Journal of Heterocyclic Chemistry p. 243 - 247 (1995)
Update date:2022-08-04
Topics:
Gangjee
Zaveri
Queener
Kisliuk
(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 < 1.0 x 10-8 M.
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Doi:10.1021/ja01000a059
(1967)Doi:10.1016/S0040-4020(01)97604-5
(1964)Doi:10.1021/ja00240a030
(1987)Doi:10.1016/S0040-4020(01)91282-7
(1984)Doi:10.1016/S0039-128X(84)90120-X
(1984)Doi:10.1039/jr9630000548
(1963)