나프토퀴논 유도체의 합성 및 활성평가

Abstract

Quinone is a common constituent of biologically relevant molecules (e.g. Vitamin K1 is phylloquinone). Others serve as electron accepters in electron transport chains such as those in Photosystems I & II of photosynthesis, and aerobic respiration. They are widely distributed in nature and play a important biological part, but also happen as substances of potential toxicological significance in environmental pollutants, and some are used to anticancer drugs. The compound which is consisted of a structure of naphthoquinone has an antimicrobial and antitumor activity. The cytotoxicity of these quinone analogues results from the inhibition of DNA topoisomerase-II. In the study, 20 compounds with a naphthoquinone moiety were designed and synthesized to investigate the cytotoxicity anti-cancer cell activity against AML-2 /WT (leukemia disease) and A549 (lung cancer). 6- and 2-sunstituted naphthoquinone derivatives were prepared and investigated in order to figure out the relation between the position of dione and the cytotoxicity and antitumor activity. 2-Formyl-1,4,5,8-tetramethoxynaphtalene, the key starting material, was synthesized from 1,5-Dihydroxynaphthalene via four-step reaction which has a methylation, bromination, methoxylation and formylation. The oxidative demethylation of substituted 1,4,5,8-tetramethoxynaphtalenes by chromium (VI) oxide and cerium (IV) ammonium nitrate yielded two different isomers: 6- substituted and 2- substituted 5,8-dimethoxy-1,4-naphthoquinone derivatives. Synthesized 6- and 2- substituted 5,8-dimethoxy-1,4-naphthoquinone derivatives showed a potent anticancer activity in MTT Assay against AML-2/WT and A549 anti-cancer. Most 2-substituted 5,8-dimethoxy-1,4-naphthoquinone derivatives showed much higher cytotoxicity in antitumor activity than 6-substituted 5,8-dimethoxy-1,4-naphthoquinone derivatives. We concluded that 1,4-dione functional group should be located at the right rather than the left one for better activities. Moreover, introduction of benzothiazole and thiazole side chain at the C-2 or C-6 position of 5,8-dimethoxy-1,4-naphtho quinone showed much better anti activity than other 2-formyl-1,4,5,8-tetra methoxynaphtalene and other substituted-N-((1,4,5,8-tetramethoxynaphthalen-2- yl)methylene)thiazol-2-amine.