新型全氮杂环醚类似物：设计、合成及激酶筛选、分子对接和ADME研究增强的抗肿瘤效果
Novel alloxazine analogues: design, synthesis, and antitumour efficacy enhanced by kinase screening, molecular docking, and ADME studies
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影响因子:5.4
分区:医学2区 / 生化与分子生物学2区 药物化学2区
发表日期:2024 Dec
作者:
Doaa Samaha, Sawsan Mahmoud, Mosaad Sayed Mohamed, Rokaia S Abdullah, Nageh A Abou Taleb, Tomohisa Nagamatsu, Hamed I Ali
DOI:
10.1080/14756366.2024.2398551
摘要
本研究描述了新型全氮杂环醚类似物作为具有增强选择性的潜在抗肿瘤剂的开发。45种新化合物中的29种在体外对两种人类肿瘤细胞系（人T细胞急性淋巴母细胞白血病细胞系（CCRF-HSB-2）和人口腔表皮样癌细胞系（KB））的生长抑制活性进行了测试，抗肿瘤药“阿糖胞苷（Ara-C）”作为阳性对照。化合物9e和10J在两种肿瘤细胞系（CCRF-HSB-2和KB）中表现出最高活性。相关性分析显示，IC50值与AutoDock结合自由能或计算的抑制常数（Ki）之间存在强相关性。本研究通过结合结构基础药物设计（SBDD）使用GOLD 5.2.2、AutoDock 4.2和Accelrys Discovery Studio 3.5，深入探讨了结构-活性关系（SARs）。利用ProTox-II和Swiss ADME对最有效的全氮杂环醚衍生物的理化性质、药代动力学、药物相似性和毒性进行了预测，以筛选出具有改善选择性和抗肿瘤效果的候选药物。
Abstract
This study describes the development of novel alloxazine analogues as potent antitumor agents with enhanced selectivity for tumour cells. Twenty-nine out of 45 newly compounds were investigated in vitro for their growth inhibitory activities, against two human tumour cell lines, namely, the human T-cell acute lymphoblastoid leukaemia cell line (CCRF-HSB-2) and human oral epidermoid carcinoma cell line (KB), and the antitumor agent "Ara-C" was used as a positive reference in this investigation. Compounds 9e and 10J were the highest among their analogues, against both tumour cell lines (CCRF-HSB-2 and KB). Correlation analyses demonstrated a strong relationship between the IC50 values and AutoDock binding free energy or calculated inhibition (Ki). The study delves into structure-activity relationships (SARs) through advanced modelling tools integrated with structure-based drug design (SBDD) using GOLD 5.2.2, AutoDock 4.2, and Accelrys Discovery Studio 3.5. Physicochemical properties, pharmacokinetics, drug-likeness, and toxicity predictions of the most potent alloxazine derivatives were conducted using ProTox-II and Swiss ADME for effective antitumor agents with improved selectivity.