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聚（2,2'-联吡啶）配体的设计与合成诱导癌细胞死亡：与生物相关金属阳离子的络合/解络合控制抗癌活性。

Design and Synthesis of Poly(2,2'-Bipyridyl) Ligands for Induction of Cell Death in Cancer Cells: Control of Anticancer Activity by Complexation/Decomplexation with Biorelevant Metal Cations.

机构信息

Faculty of Pharmaceutical Sciences, Tokyo University of Science, 2641 Yamazaki, Noda 278-8510, Japan.

Research Institute for Biomedical Sciences, Tokyo University of Science, 2641 Yamazaki, Noda, Chiba 278-8510, Japan.

出版信息

Inorg Chem. 2023 Sep 11;62(36):14615-14631. doi: 10.1021/acs.inorgchem.3c01738. Epub 2023 Aug 29.

DOI:10.1021/acs.inorgchem.3c01738
PMID:37642721
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC10498496/
Abstract

Chelation therapy is a medical procedure for removing toxic metals from human organs and tissues and for the treatment of diseases by using metal-chelating agents. For example, iron chelation therapy is designed not only for the treatment of metal poisoning but also for some diseases that are induced by iron overload, cancer chemotherapy, and related diseases. However, the use of such metal chelators needs to be generally carried out very carefully, because of the side effects possibly due to the non-specific complexation with intracellular metal cations. Herein, we report on the preparation and characterization of some new poly(bpy) ligands (bpy: 2,2'-bipyridyl) that contain one-three bpy ligand moieties and their anticancer activity against Jurkat, MOLT-4, U937, HeLa S3, and A549 cell lines. The results of MTT assays revealed that the tris(bpy) and bis(bpy) ligands exhibit potent activity for inducing the cell death in cancer cells. Mechanistic studies suggest that the main pathway responsible for the cell death by these poly(bpy) ligands is apoptotic cell death. It was also found that the anticancer activity of the poly(bpy) ligands could be controlled by the complexation (anticancer activity is turned OFF) and decomplexation (anticancer activity is turned ON) with biorelevant metal cations. In this paper, these results will be described.

摘要

螯合疗法是一种通过使用金属螯合剂从人体器官和组织中去除有毒金属并治疗疾病的医学程序。例如，铁螯合疗法不仅旨在治疗金属中毒，还用于治疗由铁过载、癌症化疗和相关疾病引起的一些疾病。然而，通常需要非常小心地使用这种金属螯合剂，因为可能会由于与细胞内金属阳离子的非特异性络合而产生副作用。在此，我们报告了一些新的多（bpy）配体（bpy：2,2'-联吡啶）的制备和表征，这些配体含有一个三个 bpy 配体部分，以及它们对 Jurkat、MOLT-4、U937、HeLa S3 和 A549 细胞系的抗癌活性。MTT 分析的结果表明，三（bpy）和双（bpy）配体对诱导癌细胞死亡具有很强的活性。机制研究表明，这些多（bpy）配体引起细胞死亡的主要途径是细胞凋亡。还发现，多（bpy）配体的抗癌活性可以通过与生物相关的金属阳离子的络合（抗癌活性关闭）和解络合（抗癌活性开启）来控制。本文将描述这些结果。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/60a7/10498496/e346618e40d1/ic3c01738_0020.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/60a7/10498496/16c5c90d9cc2/ic3c01738_0015.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/60a7/10498496/bac37b5cf274/ic3c01738_0016.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/60a7/10498496/851a1003d863/ic3c01738_0017.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/60a7/10498496/2dfc1d010fc9/ic3c01738_0018.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/60a7/10498496/b6c3423d506c/ic3c01738_0002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/60a7/10498496/a44586854e3b/ic3c01738_0003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/60a7/10498496/081fe7e819e5/ic3c01738_0019.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/60a7/10498496/d55e2a83ff03/ic3c01738_0004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/60a7/10498496/306621c8062d/ic3c01738_0005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/60a7/10498496/64835ad498e0/ic3c01738_0006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/60a7/10498496/591d66b7699b/ic3c01738_0007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/60a7/10498496/51ce17a941a6/ic3c01738_0008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/60a7/10498496/b6990e9ee0fa/ic3c01738_0009.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/60a7/10498496/68b7b622eb85/ic3c01738_0010.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/60a7/10498496/2438f4a37801/ic3c01738_0011.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/60a7/10498496/e78babd7f720/ic3c01738_0012.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/60a7/10498496/cb3e68068cb4/ic3c01738_0013.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/60a7/10498496/b555d94d7284/ic3c01738_0014.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/60a7/10498496/e346618e40d1/ic3c01738_0020.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/60a7/10498496/16c5c90d9cc2/ic3c01738_0015.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/60a7/10498496/bac37b5cf274/ic3c01738_0016.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/60a7/10498496/851a1003d863/ic3c01738_0017.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/60a7/10498496/2dfc1d010fc9/ic3c01738_0018.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/60a7/10498496/b6c3423d506c/ic3c01738_0002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/60a7/10498496/a44586854e3b/ic3c01738_0003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/60a7/10498496/081fe7e819e5/ic3c01738_0019.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/60a7/10498496/d55e2a83ff03/ic3c01738_0004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/60a7/10498496/306621c8062d/ic3c01738_0005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/60a7/10498496/64835ad498e0/ic3c01738_0006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/60a7/10498496/591d66b7699b/ic3c01738_0007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/60a7/10498496/51ce17a941a6/ic3c01738_0008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/60a7/10498496/b6990e9ee0fa/ic3c01738_0009.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/60a7/10498496/68b7b622eb85/ic3c01738_0010.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/60a7/10498496/2438f4a37801/ic3c01738_0011.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/60a7/10498496/e78babd7f720/ic3c01738_0012.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/60a7/10498496/cb3e68068cb4/ic3c01738_0013.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/60a7/10498496/b555d94d7284/ic3c01738_0014.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/60a7/10498496/e346618e40d1/ic3c01738_0020.jpg

