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Non-classical Antifolates, 5-(N-phenylpyrrolidin-3-yl)-2,4,6-triaminopyrimidines and 2,4-Diamino-6(5H)-oxopyrimidines, Synthesis and Antitumor Studies

Non-classical Antifolates, 5-(N-phenylpyrrolidin-3-yl)-2,4,6-triaminopyrimidines and 2,4-Diamino-6(5H)-oxopyrimidines, Synthesis and Antitumor Studies

Yen-Lin Huang, Chyun-Feng Lin, Yi-Jen Lee, Wei-Wei Li, Ting-Chou Chao, Valeriy A Bacherikov, Kuo-Tung Chen, Chin-Ming Chen, Tsann-Long Su

Bioorg Med Chem. 2003 Jan 2;11(1):145-57.

PMID: 12467717

Abstract:

A series of non-classical antifolates, namely 5-(N-phenylpyrrolidin-3-yl)-2,4,6-triaminopyrimidines (25a-i) and 2,4-diamino-(N-phenylpyrrolidin-3-yl)-6(5H)-oxopyrimidines (26a,b,c,f,h,i) was synthesized and evaluated for their in vitro cytotoxicity. Reacting aniline derivatives with 1,4-dibromo-2-butanol gave 1-phenyl-3-pyrrolidinols (19a--i), which were oxidized to pyrrolidin-3-ones (20a-i). The Knoevenagel reaction of 20a-i with malononitrile or ethyl cyanoacetate gave 3-(dicyanomethylene)- (21a-i) and 3-[cyano(ethoxycarbonyl)methylene]-pyrrolidines (22a,b,c,f,h,i), respectively, which were subsequently reduced to the corresponding 3-(dicyano)methyl- or 3-[cyano(ethoxycarbonyl)methyl)]pyrrolidines (23a-i and 24a,b,c,f,h,i, respectively). Condensation of either 23a-i or 24a,b,c,f,h,i with guanidine afforded the target compounds. The cytotoxicity of these compounds was evaluated based on their ability to inhibit various human tumors (human colon adenocarcinoma COLO 205, lung carcinoma H23 and its adriamycin resistant cell line H23/0.3, T-cell leukemia MOLT-4, promyelocytic leukemia HL-60, and T-cell acute lymphocytic leukemia CCRF-CEM) cell growth in culture. These studies revealed that the 2,4,6-triaminopyrimidine derivatives were more cytotoxic than the 2,4-diamino-6(5H)-oxopyrimidine counter parts, in which the latter was inactive in all testing systems. The 2,4,6-triaminopyrimidine derivatives bearing halogen substituent on the phenyl ring (25f,h,i) were cytotoxic in all cultured leukemia cell growth. Among these compounds, 5-(4-fluoro and 4-chlorophenyl)-2,4,6-triaminopyrimidines (25e and 25h, respectively) were more potent than methotrexate (MTX) in inhibiting of H23/0.3 cell growth. These compounds inhibit the folate metabolic pathways as indicated by tritium release from [5-3H]deoxyuridine in MTX sensitive human fibrosarcoma HT-1080 cells. Dihydrofolate reductase is the major target for 25f,h,i, as shown by leucovorin (LV) rescue of MTX cytotoxicity.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
AP1335150098	2-{[7-(5-N,N-Ditolylaminothiophen-2-yl)-2,1,3-benzothiadiazol-4-yl]methylene}malononitrile		1335150-09-8	Price

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