Department of Chemistry, National Institute of Technology-Tiruchirappalli, Tamil Nadu, 620015, India.
Facultad de Medicina, Universidad de Atacama, Los Carreras 1579, Copiapo 1532502, Chile; Chennai Institute of Technology (CIT), Chennai 600069, India.
Spectrochim Acta A Mol Biomol Spectrosc. 2024 May 15;313:124117. doi: 10.1016/j.saa.2024.124117. Epub 2024 Mar 5.
Cancer's global impact necessitates innovative and less toxic treatments. Thiosemicarbazones (TSCs), adaptable metal chelators, offer such potential. In this study, we have synthesized N (4)-substituted heterocyclic TSCs from syringaldehyde (TSL1, TSL2), and also report the unexpected copper-mediated cyclization of the TSCs to form thiadiazoles (TSL3, TSL4), expanding research avenues. This work includes extensive characterization and studies such as DNA/protein binding, molecular docking, and theoretical analyses to demonstrate the potential of the as-prepared TSCs and thiadiazoles against different cancer cells. The DFT results depict that the thiadiazoles exhibit greater structural stability and reduced reactivity compared to the corresponding TSCs. The docking results suggest superior EGFR inhibition for TSL3 with a binding constant value of - 6.99 Kcal/mol. According to molecular dynamics studies, the TSL3-EGFR complex exhibits a lower average RMSD (1.39 nm) as compared to the TSL1-EGFR complex (3.29 nm) suggesting that both the thiadiazole and thiosemicarbazone examined here can be good inhibitors of EGFR protein, also that TSL3 can inhibit EGFR better than TSL1. ADME analysis indicates drug-likeness and oral availability of the thiadiazole-based drugs. The DNA binding experiment through absorption and emission spectroscopy discovered that TSL3 is more active towards DNA which is quantitatively calculated with a K value of 4.74 × 10 M, K value of 4.04 × 10 Mand K value of 5 × 10 M. Furthermore, the BSA binding studies carried out with fluorescence spectroscopy showed that TSL3 shows better binding capacity (1.64 × 10 M) with BSA protein. All the compounds show significant cytotoxicity against A459-lung, MCF-7-breast, and HepG2-liver cancer cell lines; TSL3 exhibits the best cytotoxicity, albeit less effective than cisplatin. Thiadiazoles demonstrate greater cytotoxicity than the TSCs. Overall, the promise of TSCs and thiadiazoles in cancer research is highlighted by this study. Furthermore, it unveils unexpected copper-mediated cyclization of the TSCs to thiadiazoles.
癌症的全球影响需要创新和毒性更低的治疗方法。噻唑烷酮（TSCs）作为一种适应性强的金属螯合剂，具有这种潜力。在这项研究中，我们从水杨醛（TSL1、TSL2）合成了 N（4）取代的杂环 TSCs，并且还报告了 TSCs 意外的铜介导环化形成噻二唑（TSL3、TSL4），扩展了研究途径。这项工作包括广泛的表征和研究，如 DNA/蛋白质结合、分子对接和理论分析，以证明所制备的 TSCs 和噻二唑对不同癌细胞的潜在作用。DFT 结果表明，与相应的 TSCs 相比，噻二唑表现出更大的结构稳定性和更低的反应性。对接结果表明，TSL3 对 EGFR 的抑制作用更强，结合常数值为-6.99 Kcal/mol。根据分子动力学研究，与 TSL1-EGFR 复合物（3.29nm）相比，TSL3-EGFR 复合物的平均 RMSD（1.39nm）更低，这表明这里研究的噻二唑和噻唑烷酮都可以作为 EGFR 蛋白的良好抑制剂，而且 TSL3 可以比 TSL1 更好地抑制 EGFR。ADME 分析表明，噻二唑类药物具有类药性和口服可用性。通过吸收和发射光谱的 DNA 结合实验发现，TSL3 对 DNA 的活性更高，其定量计算的 K 值为 4.74×10 M，K 值为 4.04×10 M 和 K 值为 5×10 M。此外，通过荧光光谱进行的 BSA 结合研究表明，TSL3 与 BSA 蛋白具有更好的结合能力（1.64×10 M）。所有化合物对 A459-肺癌、MCF-7-乳腺癌和 HepG2-肝癌细胞系均表现出显著的细胞毒性；TSL3 表现出最好的细胞毒性，尽管不如顺铂有效。噻二唑比 TSCs 具有更高的细胞毒性。总的来说，这项研究强调了 TSCs 和噻二唑在癌症研究中的潜力。此外，它揭示了 TSCs 意外的铜介导环化形成噻二唑。
