Chemical synthesis and biological activities of 5-deazaaminopterin analogs bearing substituent(s) at the 5- and/or 7-position(s)

• Published in: Journal of medicinal chemistry Vol. 31; no. 6; pp. 1209 - 1215
• Main Authors: Su, Tsann Long, Huang, Jai Tung, Chou, Ting Chao, Otter, Glenys M, Sirotnak, Francis M, Watanabe, Kyoichi A
• Format: Journal Article
• Language: English
• Published: Washington, DC American Chemical Society 01.06.1988
• Subjects: Aminopterin - analogs & derivatives; Aminopterin - chemical synthesis; Aminopterin - pharmacology; Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - pharmacology; Chemistry; Exact sciences and technology; Heterocyclic compounds; Heterocyclic compounds with several n hetero atoms in the same ring, in separated rings or in fused rings; Humans; Methotrexate - pharmacology; Organic chemistry; Preparations and properties; Structure-Activity Relationship; Tumor Cells, Cultured - drug effects; Antineoplastic agent; Nitrogen heterocycle; Aminoacid; Bicyclic compound; Benzenic compound; Dicarboxylic acid; Guanidines; Biological activity; Secondary amine
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm00401a023

Condensation of cyanothioacetamide (4) with ethyl alpha-(ethoxymethylene)acetoacetate (5b), ethyl 4-ethoxy-2-(ethoxymethylene)-3-oxobutanoate (5c), ethyl 2-(ethoxymethylene)-3-oxo-4-phenylpropanoate (5d) afforded exclusively the corresponding 6-substituted pyridines (6b-d). Cyclization of 4 with 3-carbethoxybutane-2,4-dione (5e) gave 3-cyano-5-(ethoxycarbonyl)-4,6-dimethylpyridine-2(1H)-thione (6e), whereas reaction of 4 with 3-carbethoxy-1-phenylpropane-1,3-dione (5f) yielded two products, 3-cyano-5-(ethoxycarbonyl)-4-methyl-6-phenylpyridine-2(1H)-thione (6f) and the 6-methyl-4-phenyl isomer 6g. The structural assignments for 6f and 6g are made on the basis of 1H and 13C NMR spectral analyses of the 2-(methylthio)nicotinates (7f,g) prepared from 6f and 6g by treatment with MeI/K2CO3. Nicotinates 7b,d-g were converted into their corresponding 2,4-diaminopyrido[2,3-d]pyrimidines 12b,d-g in five steps, via reduction, protection, oxidation, condensation with guanidine, and deprotection. The 7-mono- and 5,7-disubstituted-5-deazaaminopterins (1b,d-g) were prepared from the respective pyrido[2,3-d]pyrimidines 12b,d-g. Preliminary biological studies showed that 7-methyl and 5,7-dimethyl analogues (1b and 1e) were less active than methotrexate against human leukemic HL-60 and murine L-1210 cells in tissue culture. Compound 1e produced an ILS of 71% at 100 mg/kg per day X 5 (ip) in BDF mice inoculated ip with 10(6) L-1210 cells.