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).

• Authors: Natalia Kleczewska, Piotr Ruszkowski, Aleksandra Singh, Roksana Trznadel, Lech Celewicz
• Journal: Nucleosides, nucleotides & nucleic acids (Nucleosides Nucleotides Nucleic Acids) Vol. 38 Issue 9 Pg. 605-641 ( 2019) ISSN: 1532-2335 [Electronic] United States
• PMID: 30968733 (Publication Type: Journal Article)

Chemical References

• Amides
• Antineoplastic Agents
• Phosphoric Acids
• Triazoles
• phosphoramidic acid
• Thymidine

Topics

• Amides (chemistry)
• Antineoplastic Agents (chemical synthesis, pharmacology)
• Cell Line, Tumor
• Cell Survival (drug effects)
• Drug Design
• Humans
• Molecular Structure
• Phosphoric Acids (chemistry)
• Structure-Activity Relationship
• Thymidine (analogs & derivatives, chemical synthesis, pharmacology)
• Triazoles (chemical synthesis, pharmacology)