Centre for Computational Modeling and Data Engineering , Indian Institute of Information Technology and Management-Kerala (IIITM-K) , Thiruvananthapuram 695581 , India.
J Med Chem. 2019 Sep 12;62(17):8311-8329. doi: 10.1021/acs.jmedchem.9b01098. Epub 2019 Aug 22.
Hydnocarpin (Hy) is a flavonoid isolated and purified from the seeds of Blume. Herein, we have developed a built-in semi-synthetic modification on Hy by one-pot multi-component reaction and a [3 + 2] cycloaddition strategy to append five membered isoxazole and isoxazolone as new phytochemical entities (NPCEs). Two selected NPCEs viz Hy-ISO-VIII and Hy-ISO-G from the library of 20 newly synthesized derivatives after in vitro screening unveiled promising cytotoxicity and induced caspase-mediated apoptosis against the human lung and melanoma cancer cells which were well supported by virtual screening based on ligand binding affinity and molecular dynamic simulations. As a new insight, we introduced surface-enhanced Raman spectroscopy to identify the chemo-marker molecular fingerprint to confirm the cellular uptake, cytochrome release, and DNA fragmentation in a label-free manner. The present findings throw up a surfeit of seminal reasons behind the semi-synthetic modification of Hy, stepping forward to cancer chemotherapy.
从 Blume 的种子中分离和纯化得到角鲨烯（Hy）。在这里，我们通过一锅多组分反应和 [3+2] 环加成策略对 Hy 进行了内置的半合成修饰，将五元异噁唑和异噁唑酮作为新的植物化学实体（NPCE）附加。从 20 个新合成衍生物的文库中筛选出的两种选定的 NPCEs（Hy-ISO-VIII 和 Hy-ISO-G）在体外筛选后显示出对人肺和黑色素瘤癌细胞的有希望的细胞毒性和诱导半胱天冬酶介导的细胞凋亡，这得到了基于配体结合亲和力和分子动力学模拟的虚拟筛选的很好支持。作为一个新的见解，我们引入了表面增强拉曼光谱来识别化学标记分子指纹，以非标记方式确认细胞摄取、细胞色素 C 释放和 DNA 片段化。这些发现为 Hy 的半合成修饰提供了充足的理由，为癌症化疗提供了新的思路。
