Department of Chemistry, Aligarh Muslim University, Aligarh, India.
Department of Chemistry, Aligarh Muslim University, Aligarh, India.
Bioorg Chem. 2020 Nov;104:104327. doi: 10.1016/j.bioorg.2020.104327. Epub 2020 Sep 30.
Copper-based antitumor drug entities 1-3 derived from substituted (F, Br, -CH) 3-formylchromone pharmacophore were synthesized and thoroughly characterized by spectroscopic and single X-ray crystallographic studies. These complexes show structural novelty due to presence of the X-bonds in chromone scaffold which could facilitate higher propensity for nucleic acids via sigma σ-hole interactions. Therefore, structure-activity relationship of 1-3 was studied by performing ct-DNA binding, pBR322 cleavage and cytotoxicity activity to validate their potential to act as chemotherapeutic drug entities. The binding studies of 1-3 with ct- DNA were carried out employing many biophysical techniques and the corroborative results of these experiments showed intercalation mode of binding and the order of binding was found to be 2 > 1 > 3. The structure of drug entities could facilitated strong halogen bonding interaction (in case of 1 &2) and stability of X bond was rationalized by sigma hole region of positive electrostatic potential on the surface of C-X covalent bond, as determined by gas phase B3LYP computational DFT studies. Interestingly, 2 exhibited most avid binding affinity due to presence of Br electron withdrawing and polarizable group. Further, cleavage studies of 1-3 with pBR322 plasmid DNA were performed which demonstrated significant cleavage activity, the supercoiled form (Form I) of plasmid DNA was converted to nicked form (Form II) with the appearance of linearized form (Form III) in between two, implicating lethal double strand breaks of DNA. 2 showed predominantly higher cleavage activity following the similar trend as observed for binding studies. The cytotoxicity of the complexes 1-3 was evaluated by MTT assay against the human liver carcinoma (Huh-7) and prostate cancer (DU-145) cell lines; complex 2 exhibited specific and selective cytotoxicity for the DU-145 cancer cell line with LC value of 1.6 μM.
基于取代的（F、Br、-CH）3-甲酰基色酮药效团的铜基抗肿瘤药物实体 1-3 通过光谱和单晶 X 射线晶体学研究进行了合成和彻底表征。这些配合物由于色酮支架中存在 X 键，因此具有结构新颖性，这可能通过 sigma σ-hole 相互作用促进更高的与核酸结合的倾向。因此，通过进行 ct-DNA 结合、pBR322 切割和细胞毒性活性研究来研究 1-3 的构效关系，以验证它们作为化疗药物实体的潜力。使用多种生物物理技术进行了 1-3 与 ct-DNA 的结合研究，这些实验的协同结果表明结合方式为插入模式，并且发现结合顺序为 2 > 1 > 3。药物实体的结构可以促进强卤键相互作用（在 1 和 2 的情况下），并且通过气相 B3LYP 计算 DFT 研究确定的 C-X 共价键表面上的正静电势能的 sigma 孔区域，可以合理地解释 X 键的稳定性。有趣的是，由于 Br 吸电子和极化基团的存在，2 表现出最强烈的结合亲和力。进一步，对 1-3 与 pBR322 质粒 DNA 的切割研究表明，它们具有显著的切割活性，质粒 DNA 的超螺旋形式（形式 I）转化为缺口形式（形式 II），同时在两者之间出现线性形式（形式 III），暗示 DNA 的致命双链断裂。2 表现出更高的切割活性，遵循与结合研究中观察到的相似趋势。通过 MTT 测定法评估了配合物 1-3 对人肝癌（Huh-7）和前列腺癌（DU-145）细胞系的细胞毒性；配合物 2 对 DU-145 癌细胞系具有特异性和选择性细胞毒性，LC 值为 1.6 μM。
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