazoline Antifolate Thymidylate Synthase Inhibitors: Bridge Modifications and Conformationally Restricted Analogues in the C-2-Methyl Series
Marsham, Peter R.,Jackman, Ann L.,Hayter, Anthony J.,Daw, Melanie R.,Snowden, Jayne L.,et al.
, p. 2209 - 2218 (2007/10/02)
Several C2-methylquinazoline-based antifolates (14-26) have been prepared in which the C9,N10 bridge has been replaced by the reversed N9,C10 unit.This series was extensively studied by incorporating further substituents at N9 and C10 as well as by modifications to the p-aminobenzoate ring.The C-2-methylquinazoline analogues 29, 30, and 31 containing the methyleneoxa, methylenethia, and thia bridge units were also synthesized.In general these isosteric replacements of the bridge unit in the parent C2-methyl-N10-propargylquinazoline antifolate 2 were much less potent as inhibitors of isolated thymidylate synthase (TS) but several were at least as potent as inhibitors of L1210 cell growth in culture.The fusion of the p-aminobenzoate ring into the bicyclic systems 75 and 76 also reduced activity against TS but again gave highly cytotoxic compounds.The cytotoxicities were largely prevented by thymidine, confirming that TS in the major locus.
