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). Tm 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 (Kd≈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.
Highlights
IntroductionDrugs used for the control of cancer are broadly classified into two groups, cytotoxic (cell killing) and cytostatic (cell stabilizing)
Drugs used for the control of cancer are broadly classified into two groups, cytotoxic and cytostatic
MTT assay This assay indicates the rate of tumor cell proliferation and useful to assess the potential of synthetic ligands in the induction of apoptosis
Summary
Drugs used for the control of cancer are broadly classified into two groups, cytotoxic (cell killing) and cytostatic (cell stabilizing). Several nitrogen-containing ligands have been successfully tested as cytotoxic drugs for cancer treatment. Triazole derivatives were found to be ideal because they are non-toxic, more likely to be water soluble and highly stable [1] They are not naturally occurring scaffolds but their roles in analgesic [2], antiinflammatory [3,4], antiviral [5], antimicrobial [6,7], antifungal [8,9,10], antibacterial [11], antitubercular [12] and antitumor [13] activities are well documented. Considering the broad spectrum of activities that triazoles exhibit, 2 different classes of triazole scaffolds (with and without nucleoside) were synthesized and their physico-chemical, biological characteristics as well as their efficacy in reducing tumor size and control tumor cell proliferation was examined
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