Non-classical antifolates, 5-(N-phenylpyrrolidin-3-yl)-2,4,6-triaminopyrimidines and 2,4-Diamino-6(5H)-oxopyrimidines, synthesis and antitumor studies.
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.
Huang
Yen-Lin
YL
Laboratory of Bioorganic Chemistry, Institute of Biomedical Sciences, Academia Sinica, 115, Taipei, Taiwan
Lin
Chyun-Feng
CF
Lee
Yi-Jen
YJ
Li
Wei-Wei
WW
Chao
Ting-Chou
TC
Bacherikov
Valeriy A
VA
Chen
Kuo-Tung
KT
Chen
Chin-Ming
CM
Su
Tsann-Long
TL
D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000494:pharmacology*; D002470:Cell Survival / Q000187:drug effects; D003857:Deoxyuridine / Q000378:metabolism; D004354:Drug Screening Assays, Antitumor; D005492:Folic Acid / Q000378:metabolism; D005493:Folic Acid Antagonists / Q000138:chemical synthesis* / Q000494:pharmacology*; D006801:Humans; D002955:Leucovorin / Q000494:pharmacology; D008727:Methotrexate / Q000494:pharmacology / Q000633:toxicity; D011743:Pyrimidines / Q000138:chemical synthesis* / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D013762:Tetrahydrofolate Dehydrogenase / Q000378:metabolism; D014316:Tritium; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D005493:Folic Acid Antagonists; D011743:Pyrimidines; D014316:Tritium; D005492:Folic Acid; D013762:Tetrahydrofolate Dehydrogenase; D002955:Leucovorin; D003857:Deoxyuridine; D008727:Methotrexate