Department of Medicinal Chemistry, School of Pharmacy, Fudan University, Shanghai 201203, China.
Pharmaceutical Sciences Division, School of Pharmacy, University of Wisconsin-Madison, 777 Highland Avenue, Madison, WI, 53705-2222,USA.
Molecules. 2020 Jan 28;25(3):573. doi: 10.3390/molecules25030573.
The crystal structure of the sorafenib and B-RAF complex indicates that the binding cavity occupied by the pyridine-2-carboxamide in sorafenib has a large variable space, making it a reasonable modification site. In order to identify novel compounds with anti-cancer activity, better safety and polar groups for further application, five sorafenib analogs with new pyridine-2-amide side chains were designed and synthesized. Preliminary pharmacologic studies showed that these compounds displayed much lower toxicities than that of sorafenib. Among them, compound bearing mercaptoethyl group kept relevant antiproliferation potency compared to sorafenib in Huh7 and Hela cell lines with values of IC 58.79 and 63.67 M, respectively. As a small molecule inhibitor targeting protein tyrosine kinases, thiol in compound would be an active group to react with maleimide in a mild condition for forming nanoparticles Sorafenib-PEG-DGL, which could be developed as a delivery vehicle to improve the concentration of anti-tumor therapeutic agents in the target cancer tissue and reduce side effects in the next study.
索拉非尼和 B-RAF 复合物的晶体结构表明，索拉非尼中吡啶-2-甲酰胺占据的结合腔具有较大的可变空间，使其成为合理的修饰部位。为了鉴定具有抗癌活性、更好的安全性和极性基团的新型化合物，用于进一步应用，设计并合成了 5 种具有新型吡啶-2-酰胺侧链的索拉非尼类似物。初步药理研究表明，这些化合物的毒性明显低于索拉非尼。其中，带有巯基乙基的化合物在 Huh7 和 Hela 细胞系中的增殖抑制活性与索拉非尼相当，IC50 值分别为 63.67 和 63.67 M。作为一种靶向蛋白酪氨酸激酶的小分子抑制剂，化合物中的巯基可以在温和条件下与马来酰亚胺反应，形成纳米颗粒索拉非尼-PEG-DGL，可作为一种递药载体，以提高肿瘤组织中抗肿瘤治疗剂的浓度，减少副作用，这将是下一步研究的方向。
