Novel alloxazine analogues: design, synthesis, and antitumour efficacy enhanced by kinase screening, molecular docking, and ADME studies.

IF 5.6 2区医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Journal of Enzyme Inhibition and Medicinal Chemistry Pub Date : 2024-09-17 DOI:10.1080/14756366.2024.2398551

Doaa Samaha,Sawsan Mahmoud,Mosaad Sayed Mohamed,Rokaia S Abdullah,Nageh A Abou Taleb,Tomohisa Nagamatsu,Hamed I Ali

{"title":"Novel alloxazine analogues: design, synthesis, and antitumour efficacy enhanced by kinase screening, molecular docking, and ADME studies.","authors":"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","DOIUrl":null,"url":null,"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.","PeriodicalId":15769,"journal":{"name":"Journal of Enzyme Inhibition and Medicinal Chemistry","volume":null,"pages":null},"PeriodicalIF":5.6000,"publicationDate":"2024-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Journal of Enzyme Inhibition and Medicinal Chemistry","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1080/14756366.2024.2398551","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"BIOCHEMISTRY & MOLECULAR BIOLOGY","Score":null,"Total":0}

引用次数: 0

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.

查看原文本刊更多论文

新型烯丙基嗪类似物：通过激酶筛选、分子对接和 ADME 研究提高设计、合成和抗肿瘤功效。

本研究介绍了新型烯丙基嗪类似物作为强效抗肿瘤药的开发情况，它们对肿瘤细胞的选择性更强。研究人员对 45 个新化合物中的 29 个进行了体外研究，以检测它们对两种人类肿瘤细胞系（即人类 T 细胞急性淋巴母细胞白血病细胞系（CCRF-HSB-2）和人类口腔表皮样癌细胞系（KB））的生长抑制活性，并以抗肿瘤药物 "Ara-C "作为阳性参照物。在其类似物中，化合物 9e 和 10J 对两种肿瘤细胞系（CCRF-HSB-2 和 KB）的抗肿瘤能力最强。相关分析表明，IC50 值与 AutoDock 结合自由能或计算抑制率（Ki）之间存在密切关系。该研究使用 GOLD 5.2.2、AutoDock 4.2 和 Accelrys Discovery Studio 3.5，通过与基于结构的药物设计（SBDD）集成的先进建模工具深入研究了结构-活性关系（SARs）。使用 ProTox-II 和 Swiss ADME 对最有效的烯丙基嗪衍生物的理化性质、药代动力学、药物相似性和毒性进行了预测，以寻找具有更好选择性的有效抗肿瘤药物。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

求助全文

约1分钟内获得全文求助全文

来源期刊

Journal of Enzyme Inhibition and Medicinal Chemistry 医学-生化与分子生物学

CiteScore

10.30

自引率

10.70%

发文量

195

审稿时长

4-8 weeks

期刊介绍： Journal of Enzyme Inhibition and Medicinal Chemistry publishes open access research on enzyme inhibitors, inhibitory processes, and agonist/antagonist receptor interactions in the development of medicinal and anti-cancer agents. Journal of Enzyme Inhibition and Medicinal Chemistry aims to provide an international and interdisciplinary platform for the latest findings in enzyme inhibition research. The journal’s focus includes current developments in: Enzymology; Cell biology; Chemical biology; Microbiology; Physiology; Pharmacology leading to drug design; Molecular recognition processes; Distribution and metabolism of biologically active compounds.