Jannuzzi Ayse Tarbin, Yilmaz Goler Ayse Mine, Bayrak Nilüfer, Yıldız Mahmut, Yıldırım Hatice, Karademir Yilmaz Betul, Shilkar Deepak, Venkatesan Raghusrinivasan Jayaprakash, Jayaprakash Venkatesan, TuYuN Amaç Fatih
Department of Pharmaceutical Toxicology, Faculty of Pharmacy, Istanbul University, Beyazit, Istanbul 34116, Turkey.
Department of Biochemistry, School of Medicine, Marmara University, Istanbul 34854, Turkey.
Pharmaceuticals (Basel). 2022 Jun 22;15(7):777. doi: 10.3390/ph15070777.
Plastoquinone analogs are privileged structures among the known antiproliferative natural product-based compound families. Exploiting one of these analogs as a lead structure, we report the investigation of the brominated PQ analogs (BrPQ) in collaboration with the National Cancer Institute of Bethesda within the Developmental Therapeutics Program (DTP). These analogs exhibited growth inhibition in the micromolar range across leukemia, non-small cell lung cancer (EKVX, HOP-92, and NCI-H522), colon cancer (HCT-116, HOP-92), melanoma (LOX IMVI), and ovarian cancer (OVCAR-4) cell lines. One brominated PQ analog () was selected for a full panel five-dose in vitro assay by the NCI's Development Therapeutic Program (DTP) division to determine GI, TGI, and LC parameters. The brominated PQ analog () displayed remarkable activity against most tested cell lines, with GI values ranging from 1.55 to 4.41 µM. The designed molecules (BrPQ analogs) obeyed drug-likeness rules, displayed a favorable predictive Absorption, Distribution, Metabolism, and Excretion (ADME) profile, and an in silico simulation predicted a possible interaction with proteasome catalytic subunits. Furthermore, the in vitro cytotoxic activity of was assessed, and IC values for U-251 glioma, MCF-7 and MDA-MB-231 breast cancers, DU145 prostate cancer, HCT-116 colon cancer, and VHF93 fibroblast cell lines were evaluated using an MTT assay. MCF-7 was the most affected cell line, and the effects of on cell proliferation, cell cycle, oxidative stress, apoptosis/necrosis induction, and proteasome activity were further investigated in MCF-7 cells. The in vitro assay results showed that caused cytotoxicity in MCF-7 breast cancer cells via cell cycle arrest and oxidative stress induction. However, did not inhibit the catalytic activity of the proteasome. These results provide valuable insights for further discovery of novel antiproliferative agents.
在已知的基于天然产物的抗增殖化合物家族中，质体醌类似物是具有特殊结构的化合物。以其中一种类似物作为先导结构，我们与贝塞斯达国家癌症研究所合作，在发展治疗计划（DTP）中对溴化质体醌类似物（BrPQ）进行了研究。这些类似物在白血病、非小细胞肺癌（EKVX、HOP-92和NCI-H522）、结肠癌（HCT-116、HOP-92）、黑色素瘤（LOX IMVI）和卵巢癌（OVCAR-4）细胞系中表现出微摩尔范围内的生长抑制作用。一种溴化质体醌类似物（）被美国国立癌症研究所发展治疗计划（DTP）部门选用于全板五剂量体外试验，以确定GI、TGI和LC参数。该溴化质体醌类似物（）对大多数测试细胞系表现出显著活性，GI值范围为1.55至4.41μM。设计的分子（BrPQ类似物）符合类药规则，显示出良好的预测吸收、分布、代谢和排泄（ADME）特征，并且计算机模拟预测其可能与蛋白酶体催化亚基相互作用。此外，评估了的体外细胞毒性活性，并使用MTT试验评估了U-251胶质瘤、MCF-7和MDA-MB-231乳腺癌、DU145前列腺癌、HCT-116结肠癌和VHF93成纤维细胞系的IC值。MCF-7是受影响最大的细胞系，并在MCF-7细胞中进一步研究了对细胞增殖、细胞周期、氧化应激、凋亡/坏死诱导和蛋白酶体活性的影响。体外试验结果表明，通过细胞周期阻滞和氧化应激诱导在MCF-7乳腺癌细胞中引起细胞毒性。然而，并未抑制蛋白酶体的催化活性。这些结果为进一步发现新型抗增殖剂提供了有价值的见解。
