title: Phenyl 1,2,3-triazole-thymidine ligands stabilize G-quadruplex DNA, inhibit DNA synthesis and potentially reduce tumor cell proliferation over 3'-azido deoxythymidine.
abstract: Triazoles are known for their non-toxicity, higher stability and therapeutic activity. Few nucleoside (L1, L2 and L3) and non-nucleoside 1,2,3-triazoles (L4-L14) were synthesised using click chemistry and they were screened for tumor cell cytotoxicity and proliferation. Among these triazole ligands studied, nucleoside ligands exhibited higher potential than non-nucleoside ligands. The nucleoside triazole analogues, 3'-Phenyl-1,2,3- triazole-thymidine (L2) and 3'-4-Chlorophenyl-1,2,3-triazole-thymidine (L3), demonstrated higher cytotoxicity in tumor cells than in normal cells. The IC₅₀ value for L3 was lowest (50 µM) among the ligands studied. L3 terminated cell cycle at S, G2/M phases and enhanced sub-G1 populations, manifesting induction of apoptosis in tumor cells. Confocal studies indicated that nucleoside triazole ligands (L2/L3) cause higher DNA fragmentation than other ligands. Preclinical experiments with tumor-induced mice showed greater reduction in tumor size with L3. In vitro DNA synthesis reaction with L3 exhibited higher DNA synthesis inhibition with quadruplex forming DNA (QF DNA) than non quadruplex forming DNA (NQF DNA). T(m) of quadruplex DNA increased in the presence of L3, indicating its ability to enhance stability of quadruplex DNA at elevated temperature and the results indicate that it had higher affinity towards quadruplex DNA than the other forms of DNA (like dsDNA and ssDNA). From western blot experiment, it was noticed that telomerase expression levels in the tissues of tumor-induced mice were found to be reduced on L3 treatment. Microcalorimetry results emphasise that two nucleoside triazole ligands (L2/L3) interact with quadruplex DNA with significantly higher affinity (K(d)≈10⁻⁷ M). Interestingly the addition of an electronegative moiety to the phenyl group of L2 enhanced its anti-proliferative activity. Though IC₅₀ values are not significantly low with L3, the studies on series of synthetic 1,2,3-triazole ligands are useful for improving and building potential pro-apoptotic ligands.
authors: CSIR-Centre for Cellular and Molecular Biology, Hyderabad, India.
authors: Jerald
authors: J
authors: Mahesh Kumar
authors: Mohammed M
authors: MM
authors: Idris
authors: Gunda
authors: G
authors: Srinivas
authors: Pallerla
authors: P
authors: Vinay Kumar
authors: Vuppalapaty
authors: V
authors: Meghah
authors: Mitta
authors: M
authors: Kavitha
authors: Chada Raji
authors: CR
authors: Reddy
authors: Prathama S
authors: PS
authors: Mainkar
authors: Biswajit
authors: B
authors: Pal
authors: Srivari
authors: S
authors: Chandrasekar
authors: Narayana
authors: N
authors: Nagesh
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D057930:Click Chemistry; D053938:DNA Fragmentation / Q000187:drug effects; D004273:DNA, Neoplasm / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D054856:G-Quadruplexes / Q000187:drug effects*; D006801:Humans; D008024:Ligands; D008546:Melanoma, Experimental / Q000737:chemistry / Q000188:drug therapy* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D012878:Skin Neoplasms / Q000737:chemistry / Q000188:drug therapy* / Q000473:pathology; D013936:Thymidine / Q000737:chemistry*; D014230:Triazoles / Q000737:chemistry*; D047368:Tumor Burden / Q000187:drug effects; D015215:Zidovudine / Q000737:chemistry
chemical_list: D000970:Antineoplastic Agents; D004273:DNA, Neoplasm; D008024:Ligands; D014230:Triazoles; D015215:Zidovudine; D013936:Thymidine
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