Synthesis and antitumor activities of novel 6-5 fused ring heterocycle antifolates: N-[4-[omega-(2-amino-4-substituted-6,7-dihydrocyclopenta [d]pyrimidin-5-yl)alkyl]benzoyl]-L-glutamic acids.

Abstract

Novel antifolates with a 6-5 fused ring system, 6,7-dihydrocyclopenta [d]pyrimidine, (3a,b and 4a,b) were synthesized on the basis of combined modification of the heterocycle and bridge regions of the folate molecule. The synthetic method involves (1) synthesis of key intermediates of tert-butyl 4-[omega-(2-substituted-3-oxocyclopentanyl) alkyl]benzoates (8a,b and 9a,b) by a carbon-carbon radical coupling of tert-butyl 4-(omega-iodoalkyl)benzoates (7a,b) with 2-substituted-2-cyclopenten-1-ones (5 and 6) utilizing tributyltin hydride, (2) cyclization of either the methyl enol-ethers derived from the 2-cyanocyclopentanones (8a,b) or the 2-(methoxycarbonyl)cyclopentanones (9a,b) themselves by treatment with guanidine which leads to 6,7-dihydrocyclopenta [d]pyrimidines with a 4-(tert-butoxycarbonyl)phenylalkyl group (11a,b and 14a,b), (3) deprotection to the corresponding carboxylic acids (12a,b and 15a,b), and (4) amidation with diethyl glutamate and deesterification. Potent dihydrofolate reductase inhibition and highly potent cell growth inhibition were found with 2,4-diaminopyrimidine-fused cyclopentene compounds containing the trimethylene (3a) or ethylene bridge (3b) but not with the corresponding 2-amino-4-hydroxy analogs (4a,b). Compounds 3a and 3b were more growth inhibitory to several tumor cell lines (P388, colon 26, colon 38, and KB) than was methotrexate, with 3a being the most potent. Both 3a and 3b gave increases in the lifespan of P388 leukemic mice comparable to that observed with MTX. Both compounds were therapeutic against colon 26 colorectal carcinoma in mice. Compound 3a was highly effective against LC-6 non-small cell lung carcinoma in nude mice.

• Authors: Y Kotake, A Iijima, K Yoshimatsu, N Tamai, Y Ozawa, N Koyanagi, K Kitoh, H Nomura
• Journal: Journal of medicinal chemistry (J Med Chem) Vol. 37 Issue 11 Pg. 1616-24 (May 27 1994) ISSN: 0022-2623 [Print] United States
• PMID: 8201595 (Publication Type: Comparative Study, Journal Article, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• Antineoplastic Agents
• Folic Acid Antagonists
• Glutamates
• Pyrimidines
• N-(4-(2-(2,4-diamino-6,7-dihydro-5H-cyclopenta(d)pyrimidin-5-yl)ethyl)benzoyl)glutamic acid
• N-(4-(3-(2,4-diamino-6,7-dihydro-5H-cyclopenta(d)pyrimidin-5-yl)propyl)benzoyl)glutamic acid
• Methotrexate

Topics

• Animals
• Antineoplastic Agents (chemical synthesis, pharmacology, therapeutic use)
• Carcinoma, Squamous Cell (drug therapy)
• Cell Division (drug effects)
• Colonic Neoplasms (drug therapy)
• Folic Acid Antagonists (chemical synthesis, therapeutic use)
• Glutamates (chemical synthesis, pharmacology, therapeutic use)
• Humans
• Leukemia P388 (drug therapy)
• Methotrexate (therapeutic use)
• Mice
• Mice, Inbred BALB C
• Mice, Inbred DBA
• Mice, Nude
• Neoplasm Transplantation
• Pyrimidines (chemical synthesis, pharmacology, therapeutic use)
• Structure-Activity Relationship
• Tumor Cells, Cultured