Synthesis and Biochemical Evaluation of Novel Acridone Derivatives as Topoisomerase II Inhibitor

Abiodun Samuel Oyedele, Tennessee State University


Cancer is a disparate disease with an ever-growing worldwide occurrence. Despite advances in research and modern technology, coupled with medical bills and lost productivity by the patient, cancer remains an unmet medical need. It is the second leading cause of death worldwide, accounting for over 18 million new cases and 9.8 million deaths according to 2018 data. A number of acridine- and acridone-based compounds display potent anticancer activity. Some, such as amsacrine, are used currently in the clinic. A common feature of many of these compounds is that they target type II topoisomerases and act by increasing levels of enzyme-associated DNA strand breaks. In this research, we hypothesize that novel small molecule acridone compounds containing electron-donating and electron-withdrawing substituents on the benzene ring of the quinoline component will kill cancer cells, as well as inhibit topoisomerase IIα. We synthesized two series of acridone derivatives. One series (10) with no substitution at the 9-position displayed good in vitro anticancer activity in the NCI panel of 60 cancer cell line. The above 10 compounds were screened virtually using PyRx ver 1.9 molecular modeling program by Schrodinger LLC. All the 10 compounds showed binding affinities that ranged in values from -7.9 to -8.5 kcal/mole, indicating significant interaction with the protein 1zxm that was downloaded from the protein databank RCSB. The binding affinity data are consistent with catalytic inhibition of topoisomerase II. Five compounds emerged as excellent leads for further optimization. The second series (10) contained 3-phenyl groups, in addition to a 9-amino group. Seven compounds from the second series were tested for activity in DNA-topoisomerase cleavage assay. Five out of the seven exhibited activity in the cleavage assay that is approximately 5.5 to 8.5-fold over baseline. The chloro derivative was the most active in the topoisomerase cleavage assay. The 9-aminoacridone series have been submitted to the NCI developmental therapeutic program for in vitro cytotoxicity testing, in order to see if there is any correlation between their in vitro anticancer activity and topoisomerase inhibition. The results of this research will guide further studies toward the synthesis of more potent and selective compounds and to determine their mode of interaction with topoisomerase

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Recommended Citation

Abiodun Samuel Oyedele, "Synthesis and Biochemical Evaluation of Novel Acridone Derivatives as Topoisomerase II Inhibitor" (2020). ETD Collection for Tennessee State University. Paper AAI27832920.