Department of Biochemistry, School of Medicine/Genetic and Metabolic Diseases Research and Investigation Center, Marmara University, 34854, İstanbul, Türkiye.
Department of Pharmaceutical Toxicology, Faculty of Pharmacy, İstanbul University, 34116, İstanbul, Türkiye.
Chem Biodivers. 2023 Sep;20(9):e202300848. doi: 10.1002/cbdv.202300848. Epub 2023 Aug 23.
It is quite challenging to find out bioactive molecules in the vast chemical universe. Quinone moiety is a unique structure with a variety of biological properties, particularly in the treatment of cancer. In an effort to develop potent and secure antiproliferative lead compounds, five quinolinequinones (AQQ1-5) described previously have been selected and submitted to the National Cancer Institute (NCI) of Bethesda to envisage their antiproliferative profile based on the NCI Developmental Therapeutics Program. According to the preliminary in vitro single-dose anticancer screening, four of five quinolinequinones (AQQ2-5) were selected for five-dose screening and they displayed promising antiproliferative effects against several cancer types. All AQQs showed a excellent anticancer profile with low micromolar GI and TGI values against all leukemia cell lines, some non-small cell lung and ovarian cancer, most colon, melanoma, and renal cancer, and in addition to some breast cancer cell lines. AQQ2-5 reduced the proliferation of all leukemia cell lines at a single dose and five additional doses, as well as some non-small cell lung and ovarian cancer, the majority of colon cancer, melanoma and renal cancer, and some breast cancer cell lines. This motivated us to use in vitro, in silico, and in vivo technologies to further investigate their mode of action. We investigated the in vitro cytotoxic activities of the most promising compounds, AQQ2 and AQQ3, in HCT-116 colon cancer, MCF7 and T-47D breast cancer, and DU-145 prostate cancer cell lines, and HaCaT human keratinocytes. Concomitantly, IC values of AQQ2 and AAQ3 against MCF7 and T-47D cell lines of breast cancer, DU-145 cell lines of prostate cancer, HCT-116 cell lines of colon cancer, and HaCaT human keratinocytes were determined. AQQ2 exhibited anticancer activity through the induction of apoptosis and caused alterations in the cell cycle. In silico pharmacokinetic studies of all analogs have been carried out against ATR, CHK1, WEE1, CDK1, and CDK2. In addition to this, in vitro ADME and in vivo pharmacokinetic profiling for the most effective AAQ (AAQ2) have been studied.
在浩如烟海的化学世界中寻找具有生物活性的分子颇具挑战性。醌部分是一种具有多种生物特性的独特结构，特别是在癌症治疗方面。为了开发强效且安全的抗增殖先导化合物，我们选择了之前描述的五种喹啉醌（AQQ1-5），并将其提交给贝塞斯达的国家癌症研究所（NCI），根据 NCI 发展治疗学计划来评估它们的抗增殖特征。根据初步的体外单次剂量抗癌筛选结果，五种喹啉醌中的四种（AQQ2-5）被选中进行五次剂量筛选，它们对多种癌症类型表现出了有前景的抗增殖作用。所有 AQQ 都显示出极好的抗癌特征，对所有白血病细胞系、一些非小细胞肺癌和卵巢癌、大多数结肠癌、黑色素瘤和肾癌以及部分乳腺癌细胞系的 GI 和 TGI 值均低于微摩尔。AQQ2-5 在单次剂量和另外五次剂量时均可减少所有白血病细胞系的增殖，以及一些非小细胞肺癌和卵巢癌、大多数结肠癌、黑色素瘤和肾癌以及部分乳腺癌细胞系的增殖。这促使我们使用体外、计算和体内技术来进一步研究它们的作用模式。我们研究了最有前途的化合物 AQQ2 和 AQQ3 在 HCT-116 结肠癌、MCF7 和 T-47D 乳腺癌以及 DU-145 前列腺癌细胞系和 HaCaT 人角质形成细胞中的体外细胞毒性活性。同时，还确定了 AQQ2 和 AAQ3 对 MCF7 和 T-47D 乳腺癌细胞系、DU-145 前列腺癌细胞系、HCT-116 结肠癌细胞系和 HaCaT 人角质形成细胞系的 IC 值。AQQ2 通过诱导细胞凋亡和引起细胞周期改变发挥抗癌活性。对所有类似物进行了针对 ATR、CHK1、WEE1、CDK1 和 CDK2 的计算药代动力学研究。除此之外，还研究了最有效的 AAQ（AAQ2）的体外 ADME 和体内药代动力学特征。
