Wu Yu, Ma Zongchen, Mai Xiaoyuan, Liu Xiaoling, Li Pinglin, Qi Xin, Li Guoqiang, Li Jing
Key Laboratory of Marine Drugs, Chinese Ministry of Education, School of Medicine and Pharmacy, Ocean University of China, Qingdao 266003, China.
Laboratory for Marine Drugs and Bioproducts, Open Studio for Druggability Research of Marine Natural Products, Qingdao National Laboratory for Marine Science and Technology, Qingdao 266237, China.
Antioxidants (Basel). 2022 Apr 25;11(5):834. doi: 10.3390/antiox11050834.
The transferrin receptor 1 (TfR1) plays a key role in cellular iron uptake through its interaction with iron-bound Tf. TfR1 is often reported to be overexpressed in malignant cells, and this increase may be associated with poor prognosis in different types of cancer, which makes it an attractive target for antitumor therapy. The marine natural product Muriceidine A is a potent anticancer agent reported in our previous work. In this study, we designed and synthesized a series of Muriceidine A derivatives and described the systematic investigation into their cytotoxic activities against four tumor cells. Most of the derivatives showed stronger antitumor activity and we found that the introduction of electron-donating groups at position C-2 of unsaturated piperidine was beneficial to anticancer activity and unsaturated piperidine was responsible for the antiproliferative activity. Among these compounds, (methyl at position C-2 of unsaturated piperidine) exhibited the strongest cytotoxicity against MDA-MB-231 cells. Further pharmacological research showed that bound to Transferrin receptor 1 (TfR1) directly caused iron deprivation and ROS imbalance along with the degradations of several oncoproteins, especially FGFR1, through the proteasome pathway; thus, inducing cell cycle arrest and apoptosis in MDA-MB-231 breast cancer cells. Our findings indicate that is a promising lead compound targeting TfR1 for triple negative breast cancer.
转铁蛋白受体1（TfR1）通过与铁结合的转铁蛋白（Tf）相互作用，在细胞铁摄取中起关键作用。TfR1在恶性细胞中常被报道过表达，这种增加可能与不同类型癌症的不良预后相关，这使其成为抗肿瘤治疗的一个有吸引力的靶点。海洋天然产物Muriceidine A是我们之前工作中报道的一种有效的抗癌剂。在本研究中，我们设计并合成了一系列Muriceidine A衍生物，并描述了对其针对四种肿瘤细胞的细胞毒活性的系统研究。大多数衍生物显示出更强的抗肿瘤活性，并且我们发现，在不饱和哌啶的C-2位引入供电子基团有利于抗癌活性，且不饱和哌啶负责抗增殖活性。在这些化合物中，（不饱和哌啶C-2位的甲基）对MDA-MB-231细胞表现出最强的细胞毒性。进一步的药理学研究表明，与转铁蛋白受体1（TfR1）直接结合导致铁缺乏和ROS失衡，同时几种癌蛋白，尤其是FGFR1，通过蛋白酶体途径降解；从而诱导MDA-MB-231乳腺癌细胞的细胞周期停滞和凋亡。我们的研究结果表明，是一种有前景的针对三阴性乳腺癌靶向TfR1的先导化合物。
