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Zinc(II)-berberine-based complexes targeting mitochondria exhibit enhanced antiproliferative activity as single drugs
Zhen-Feng Wang1, Xiao-Qiong Huang2, Run-Chun Wu2
1Key Laboratory of New Processing Technology for Nonferrous Metal & Materials, Ministry of Education/Guangxi Key Laboratory of Optical and Electronic Materials and Devices, College of Material Science and Engineering, Guilin University of Technology, Guilin 541004, China.
Abstract:
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.
Insights
Researchers developed novel zinc(II)-berberine complexes (BerT1-BerT8) that target mitochondria and inhibit myeloid cell leukemia-1 (Mcl-1) expression. These compounds show potent anticancer activity against breast cancer cells, offering a promising non-platinum drug alternative.
Area of Science:
- Medicinal Chemistry
- Cancer Biology
- Mitochondrial Biology
Background:
- Myeloid cell leukemia-1 (Mcl-1) is an antiapoptotic protein promoting tumor growth, primarily located in mitochondria.
- Targeting Mcl-1 is a key strategy for developing novel cancer therapeutics.
- Developing non-platinum-based anticancer drugs is crucial for overcoming resistance and reducing toxicity.
Purpose of the Study:
- To design and synthesize novel berberine-based zinc(II) complexes for mitochondrial targeting and Mcl-1 inhibition.
- To evaluate the in vitro anticancer efficacy of these complexes against human breast cancer cells.
- To explore the potential of these complexes as imaging agents and in combination therapies.
Main Methods:
- Synthesis and characterization of berberine-based ligand (BerT) and its eight zinc(II) complexes (BerT1-BerT8).
- In vitro cytotoxicity assays using human breast MDA-MB-231 cancer cells.
- Assessment of apoptosis induction and synergistic effects with ABT-199.
- In vivo efficacy and tolerability studies in mouse models.
Main Results:
- BerT1-BerT8 complexes demonstrated potent inhibition of MDA-MB-231 cancer cell growth (IC50 = 0.52-1.97 μM), outperforming cisplatin.
- BerT1 and BerT3 exhibited intrinsic green fluorescence for potential mitochondrial imaging.
- BerT1 and BerT3 selectively bound to Mcl-1, induced Bax/Bak-dependent apoptosis, and synergized with ABT-199 to overcome drug resistance.
- BerT3 showed efficacy and tolerability in vivo in mouse models.
Conclusions:
- Novel Zn(II)-berberine complexes (BerT1-BerT8) effectively target mitochondria and inhibit Mcl-1.
- BerT1 and BerT3 show significant promise as anticancer agents and potential imaging probes.
- These complexes represent a new class of non-platinum drugs with potential for treating various cancers, including drug-resistant types.
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