Synthesis and antiproliferative activities of 5-azacytidine analogues in human leukemia cells

• Published in: Molecules (Basel, Switzerland) Switzerland), 2008-07, Vol.13 (7), p.1487-1500
• Main Authors: Guo, Gang, Li, Gang, Liu, Dan, Yang, Qian-jiao, Liu, Yu, Jing, Yong-kui, Zhao, Lin-xiang
• Format: Article
• Language: English
• Subjects: 5-Azacytidine analogues; Antimetabolites, Antineoplastic - chemical synthesis; Antimetabolites, Antineoplastic - pharmacology; antiproliferative activity; Azacitidine - analogs & derivatives; Azacitidine - chemical synthesis; Azacitidine - pharmacology; Cell Proliferation - drug effects; Cytotoxicity; differentiation; DNA methylation; Growth Inhibitors - chemical synthesis; Growth Inhibitors - pharmacology; HL-60 Cells; Humans; Leukemia; Leukemia - drug therapy; Leukemia - pathology; structure-activity relationship
• ISSN: 1420-3049; 1420-3049
• DOI: 10.3390/molecules13071487

Twenty-six 5-azacytidine analogues have been synthesized, including 4-amino- 6-alkyl-1-pyranosyl/ribofuranosyl-1,3,5-triazin-2(1H)-ones 1a-j, 6-amino-4-alkyl/aryl-1- pyranosyl/ribofuranosyl-1,3,5-triazin-2(1H)-ones 2a-f and 4-amino-6-alkyl-1,3,5-triazin-2- yl-1-thio-pyranosides/ribofuranosides 3a-j. The antiproliferative activities of these synthetic analogues were investigated in human leukemia HL-60 cells. Ribofuranosyl S-nucleoside 3a, a bioisostere of 5-azacytidine, had a similar antiproliferative ability as that of the latter. Introduction of a methyl at the 6 position of 5-azacytidine and/or replacement of the ribofuranosyl moiety with pyranosyl sugars or disaccharides significantly decreased the antiproliferative activities of the 5-azacytidine derivatives. Several compounds with the replacement of pyranosyl sugars enhanced all-trans retinoic acid-induced differentiation ability in human leukemia HL-60 cells.