State Key Laboratory for Chemistry and Molecular Engineering of Medicinal Resources, School of Chemistry and Pharmacy, Guangxi Normal University, Guilin, 541004, PR China.
Department of Chemistry, Faculty of Science, The University of British Columbia, 2036 Main Mall, Vancouver, BC, V6T1Z1, Canada.
Eur J Med Chem. 2019 Nov 1;181:111567. doi: 10.1016/j.ejmech.2019.111567. Epub 2019 Jul 30.
Mcl-1 is an anti-apoptotic member of Bcl-2 family proteins. The development of inhibitors of Mcl-1 has been challenging. To develop metal-based Mcl-1inhibitors, twenty two copper(II) complexes 25-46 with 9-substituted β-carboline derivatives were reported. Complexes 38 and 39 showed higher cytotoxicity than the corresponding ligands or cisplatin. The most potent complex 39 presented higher selectivity to Mcl-1 than other Bcl-2 family proteins, and killed cancer cells via Bax/Bak mediated apoptosis. Complex 39 showed an excellent safety profile in mouse model, and significantly inhibited the tumor growth in NCI-H460 tumor bearing model, which is more potent than AZD5991 at the same dosage. Complex 39 prolonged the survival time of the tumor bearing mice. Complex 39 is the first metal-based Mcl-1 inhibitor acting as a potential anticancer agent.
Mcl-1 是 Bcl-2 家族蛋白中的一种抗凋亡成员。开发 Mcl-1 的抑制剂一直具有挑战性。为了开发基于金属的 Mcl-1 抑制剂，报道了 22 种具有 9-取代 β-咔啉衍生物的铜（II）配合物 25-46。配合物 38 和 39 的细胞毒性高于相应的配体或顺铂。最有效的配合物 39 对 Mcl-1 的选择性高于其他 Bcl-2 家族蛋白，通过 Bax/Bak 介导的细胞凋亡杀死癌细胞。配合物 39 在小鼠模型中表现出良好的安全性，在 NCI-H460 荷瘤模型中显著抑制肿瘤生长，在相同剂量下比 AZD5991 更有效。配合物 39 延长了荷瘤小鼠的存活时间。配合物 39 是第一个作为潜在抗癌剂的基于金属的 Mcl-1 抑制剂。
