Synthesis, in silico studies and in vitro cytotoxicity evaluation of novel posaconazole derivative as a ALK TK inhibitor

Oncology research progresses, yet cancer remains the largest medical need. The use of a medication with an accessible lead molecule shows great potential for long-term cancer therapy. It may help target cancer therapy and drug resistance. This work uses FDA-approved, clinically proven compounds to build novel cancer therapeutic ligands to prevent treatment resistance. Based on the reported findings, an in-silico docking experiment was performed using FDA-licensed fungus medication posaconazole. The ALK TK pdb:4cmu ligand and posaconazole docked similarly in the research. Posaconazole's in silico docking findings were then tested against A549 lung cancer cells. Posaconazole, the lead, underwent an ADME investigation. Given in silico and experimental confirmation, acetyl, benzyl, and benzoyl derivatives of the lead molecule posaconazole was synthesized. IR, mass, 1H NMR, 13C NMR, and elemental analysis were performed on the synthesized compounds. Next, the three variants were evaluated against A549 lung cancer cells. They were then examined by utilizing computational approaches such as molecular docking, DFT analysis, MD simulation, and MMGBSA analysis. The ADME studies were conducted on posaconazole and its derivatives based on the in-vitro cell line investigation. Based on the results of an ADME study, two new ALK TK inhibitors that don't work as Pgp substrates are good lead candidates. Thus, the present investigation fruitfully reported two lead drug candidates against the issue of resistance in cancer therapy.肿瘤学研究虽持续推进，但癌症仍是最亟待解决的重大医疗需求。选用具备易得先导分子的药物，在癌症长期治疗领域展现出巨大潜力，其有望助力靶向癌症治疗并解决耐药性难题。本研究采用美国食品药品监督管理局（FDA）批准且经临床验证的化合物，构建新型癌症治疗用配体，以规避治疗耐药性。基于已报道的研究结果，本研究采用FDA获批的抗真菌药物泊沙康唑（posaconazole）开展了硅基对接（in silico docking）实验。本研究中，间变性淋巴瘤激酶酪氨酸激酶（ALK TK）的pdb:4cmu配体与泊沙康唑的对接结果相似。随后，针对A549肺癌细胞验证了泊沙康唑的硅基对接实验结果。作为先导分子的泊沙康唑接受了ADME（吸收、分布、代谢、排泄）研究。基于硅基模拟与实验验证结果，本研究合成了先导分子泊沙康唑的乙酰基、苄基及苯甲酰基衍生物。对合成得到的化合物开展了红外光谱（IR）、质谱、氢核磁共振（¹H NMR）、碳核磁共振（¹³C NMR）及元素分析。随后，针对A549肺癌细胞对这三种衍生物进行了活性评估，并通过分子对接、密度泛函理论（DFT）分析、分子动力学（MD）模拟及MMGBSA分析等计算手段对其进行了表征。基于体外细胞系实验结果，本研究对泊沙康唑及其衍生物开展了ADME研究。基于ADME研究结果，两款新型ALK TK抑制剂并非P-糖蛋白（Pgp）底物，可作为优质先导候选药物。综上，本研究成功报道了两款可用于解决癌症治疗耐药性问题的先导候选药物。