95943-67-2Relevant academic research and scientific papers
Synthesis and biological activities of tetrahydroquinazoline analogs of aminopterin and methotrexate
Gangjee,Zaveri,Queener,Kisliuk
, p. 243 - 247 (1995)
(6R,6S)-5,8-Dideaza-5,6,7,8-tetrahydroaminopterin (1) and (6R,6S)-5,8-dideaza-5,6,7,8-tetrahydromethotrexate (2) were synthesized as potential inhibitors of dihydrofolate reductase (DHFR) and as antitumor agents. Cyclohexanone-4-carboxaldehyde dimethyl acetal, a key intermediate was synthesized from cyclohexane-1,4-dione monoethylene ketal, which was converted via a Wittig reaction to its exocyclic 4-methylene derivative which in turn, was converted to the 4-aldehyde via a hydroboration-oxidation sequence. Selective protection of the 4-aldehyde as the dimethylacetal and cyclization with dicyandiamide afforded the 6-dimethylacetal of 2,4-diamino-5,6,7,8-tetrahydroquinazoline. Protection of the 2,4-diamino moieties and selective deprotection of the 6-aldehyde followed by reductive amination with p-aminobenzoyl-L-glutamate afforded 2,4-bisacetamido-5,8-dideaza-5,6,7,8-tetrahydroaminopterin (11). Deprotection of 11 afforded 1. Compound 2 was obtained from 11 via N10-methylation and deprotection. The N10-methyl analogue 2 was 2-10 fold more potent than 1 as an inhibitor of various DHFRs. In the in vitro preclinical screening program of the National Cancer Institute, compound 2 inhibited the growth of eighteen of the twenty nine tumor cell lines in culture at a GI50 -8 M.
