Synthesis of novel acridone derivatives as potential biologically active compounds

Amine Laradji, Tennessee State University


A number of acridine and acridone derivatives have been reported to exhibit potent anticancer and antiviral properties. Amsacrine is currently being used in the clinic for the treatment of leukemia. Based on the above literature report, along with the research interest of the Okoro group in the chemistry of cyclic β-diketone, we became motivated to synthesize a diverse library of heterocyclic ring systems and to evaluate them for cytotoxic and other activities, such as antioxidant and antimicrobial activities. The major highlight of this work is the incorporation of a trifluoromethyl group in all the compounds synthesized. The trifluoromethyl group enjoys a privileged role in medicinal chemistry, because its introduction often enhances efficacy by promoting electrostatic interactions with protein targets, improving membrane penetration, as well as increasing robustness towards oxidative metabolism by liver enzyme. Substitued-(3-Oxo-5-trifluoromethyl-cyclohex-1-enylamino)-benzonitrile 75-85 were prepared from substituted-2-aminobenzonitrile by treatment with 5-trifluoromethyl-1,3-cyclohexanedione 18 in dilute aqueous hydrochloric acid. Compounds 75-85 were each reacted with a mixture of cuprous chloride and potassium carbonate in toluene to furnish novel fluorinated acridone derivatives (86-96). The structures of the above compounds were established by IR, NMR and LC-MS. Preliminary biochemical evaluation in collaboration with the Osheroff group at Vanderbilt University School of Medicine delineated 86 (9-amino-3-trifluoromethyl-acridone) as a poison of human topoisomerase II. 86 enhances enzyme-mediated DNA cleavage 6-fold (similar to levels seen in established anticancer drugs such as etoposide and amsacrine) in a concentration-dependent manner. Compounds 86-96 will be submitted to the National Cancer Institute (NCI) Chemotherapeutic Agents Repository Fisher BioServices for in vitro cytotoxicity testing in a panel of 60 cancer cell lines. In silico analysis indicate drug-like properties and absence of mutagenic and tumorigenic properties compared to THA. Our studies have identified a potent lead compound (86) that will guide further synthesis and structure-activity relationship (SAR) studies. In addition, the acridone derivatives could be derivatized to tacrine derivatives in a future exciting research leading to novel fluorinated tacrines for the treatment of AD (Alzheimer's disease) patients.

Subject Area

Organic chemistry

Recommended Citation

Amine Laradji, "Synthesis of novel acridone derivatives as potential biologically active compounds" (2013). ETD Collection for Tennessee State University. Paper AAI1541419.