Organic Synthesis, Faculty of Sciences, University of Antwerp, Groenenborgerlaan 171, B-2020 Antwerp, Belgium.
Org Biomol Chem. 2019 Mar 13;17(11):2923-2939. doi: 10.1039/c8ob02690d.
In this study, a small library of twenty benzo[g]isoquinoline-5,10-diones were synthesized in a novel straightforward approach, starting from 2-methyl-1,4-naphthoquinone (vitamin K). An intramolecular Heck reaction of a N-vinylacetamide was a crucial step in the synthetic route, at which the combination of cesium carbonate and a bulky, electron rich trialkylphosphine (tBuCy2P.HBF4) provided high 6-endo-trig selectivity. The anti-tubercular activity against Mycobacterium tuberculosis H37Ra and acute cytotoxicity against J774 A.1 macrophages were studied. From the structure activity relationship, it could be derived that in general the substitution of position 3 yielded analogs with a higher antitubercular potency. Among these, two analogs, 27a and 27b, showed remarkable activity with minimal inhibition concentrations of respectively 28.92 μM and 1.05 μM, and acute cytotoxic concentrations of >128 μM and 34.85 μM. In addition, the analogs and their possible metabolites were evaluated using a Vitotox™ assay to study the possibility of genotoxicity. Results indicated that none of the evaluated analogs and their possible metabolites showed early signs of genotoxicity.
在这项研究中，从维生素 K（2-甲基-1,4-萘醌）出发，通过一种新颖的直接方法合成了 20 个苯并[g]异喹啉-5,10-二酮的小文库。N-乙烯基乙酰胺的分子内 Heck 反应是合成路线中的关键步骤，其中碳酸铯和大位阻、富电子三烷基膦（tBuCy2P.HBF4）的组合提供了高 6-endo-trig 选择性。研究了它们对结核分枝杆菌 H37Ra 的抗结核活性和对 J774 A.1 巨噬细胞的急性细胞毒性。从构效关系可以得出，一般来说，3 位取代的化合物具有更高的抗结核活性。其中，两个类似物 27a 和 27b 表现出显著的活性，最小抑制浓度分别为 28.92 μM 和 1.05 μM，急性细胞毒性浓度>128 μM 和 34.85 μM。此外，还使用 Vitotox™ 测定法评估了类似物及其可能的代谢物，以研究它们是否具有遗传毒性。结果表明，没有一个评估的类似物及其可能的代谢物显示出遗传毒性的早期迹象。
