Synthesis and biological evaluation of 9-thia-5,10-dideazafolic acid

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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) ester (5) was prepared via the condensation of 2,6-diamino-3H-pyrimidin-4-one and S-(2-malonaldehyde)-1,1,3,3-tetramethylthiouronium bromide (4). Compound 5, in a one pot procedure, was deprotected using sodium hydroxide and then coupled to diethyl N-[(4-chloromethyl)benzoyl]-L-glutamate, followed by saponification of the ethyl esters to give the 9-thia-5,10-dideazafolic acid (3b). Compound 3b was a potent inhibitor of human 5-aminoimidazole-4-carboxamide ribonucleotide transformylase (Ki of 8 ± 5 μM) and showed no inhibition of human glycinamide ribonucleotide transformylase at concentrations as high as 50 μM. Compound 3b was screened by the National Cancer Institute Developmental Therapeutics Program against 60 human tumors and was found to be active against a leukemia RPMI-8226 cell line where the LC50 was 1 μM.

Original languageEnglish (US)
Pages (from-to)1097-1099
Number of pages3
JournalJournal of Heterocyclic Chemistry
Issue number5
StatePublished - 2002

All Science Journal Classification (ASJC) codes

  • Organic Chemistry


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