Czuczi Tamás, Murányi József, Bárány Péter, Móra István, Borbély Adina, Csala Miklós, Csámpai Antal
Department of Organic Chemistry, Eötvös Loránd University (ELTE), Budapest Pázmány P. Sétány 1/A, H-1117 Budapest, Hungary.
MTA-SE Pathobiochemistry Research Group, Tűzoltó u. 37-47, H-1094 Budapest, Hungary.
Pharmaceuticals (Basel). 2022 Apr 12;15(4):468. doi: 10.3390/ph15040468.
Imipridones, including ONC201, ONC206 and ONC212 (which are emblematic members of this class of compounds developed by Oncoceutics) constitute a novel class of anticancer agents, with promising results in clinical trials. With the aim of increasing the ROS (reactive oxygen species) responsivity of the synthesized molecules, a set of novel ferrocene-imipridone hybrids were designed and synthesized. Our strategy was motivated by the documented interplay between the imipridone-triggered activation of TRAIL (the tumor necrosis factor-related apoptosis-inducing ligand) and mitochondrial ClpP (Caseinolytic protease P) and the ROS-mediated effect of ferrocene-containing compounds. In order to obtain novel hybrids with multitarget characters, the ferrocene moiety was tethered to the imipridone scaffold through ethynylene and 1,2,3-triazolyl linkers by using Sonogashira coupling of Cu(I)- and Ru(II)-catalyzed azide-alkyne cycloadditions. The biological activities of the new hybrids were examined by using in vitro cell viability assays on four malignant cell lines (PANC-1, A2058, EBC-1 and Fadu), along with colony formation assays on the most resistant PANC-1 cell line. Several hybrids caused a significantly greater drop in the cell viability compared to ONC201, and two of them completely overcame the resistance, with IC values comparable to those produced by ONC201. The two most potent hybrids, but not ONC201, induced apoptosis/necrosis in PANC-1 and A2058 cells after 24 h of treatment.
米氮平类化合物，包括ONC201、ONC206和ONC212（它们是Oncoceutics公司开发的这类化合物的代表性成员）构成了一类新型抗癌药物，在临床试验中取得了有前景的结果。为了提高合成分子对活性氧（ROS）的反应性，设计并合成了一组新型二茂铁-米氮平杂化物。我们的策略是基于已报道的米氮平触发的肿瘤坏死因子相关凋亡诱导配体（TRAIL）激活与线粒体酪蛋白水解蛋白酶P（ClpP）之间的相互作用以及含二茂铁化合物的ROS介导效应。为了获得具有多靶点特性的新型杂化物，通过使用铜（I）催化的叠氮化物-炔烃环加成反应和钌（II）催化的叠氮化物-炔烃环加成反应，通过乙炔基和1,2,3-三唑基连接体将二茂铁部分连接到米氮平骨架上。通过对四种恶性细胞系（PANC-1、A2058、EBC-1和Fadu）进行体外细胞活力测定以及对最具抗性的PANC-1细胞系进行集落形成测定，研究了新杂化物的生物活性。与ONC201相比，几种杂化物导致细胞活力显著下降，其中两种完全克服了抗性，其半数抑制浓度（IC）值与ONC201产生的值相当。两种最有效的杂化物，而不是ONC201，在处理24小时后诱导PANC-1和A2058细胞凋亡/坏死。
