Oxadiazole-substituted naphtho[2,3-b]thiophene-4,9-diones as potent inhibitors of keratinocyte hyperproliferation. Structure-activity relationships of the tricyclic quinone skeleton and the oxadiazole substituent

被引:11
作者
Basoglu, Atila [1 ]
Dirkmann, Simone [1 ]
Golpayegani, Nader Zahedi [1 ]
Vortherms, Silke [1 ]
Tentrop, Jan [1 ]
Nowottnik, Dominica [1 ]
Prinz, Helge [1 ]
Froehlich, Roland [2 ]
Mueller, Klaus [1 ]
机构
[1] Westphalian Wilhelms Univ, Inst Pharmaceut & Med Chem, PharmaCampus,Corrensstr 48, D-48149 Munster, Germany
[2] Westphalian Wilhelms Univ, Organ Chem Inst, Corrensstr 40, D-48149 Munster, Germany
关键词
Antiproliferative activity; HaCaT cells; Quinone; Redox activation; Superoxide radical; MODULATED REDOX PROPERTIES; ANTIPROLIFERATIVE ACTIVITY; ANTIPSORIATIC ANTHRONES; ANTIMICROTUBULE AGENTS; ANTICANCER ACTIVITIES; OXIDATIVE STRESS; BETA-LAPACHONE; DERIVATIVES; SUPEROXIDE; ACTIVATION;
D O I
10.1016/j.ejmech.2017.03.084
中图分类号
R914 [药物化学];
学科分类号
100701 ;
摘要
Novel analogues of oxadiazole-substituted naphtho[2,3-b]thiophene-4,9-diones were synthesized in which the tricyclic quinone skeleton was systematically replaced with simpler moieties, such as structures with fewer rings and open-chain forms, while the oxadiazole ring was maintained. In addition, variants of the original 1,2,4-oxadiazole ring were explored. Overall, the complete three-ring quinone was essential for potent suppression of human keratinocyte hyperproliferation, whereas analogous anthraquinones were inactive. Also, the oxadiazole ring per se was not sufficient to elicit activity. However, rearrangement of the heteroatom positions in the oxadiazole ring resulted in highly potent inhibitors with compound 24b being the most potent analogue of this series showing an IC50 in the nanomolar range. Furthermore, experiments in isolated enzymatic assays as well as in the keratinocyte-based hyperproliferation assay did not support a major role of redox cycling in the mode of action of the compounds. (C) 2017 Elsevier Masson SAS. All rights reserved.
引用
收藏
页码:119 / 132
页数:14
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