The mammalian AlkB homologue-3 (AlkBH3) is a member of the dioxygenase family of enzymes that in humans is involved in DNA dealkylation repair. Because of its role in promoting tumor cell proliferation and metastasis of cancer, extensive efforts are being directed in developing selective inhibitors for AlkBH3. Here we report synthesis, screening and evaluation of panel of arylated indenone derivatives as new class of inhibitors of AlkBH3 DNA repair activity. An efficient synthesis of 2,3-diaryl indenones from 2,3-dibromo indenones was achieved via Suzuki-Miyaura cross-coupling. Using a robust quantitative assay, we have obtained an AlkBH3 inhibitor that display specific binding and competitive mode of inhibition against DNA substrate. Finally, we established that this compound could prevent the proliferation of lung cancer cell line and enhance sensitivity to DNA damaging alkylating agent.

哺乳动物的AlkB同系物3（AlkBH3）是人类中与DNA脱烷基修复有关的双加氧酶家族的成员。由于其在促进肿瘤细胞增殖和癌症转移中的作用，因此在开发针对AlkBH3的选择性抑制剂方面进行了广泛的努力。在这里，我们报告合成，筛选和评估芳基化的茚满酮衍生物作为AlkBH3 DNA修复活性的抑制剂的一类小组。由2,3-二溴茚酮类的2,3-二芳茚酮类一种高效合成实现经由铃木宫浦交叉耦合。使用可靠的定量分析，我们获得了对DNA底物表现出特异性结合和竞争性抑制作用的AlkBH3抑制剂。最后，我们确定了该化合物可以阻止肺癌细胞的增殖并增强对DNA损伤烷基化剂的敏感性。