Synthesis, SAR, and in Silico ADME Screening Studies of Some 9-Amino-3-Phenylacridone Derivatives as Topoisomerase II Inhibitors
Synthesis, SAR, and in Silico ADME Screening Studies of Some 9-Amino-3-Phenylacridone Derivatives as Topoisomerase II Inhibitors作者机构：Department of Chemistry Tennessee State University Nashville Tennessee USA Applied Bioinformatics Laboratory Department of Biochemistry Federal University Oye-Ekiti Oye-Ekiti Nigeria Departments of Biochemistry Vanderbilt University School of Medicine Nashville Tennessee USA Medicine (Hematology/Oncology) Vanderbilt University School of Medicine Nashville Tennessee USA Vanderbilt Institute of Chemical Biology Vanderbilt University School of Medicine Nashville Tennessee USA
出 版 物：《Open Journal of Medicinal Chemistry》 (药物化学期刊（英文）)
年 卷 期：2023年第13卷第2期
页 面：15-34页
学科分类：1002[医学-临床医学] 100214[医学-肿瘤学] 10[医学]
主 题：Cancers 9-Aminoacridone Anticancer Topoisomerase II Pharmacokinetics Molecular Docking Etoposide
摘 要：Cancer is a leading cause of death globally, claiming about 9.6 million lives and approximately 420 million new cases of cancer will be diagnosed in the world by the year 2025. The aim of this study was to synthesize and computationally evaluate pharmacological potential of some derivatives of 9-amino-3-phenylacridone, as topoisomerase II (Topo II) inhibitors. In this study, 10 derivatives of 3-phenyl-9-aminoacridone were chemically synthesized and characterized, and the potential pharmacological indications of these compounds were computationally predicted by methods such as ADMET prediction, molecular target prediction and molecular docking. The results showed that two derivatives (58e and 58j) were non-permeant of blood-brain barrier, and this property was found similar to that of amsacrine and etoposide. The results of molecular docking of the ten derivatives of 3-phenyl-9-aminoacridone that were synthesized in this work showed that the synthetic compounds (58a-j) and the standard drugs have overall best binding affinities for human acetylcholine esterase than butyrylcholinesterase, and overall best binding affinities for human topo IIα than human topo IIβ. Overall, the results of this study suggest that the synthetic compounds 58a, 58c, 58f, 58g, and 58i could probably inhibit topo IIα by catalytic inhibition as seen with amsacrine, but only 58b and 58e possessed DNA non-intercalation properties as seen with etoposide, serving as topo II poison. In conclusion, this study showed that 3-phenyl-9-aminoacridone derivatives are potential inhibitor of topo IIα/β both by catalytic inhibition and poison as non-intercalator of DNA.
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