Thienyl and thiazolyl acyclic analogues of 5-deazatetrahydrofolic acid.
Analogues of N-[4-[[3-(2,4-diamino-1,6-dihydro-6-oxo-5-pyrimidinyl)propyl]amino] benzoyl]-L-glutamic acid (5-DACTHF), in which the phenylene group is replaced by either a thienoyl or a thiazolyl group were synthesized. These compounds were prepared by reductive amination of suitably protected pyrimidinylpropionaldehyde with the aminoaroyl glutamates. These glutamates were in turn synthesized from the corresponding nitroaroyl carboxylic acids by condensation with protected glutamic acid followed by catalytic reduction. The compounds were tested as inhibitors of methotrexate uptake as a measure of binding to the reduced folate transport system, as inhibitors of glycinamide ribonucleotide transformylase, as substrates for folylpolyglutamate synthetase, and as inhibitors of tumor cell growth in cell culture. The thiophene analogue was found to be equal in activity to 5-DACTHF in the MCF-7 cell growth inhibition assay while the thiazole analogue was 9-fold more active. Indeed this thiazole was over 4 times more active in the MCF-7 cell line than the clinically investigated compound 5,10-dideaza-5,6,7,8-tetrahydrofolic acid (DDATHF).
Wellcome Research Laboratories, Burroughs Wellcome Company, Research Triangle Park, North Carolina 27709.
S J
SJ
Hodson
E C
EC
Bigham
D S
DS
Duch
G K
GK
Smith
R
R
Ferone
D000230:Adenocarcinoma / Q000473:pathology; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001943:Breast Neoplasms / Q000473:pathology; D002455:Cell Division / Q000187:drug effects*; D005493:Folic Acid Antagonists / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D010084:Oxidation-Reduction; D013379:Substrate Specificity; D013763:Tetrahydrofolates / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D005493:Folic Acid Antagonists; D013763:Tetrahydrofolates; C062810:N-(4-((3-(2,4-diamino-1,6-dihydro-6-oxo-5-pyrimidinyl)propyl)amino)benzoyl)glutamic acid; C088282:N-((5-((3-(2,4-diamino-1,6-dihydro-6-oxo-5-pyrimidinyl)propyl)amino)-2-thienoyl)carbonyl)glutamic acid; C088283:N- ((5-((3-(2,4-diamino-1,6-dihydro-6-oxo-5-pyrimidinyl)propyl)amino)-2-thiazolyl)carbonyl)glutamic acid; C045894:lometrexol