Synthesis and anticancer activity of 3'-[4-fluoroaryl-(1,2,3-triazol-1-yl)]-3'-deoxythymidine analogs and their phosphoramidates.

ABSTRACT

A series of novel 4-chlorophenyl N-alkyl phosphoramidates of 3'-[4-fluoroaryl-(1,2,3-triazol-1-yl)]-3'-deoxythymidines (20-49) was synthesized by means of phosphorylation of 3'-[4-aryl-(1,2,3-triazol-1-yl)]-3'-deoxythymidines (7-11) with 4-chlorophenyl phosphoroditriazolide (14), followed by a reaction with the appropriate amine. The synthesized compounds 7-11 and 20-49 were evaluated along with four known anticancer compounds for their cytotoxic activity in human cancer cell lines cervical (HeLa), nasopharyngeal (KB), breast (MCF-7), osteosarcoma (143B) (only selected compounds 20, 24, 28, 32-36, 38, 40, 46) and normal human dermal fibroblast cell line (HDF) using the sulforhodamine B (SRB) assay. Among 3'-[4-aryl-(1,2,3-triazol-1-yl)]-3'-deoxythymidines (7-11) the highest activity in all the investigated cancer cells was displayed by 3'-[4-(3-fluorophenyl)-(1,2,3-triazol-1-yl)]-3'-deoxythymidine (9) (IC50 in the range of 2.58-3.61 µM) and its activity was higher than that of cytarabine. Among phosphoramidates 20-49 the highest activity was demonstrated by N-n-propyl phosphoramidate of 3'-[4-(3-fluorophenyl)-(1,2,3-triazol-1-yl)]-3'-deoxythymidine (35) in all the cancer cells (IC50 in the range of 0.97-1.94 µM). Also N-ethyl phosphoramidate of 3'-[4-(3-fluorophenyl)-(1,2,3-triazol-1-yl)]-3'-deoxythymidine (33) exhibited good activity in all the used cell lines (IC50 in the range of 4.79-4.96 µM).