The synthesis of novel acridine compounds with an additional fused carbonyl-containing ring at the 3,4-position as potential antitumor agents

Molecular modeling and X-ray crystallography studies on 9-aminoacridine-4-(N-methyl)-carboxamide (AAC), a highly potent anti-leukemia agent in vitro, reveals that the lowest energy geometry to be a conformation such that the carbonyl functional group of the carboxamide moiety is oriented toward the ring nitrogen and forms a hydrogen-bond with the hydrogen of the protonated ring nitrogen. The subject of this research project is synthesize and characterize new acridine antitumor agents whose structures are fixed into this lowest energy conformation of AAC. Attached to the 4-position of the novel compounds will be a carbonyl group oriented toward the acridine ring nitrogen and incorporated into a zing system. The successful syntheses of these compounds wilt allow us to investigate their structure-anticancer activity relationship.; Starting from simple molecules such as 3-nitrophthafic add, o-iodobenzoic acid, and 3-nitrophthalic anhydride, the tetracyclic fused-acridine nuclei of the target compounds are designed and constructed through convergent synthetic strategies. The key steps in this research are the synthesis of the intermediates, o-carboxydiaryiamines, via the copper(II) catalyzed Jourdan-Ullmann reaction between diphenytiodonium-2-carboxylate and various substituted anilines. Cyclizations and functionalizations of these intermediates give the tetracyclic cores of the target compounds. Substitution of 6-chloroacridine intermediate with ten substituted anilenes and ammonia afford a series of novel 6-substituted-1,3-dihydro-2-[2-(dimethybmino)ethyl]-1,3-dioxopyffolo[3,4- c]acri-dines. An interesting oxidation reaction of the benzyfic methylene to carbonyl group by thionyl chloride is observed during the course of this research, although the scope of this reaction has been limited to the fused-acridine compounds. This novel reaction is used to synthesize one of the target compounds, 1,3- dihydro-2-[2-(dimethylamino)ethyl]-1,3-dioxopyrrolo[3,4- c]acridine, from 1,3-dihydro-1(3H)-oxofuro-[3,4- c]acridine. Three fused-acridone compounds are also synthesized. All new compounds are characterized by spectroscopic methods and elemental analyses. Most target compounds resulted in topoisomerase II-mediated DNA cleavage reactions at 10 uM concentration with varied potency.