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本文引用的文献

[1]
Post-complexation Functionalization of Cyclometalated Iridium(III) Complexes and Applications to Biomedical and Material Sciences.

Top Curr Chem (Cham). 2022-8-10

[2]
Design, Synthesis, and Anticancer Activity of Triptycene-Peptide Hybrids that Induce Paraptotic Cell Death in Cancer Cells.

Bioconjug Chem. 2022-4-20

[3]
Induction of Paraptosis by Cyclometalated Iridium Complex-Peptide Hybrids and CGP37157 via a Mitochondrial Ca Overload Triggered by Membrane Fusion between Mitochondria and the Endoplasmic Reticulum.

Biochemistry. 2022-4-19

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Chelation Therapy in Patients With Cardiovascular Disease: A Systematic Review.

J Am Heart Assoc. 2022-3-15

[5]
Cyclometalated Iridium(III) Complex-Cationic Peptide Hybrids Trigger Paraptosis in Cancer Cells via an Intracellular Ca Overload from the Endoplasmic Reticulum and a Decrease in Mitochondrial Membrane Potential.

Molecules. 2021-11-21

[6]
BAPTA, a calcium chelator, neuroprotects injured neurons in vitro and promotes motor recovery after spinal cord transection in vivo.

CNS Neurosci Ther. 2021-8

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Amphiphilic Cationic Triscyclometalated Iridium(III) Complex-Peptide Hybrids Induce Paraptosis-like Cell Death of Cancer Cells via an Intracellular Ca-Dependent Pathway.

ACS Omega. 2020-3-17

[8]
Conservative iron chelation for neurodegenerative diseases such as Parkinson's disease and amyotrophic lateral sclerosis.

J Neural Transm (Vienna). 2020-2

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Nickel Toxicity Targets Cell Wall-Related Processes and PIN2-Mediated Auxin Transport to Inhibit Root Elongation and Gravitropic Responses in Arabidopsis.

Plant Cell Physiol. 2020-3-1

[10]
Metal Chelation Therapy and Parkinson's Disease: A Critical Review on the Thermodynamics of Complex Formation between Relevant Metal Ions and Promising or Established Drugs.

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