Platinum-Based Modification of Styrylbenzylsulfones as Multifunctional Antitumor Agents: Targeting the RAS/RAF Pathway, Enhancing Antitumor Activity, and Overcoming Multidrug Resistance.,Journal of Medicinal Chemistry

当前位置： X-MOL 学术 › J. Med. Chem. › 论文详情

Our official English website, www.x-mol.net, welcomes your feedback! (Note: you will need to create a separate account there.)

Platinum-Based Modification of Styrylbenzylsulfones as Multifunctional Antitumor Agents: Targeting the RAS/RAF Pathway, Enhancing Antitumor Activity, and Overcoming Multidrug Resistance.
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2019-12-26 , DOI: 10.1021/acs.jmedchem.9b01223
Zhikun Liu ₁ , Meng Wang ₂ , Hengshan Wang ₂ , Lei Fang ₁ , Shaohua Gou ₁

Affiliation

Inhibiting/disturbing the RAS/RAF pathway may benefit the treatment of cancer and overcome the resistance. Utilizing such a pathway as the target, nine styrylbenzylsulfone derivatives generated from the platinum-based modification of the side chain of Rigosertib were designed. Among them, compound 29 showed the most potent antitumor activity in vitro with IC50 values at the nanomolar level against the tested tumor cell lines and 1000-fold higher than cisplatin against the multidrug resistant cells (A549/CDDP, A549/DOX, and SKOV-3/CDDP cells), while it showed only moderate cytotoxicity against normal cells (HEUVC cells). Compound 29 could clearly disturb signaling transduction between RAS and CRAF by directly bonding to CRAF and inhibit CRAF activation. Besides, the enhanced intracellular platinum level made 29 more potent than cisplatin in DNA damage, reactive oxygen species accumulation, and mitochondrial membrane potential decrease. Moreover, 29 induced apoptosis by the endogenous pathway and efficiently inhibited tumor growth in the A549 xenograft model without side effects.

中文翻译：

苯乙烯基苄基砜作为多功能抗肿瘤药的铂基修饰：靶向RAS / RAF途径，增强抗肿瘤活性，并克服多药耐药性。

抑制/干扰RAS / RAF途径可能有益于癌症的治疗并克服耐药性。利用这种途径作为靶标，设计了九种从Rigosertib侧链的铂基修饰产生的苯乙烯基苄基砜衍生物。其中，化合物29在体外显示出最有效的抗肿瘤活性，对被测肿瘤细胞系的纳摩尔浓度IC50值，对多药耐药细胞（A549 / CDDP，A549 / DOX和SKOV- 3 / CDDP细胞），而对正常细胞（HEUVC细胞）仅显示中等程度的细胞毒性。化合物29通过与CRAF直接键合并抑制CRAF活化，可以明显干扰RAS与CRAF之间的信号转导。除了，增强的细胞内铂水平使DNA损伤，活性氧累积和线粒体膜电位降低的能力比顺铂高29。此外，在A549异种移植模型中，有29种通过内源性途径诱导了细胞凋亡并有效地抑制了肿瘤的生长，而没有副作用。

更新日期：2019-12-27

点击分享查看原文

点击收藏

阅读更多本刊最新论文本刊介绍/投稿指南11