Zinc(II)-berberine-based complexes targeting mitochondria exhibit enhanced antiproliferative activity as single drugs or in combination with ABT-199.

Myeloid cell leukemia-1 (Mcl-1), a protein mainly located in mitochondria, exhibits antiapoptotic activity, promoting tumor growth. Herein, we designed an innovative strategy for targeting mitochondria to inhibit Mcl-1 expression effectively. To this end, we synthesized a novel berberine-based ligand, BerT. We also synthesized and comprehensively characterized its corresponding Zn(II) complexes, including [Zn(BerT)(H2O)Cl2] (BerT1), [Zn(BerT)(ppe)Cl]Cl (BerT2), [Zn(BerT)(ipq)Cl]Cl (BerT3), [Zn(BerT)(phe)Cl]Cl (BerT4), [Zn(BerT)(bph)Cl]Cl (BerT5), [Zn(BerT)(dph)Cl]Cl (BerT6), [Zn(BerT)(pha)Cl]Cl (BerT7) and [Zn(BerT)(mph)Cl]Cl (BerT8) [ppe = 1,2-bis(diphenylphosphino)ethane, ipq = 2-(1H-imidazo[4,5-f][1,10]phenanthrolin-2-yl)quinolin-8-ol, phe = 1,10-phenanthroline, bph = bathophenanthroline, dph = 4,7-dichloro-1,10-phenanthroline, pha = 1,10-phenanthrolin-5-amine and mph = 5,6-dimethyl-1,10-phenanthroline]. In human breast MDA-MB-231cancer cells, compounds BerT1-BerT8 exhibited potent cancer growth inhibitory capability ranging (IC50 = 0.52-1.97 μM), as compared to cisplatin (IC50 = 10.04 ± 0.61 μM). BerT1 and BerT3 exhibited intrinsic green fluorescence, indicating their potential utility in mitochondrial imaging applications. To the best of our knowledge, BerT1 and BerT3 are the first Zn(II)-berberine-based complexes that target mitochondria. They can selectively bind to Mcl-1 with high affinity, exhibiting enhanced anticancer efficacy in MDA-MB-231 tumor cells. These two complexes also caused Bax/Bak-dependent apoptosis in MDA-MB-231 cells and acted synergistically with ABT-199 to kill ABT-199 resistant cells in multiple tumor models. BerT3 was effective and tolerable as a single probe or in combination with ABT-199 in MDA-MB-231 BALB/c mouse models. Thus, we conclude that Zn(II)-berberine-based derivatives have potential for the non‑platinum drugs development aimed at treating cancer tissue.