Author(s)

Abiodun S. Oyedele¹, Toluwase H. Fatoki^1,2, Esha Dalvie³, Neil Osheroff^3,4,5, Cosmas O. Okoro^1*

¹Department of Chemistry, Tennessee State University, Nashville, Tennessee, USA.
²Applied Bioinformatics Laboratory, Department of Biochemistry, Federal University Oye-Ekiti, Oye-Ekiti, Nigeria.
³Departments of Biochemistry, Vanderbilt University School of Medicine, Nashville, Tennessee, USA.
⁴Medicine (Hematology/Oncology), Vanderbilt University School of Medicine, Nashville, Tennessee, USA.
⁵Vanderbilt Institute of Chemical Biology, Vanderbilt University School of Medicine, Nashville, Tennessee, USA.

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.

Cancers, 9-Aminoacridone, Anticancer, Topoisomerase II, Pharmacokinetics, Molecular Docking, Etoposide

Oyedele, A. , Fatoki, T. , Dalvie, E. , Osheroff, N. and Okoro, C. (2023) Synthesis, SAR, and in Silico ADME Screening Studies of Some 9-Amino-3-Phenylacridone Derivatives as Topoisomerase II Inhibitors. Open Journal of Medicinal Chemistry, 13, 15-34. doi: 10.4236/ojmc.2023.132002.