6-(1-하이드록시 또는 아실옥시알킬)-5,8-디알콕시-1,4-나프토퀴논 유도체의 합성, DNA Topoisomerase-I에 대한 억제, 세포독성 및 항암활성

• 영문명: 6-(1-Hydroxy or Acyloxyalkyl)-5,8-Dialkoxy-1,4-Naphthoquinones: Synthesis, Evaluation of Cytotoxic Activity, Antitumor Activity and Inhibitory effect on DNA Topoisomerase-I
• 발행기관: 대한약학회
• 저자명: 김용(Yong Kim) 최수라(Su La Choi) 명평근(Pyung Keun Myung) 안병준(Byung Zun Ahn)
• 간행물 정보: 『약학회지』제44권 제2호 (2000년), 141~148쪽, 전체 8쪽
• 주제분류: 의약학 > 기타의약학
• 파일형태: PDF
• 발행일자: 2000.04.29

영문 초록

A new synthetic method of 6-(1-oxyalkyl)-5,8-dimethoxy-1,4-naphthoquinones was developed, 2-formyl-1,4,5,8-tetramethoxynaphthalene was oxidized to form 6-formyl-5,8-dimethoxy-1,4-naphthoquinone (DMNQ). This was selectively reduced and benzylated to produce 6-formyl-5,8-dimethoxy-1,4-dibenzyloxynaphthalene, to which various alkylmagnesium halide were added, followed by debenzylation and oxidation in sequence, yielding 6-(1-hydroxyalkyl)-DMNQ derivatives. 6-(1-hydroxyalkyl)-5,8-diethoxy-1,4-naphthalene (DENQ) derivatives were synthesized by similar procedure. 1'-OH of the naphthoquinone derivatives was acylated with various alkanoic acids to give 6-(1-acyloxyalkyl)-DMNQ or DENQ derivatives. TOPO-I inhibitory activity and cytotoxicity of DENQs were less potent than that of DMNQS. Among the DMNQ and DENQ analogues, the ones with alkyl group being heptyl were most potent in TOPO-I inhibition (IC50; 30.1, 36.4gM). DNWQ derivatives with a longer side chain exhibited a weaker cytotoxicity. A correlation between size of the alkyl side chain and cytotoxicity was not observed for DENQ derivatives. Acylation of 1'-hydroxyl group, in general, decreased both TOPO-I inhibitory activity and cytotoxicity. T/C (%) values of the DENQ derivatives on S-180 intraperitoneal tumor were larger than those of DMNQ derivatives. Among the compounds synthesized, 6-(1-hydroxyheptyl)-DENQ and 6-(1-hexanoyloxyoctyl)-DMNQ showed the highest T/C values of 183% and 182%, respectively.

키워드

Naphthoquinones DNA topoisomerase-I inhibition antitumor activty cytotoxicity structure-activity relationship.