Woolley Krystel L, Nadikudi Monila, Koupaei Mitra N, Corban Monika, McCartney Paul, Bissember Alex C, Lewis Trevor W, Gueven Nuri, Smith Jason A
School of Natural Sciences - Chemistry , University of Tasmania , Hobart , TAS 7001 , Australia . Email:
School of Medicine - Pharmacy , University of Tasmania , Hobart , TAS 7001 , Australia . Email:
Medchemcomm. 2019 Jan 16;10(3):399-412. doi: 10.1039/c8md00582f. eCollection 2019 Mar 1.
Naphthoquinones have been investigated as potential therapeutic molecules for neurodegenerative disorders, which is largely based on their anti-oxidative potential. However, a theoretical framework for the pleiotropic protective effects of naphthoquinone derivatives is largely missing. We synthesized a library of novel short chain 2,3-disubstituted naphthoquinone derivatives and measured their redox characteristics to identify a potential connection with their biological activity. Using two cell lines with different reducing potential, the compounds were tested for their inherent toxicity, acute rescue of ATP levels and cytoprotective activity. For the first time, a structure-activity-relationship for naphthoquinones has been established. Our results clearly demonstrate that it is the group on the alkyl side chain and not solely the redox characteristics of the naphthoquinone unit or lipophilicity that determines the extent of cytoprotection by individual compounds. From this, we developed a number of amide containing naphthoquinones with superior activity in ATP rescue and cell viability models compared to the clinically used benzoquinone idebenone.
萘醌已被作为神经退行性疾病的潜在治疗分子进行研究，这在很大程度上基于它们的抗氧化潜力。然而，萘醌衍生物多效性保护作用的理论框架在很大程度上缺失。我们合成了一系列新型短链2,3-二取代萘醌衍生物，并测定了它们的氧化还原特性，以确定其与生物活性之间的潜在联系。使用两种具有不同还原电位的细胞系，测试了这些化合物的固有毒性、ATP水平的急性挽救作用和细胞保护活性。首次建立了萘醌的构效关系。我们的结果清楚地表明，决定单个化合物细胞保护程度的是烷基侧链上的基团，而不仅仅是萘醌单元的氧化还原特性或亲脂性。据此，我们开发了一些含酰胺的萘醌，与临床使用的苯醌艾地苯醌相比，它们在ATP挽救和细胞活力模型中具有更高的活性。
