Pietkiewicz Adrian L, Zhang Yuqi, Rahimi Marwa N, Stramandinoli Michael, Teusner Matthew, McAlpine Shelli R
School of Chemistry, University of New South Wales, Sydney, NSW 2052, Australia.
ACS Med Chem Lett. 2017 Mar 6;8(4):401-406. doi: 10.1021/acsmedchemlett.6b00488. eCollection 2017 Apr 13.
The established cytotoxic agent RITA contains a thiophene-furan-thiophene backbone and two terminal alcohol groups. Herein we investigate the effect of using thiazoles as the backbone in RITA-like molecules and modifying the terminal groups of these trithiazoles, thereby generating 41 unique structures. Incorporating side chains with varied steric bulk allowed us to investigate how size and a stereocenter impacted biological activity. Subjecting compounds to growth inhibition assays on HCT-116 cells showed that the most potent compounds , , and had GI values of 4.4, 4.4, and 3.4 μM, respectively, versus RITA (GI of 800 nM). Analysis of these compounds in apoptosis assays proved that , , and were as effective as RITA at inducing apoptosis. Evaluating the impact of on proteins targeted by RITA (p53, c-Myc, and Mcl-1) indicated that it acts via a different mechanism of action to that of RITA. RITA suppressed Mcl-1 protein via p53, whereas compound suppressed Mcl-1 expression via an alternative mechanism independent of p53.
已确立的细胞毒性药物RITA含有一个噻吩-呋喃-噻吩主链和两个末端醇基。在此，我们研究了在类RITA分子中使用噻唑作为主链并修饰这些三噻唑末端基团的效果，从而生成了41种独特的结构。引入具有不同空间体积的侧链使我们能够研究大小和立体中心如何影响生物活性。对化合物进行HCT-116细胞生长抑制试验表明，最有效的化合物 、 和 的GI值分别为4.4、4.4和3.4 μM，而RITA的GI值为800 nM。在凋亡试验中对这些化合物的分析证明， 、 和 在诱导凋亡方面与RITA一样有效。评估 对RITA靶向的蛋白质（p53、c-Myc和Mcl-1）的影响表明，它通过与RITA不同的作用机制发挥作用。RITA通过p53抑制Mcl-1蛋白，而化合物 通过独立于p53的另一种机制抑制Mcl-1表达。
