Synthesis and Biological Evaluation of 2-N-bis-(benzoyl)amino- 1,4-naphthoquinone, 2-arylnaphtho[2,3-d]oxazole-4,9-dione and 2-aryl-4-phenyliminonaphtho[2,3-d]oxazol-9-one Analogs as Potential Chemotherapy for Prostate Cancer

The quinone moiety is an important part of many biologically active natural products and their synthetic analogs. Both natural and synthetic quinones have been shown to exhibit a variety of biological activities, including anticancer activities. The synthesis of some novel symmetrical and unsymmetrical 2-bis-(benzoyl)amino-1,4-naphthoquinone analogs, and 2-arylnaphtho[2,3-d]oxazole- 4,9-dione derivatives have been accomplished. These compounds were evaluated in the highly metastatic androgen-independent prostate cancer cell line (PC3). In addition, the 2-arylnaphtho[2,3- d]oxazole- 4,9-dione derivatives were also evaluated in the hormone responsive LNCaP prostate cancer cell line.;The synthesis of symmetrical and unsymmetrical 2-bis-(benzoyl)amino-1,4-naphthoquinone analogs were carried out by first converting commercially available 1,4-naphthoquinone and 2,3-dihalo-1,4-naphthoquinones along with synthesized 2,3-dimethoxy-1,4-naphthoquinone to the requisite aminonaphthoquinone derivatives using ammonia/ammonium hydroxide solution, and sodium azide in methanol for 2-amino-1,4-naphthoquinone. We explored a base promoted bis-acylation of the aminonaphthoquinones with various organic and inorganic bases like triethylamine, pyridine, 4-dimethylaminopyridine and sodium carbonate at room temperature and at elevated temperatures. These conditions did not afford the target imido compounds, but instead, recovered the starting aminonaphthoquinone and the amide derivatives. However, a sodium hydride promoted bis-acylation of 2-amino-1,4-naphthoquinone, 2-amino-3-halo-1,4-naphthoquinone and 2-amino-3-methoxy-1,4-naphthoquinone, under inert atmosphere at room temperature furnished some novel 2-dibenzoylamino-1,4-naphthoquinone analogs with an average yield of 40 %. An unsymmetrical imidonaphthoquinone was obtained under similar conditions using sodium hydride via the intermediate 2-chlorobenzoylaminonaphthoquinone.;The 2-arylnaphtho[2,3-d]oxazole- 4,9-dione derivatives were easily prepared by reacting 2-amino-3-bromo-1,4-naphthoquinone with various benzoyl chloride derivatives at elevated temperature (230 °C). This reaction proceeded by initial formation of the amide derivative followed by an in situ intramolecular cyclization to the corresponding oxazolonaphthoquionone analogs. Three of these compounds were also converted to 2-aryl-4-(phenylimino)naphtho[2,3- d]oxazol-9-one derivatives via condensation of the oxazolonaphthoquinone analogs with aniline in the presence of titanium tetrachloride at elevated temperature (230 °C). The formation of the titanium octahedral complex intermediate was essential in controlling regioselectivity and stereoselectivity of the imino analogs.;In vitro anticancer evaluation of these compounds showed that the oxazolonaphthoquinone analogs were overall more potent than the arylimidonaphthoquinones with IC50s ranging from 0.01-0.4 uM. However, structure-activity-relationship (SAR) studies of the arylimidonaphthoquinone analogs identified increased cytotoxicity with electron withdrawing groups (chlorine and bromine) on the naphthoquinone scaffold together with a para- or meta- substitution along the arylimido substituent. These results gave further insight into the structural requirements necessary for enhanced cytotoxicity of this novel class of imidonaphthoquinones; and will guide us in the goal to develop this class of compounds into more effective anti-cancer agents.