Application of Regioselective Substitution on 1,4-Benzoquinone Derivatives to Provide Potent Anticancer Agents

1,4-Benzoquinone moiety has been found existing in many natural sources, and been comprehensively exploited in the drug structural optimization. In the view of chemistry reaction, nucleophilic substitution is the common reaction type that 1,4-benzoquinone undergoes. The existence of these replacements usually helps to improve the biological activity. However, there is no guarantee that substitution will be introduced at C2 or C3 position. Due to the significant impact of high regioselectivity on the biological activity, this project is focused on 2-aroyl-quinoline-5,8-dione and denbinobin derivatives which possess 1,4-benzoquinone moiety, and is aimed to improve the regioselectivity of nucleophilic substitution through leaving group-directing, temperature-controlling, and Lewis acid-assistant methodologies. Therefore, a series of 2-aroyl-quinoline-5,8-diones and denbinobin analogues were synthesized. The preliminary result indicated that substituted 2-aroyl-quinoline-5,8-diones and denbinobin analogues exhibiting potent antiproliferation activity. Therefore, this project will continue the further SAR study and develop various heterocycle-diones as potent anticancer agents. Despite the total synthesis of denbinobin has been developed in our previous work, the unexpected E-isomer of Wittig olefination and infeasible free-radical intramolecular cyclization for scale-up lead to the insufficient denbinobin for further optimization. This project developed a suitable total synthesis toward denbinobin based on previous approaches. This study used Perkin condensation to avoid the unexpected isomer of Wittig olefination, and used Pd or Lewis acids to achieve the intramolecular cyclization, which improves the reaction yields and benefits the scale-up process. This project will apply approach to prepare analogues or derivatives containing 1,4-phenanthrenedione core towards heterocycles basis and to further fulfill the structural optimization. Preliminarily, one derivative, MPT0G266, demonstrated substantial antiproliferative activity against cancer cell lines, stronger than denbinobin with 10-fold.