Growth inhibition and induction of cellular differentiation of human myeloid leukemia cells in culture by carbamoyl congeners of ribavirin

• Published in: Journal of medicinal chemistry 1990-01, Vol.33 (1), p.336-344
• Main Authors: Sanghvi, Yogesh S, Bhattacharya, Birendra K, Kini, Ganesh D, Matsumoto, Steven S, Larson, Steven B, Jolley, Weldon B, Robins, Roland K, Revankar, Ganapathi R
• Format: Article
• Language: English
• Subjects: Acetylation; Cell Differentiation - drug effects; Chemical Phenomena; Chemistry; Glycosylation; Humans; Hydrogen Bonding; Leukemia, Promyelocytic, Acute - drug therapy; Leukemia, Promyelocytic, Acute - pathology; Magnetic Resonance Spectroscopy; Molecular Conformation; Molecular Structure; Ribavirin - analogs & derivatives; Ribavirin - chemical synthesis; Ribavirin - therapeutic use; Ribonucleosides - therapeutic use; Tumor Cells, Cultured; X-Ray Diffraction
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm00163a054

A series of 1,2,3-triazole (2), pyrazole (3 and 5), and pyrrole (4) ribonucleosides with two adjacent carbamoyl groups have been synthesized and evaluated for cell growth inhibition and induction of cellular differentiation of HL-60 cells in culture. Glycosylation of the TMS derivatives of dimethyl 1,2,3-triazole-4,5-dicarboxylate (6) and diethyl pyrazole-3,4-dicarboxylate (7) with 1-O-acetyl-2,3,5-tri-O-benzoyl-D- ribofuranose (8) in the presence of TMS triflate gave predominantly the beta-nucleosides 9 and 14, respectively. Ammonolysis of 9 and 14 furnished 2-beta-D-ribofuranosyl-1,2,3-triazole-4,5-dicarboxamide (2) and 1-beta-D-ribofuranosylpyrazole-3,4-dicarboxamide (3), respectively. Stereoselective ring annulation of 1-deoxy-1-hydrazinyl-2,3-O-isopropylidene-D- ribose (16) with tetracyanoethylene (15) gave 5-amino-1-(2,3-O-isopropylidene-beta-D-ribofuranosyl)pyrazole-3,4- dicarbonitrile (17). Deisopropylidenation of 17, followed by oxidative hydrolysis of the reaction product (18), gave the 5-amino derivative of 3 (5). Stereospecific glycosylation of the sodium salt of preformed diethyl pyrrole-3,4-dicarboxylate (22) with 1-chloro-2,3-O-isopropylidene-5-O-(tert-butyldimethylsilyl)-alpha-D- ribofuranose (23) was accomplished to furnish blocked nucleoside 24, which on ammonolysis and deisopropylidenation gave 1-beta-D-ribofuranosylpyrrole-3,4-dicarboxamide (4). The structures of 2 and 3 were assigned by single-crystal X-ray diffraction studies, which showed extensive inter- and intramolecular hydrogen bonding. Nucleosides 2-5 are devoid of significant cytotoxic properties against L1210 and WI-L2 leukemia cells in culture. However, these compounds were found to be inducers of cellular differentiation of HL-60 cells in the range of 30-60 microM and were comparable to ribavirin in this regard.