CSIR-Centre for Cellular and Molecular Biology, Hyderabad, India.
PLoS One. 2013 Aug 19;8(8):e70798. doi: 10.1371/journal.pone.0070798. eCollection 2013.
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.
三唑类化合物以其低毒性、更高的稳定性和治疗活性而闻名。使用点击化学合成了少数核苷（L1、L2 和 L3）和非核苷 1,2,3-三唑（L4-L14），并对它们进行了肿瘤细胞细胞毒性和增殖的筛选。在研究的这些三唑配体中，核苷配体比非核苷配体表现出更高的潜力。核苷三唑类似物 3'-苯基-1,2,3-三唑-胸苷（L2）和 3'-4-氯苯基-1,2,3-三唑-胸苷（L3）在肿瘤细胞中的细胞毒性高于正常细胞。在研究的配体中，L3 的 IC₅₀ 值最低（50 µM）。L3 将细胞周期阻滞在 S、G2/M 期，并增加亚 G1 群体，在肿瘤细胞中诱导细胞凋亡。共聚焦研究表明，核苷三唑配体（L2/L3）引起的 DNA 片段化高于其他配体。用肿瘤诱导的小鼠进行的临床前实验表明，L3 可使肿瘤体积减小。L3 与体外 DNA 合成反应相比，与四链体形成 DNA（QF DNA）的 DNA 合成抑制更高，而非四链体形成 DNA（NQF DNA）。L3 的存在下，四链体 DNA 的 Tm 增加，表明其在高温下增强四链体 DNA 稳定性的能力，结果表明其与其他形式的 DNA（如 dsDNA 和 ssDNA）相比，对四链体 DNA 的亲和力更高。从 Western blot 实验中注意到，在 L3 治疗后，肿瘤诱导小鼠组织中的端粒酶表达水平降低。微量热法结果强调，两种核苷三唑配体（L2/L3）与四链体 DNA 具有显著更高的亲和力（K(d)≈10⁻⁷ M）。有趣的是，将一个电负性部分添加到 L2 的苯基上增强了其抗增殖活性。虽然 L3 的 IC₅₀ 值不低，但对一系列合成 1,2,3-三唑配体的研究对于提高和构建潜在的促凋亡配体是有用的。
