Protein Metalation by Inorganic Anticancer Drugs

Marzo, Tiziano; Ferraro, Giarita; Merlino, Antonello; Messori, Luigi

doi:10.1002/9781119951438.eibc2747

Cited by 14 publications

(25 citation statements)

References 93 publications

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“…In fact, in bloodstream and cellular environment, for a generic pharmacologically active ML n complex, where L is an anionic organic carrier, the binding of several metal moieties (M, ML, ML 2 , etc.) with various binding modes (covalent and non-covalent, single or multiple) may occur . This appears to be particularly important for the first-row transition metals, whose labile complexes can lose one or more ligands depending on the conditions such as pH and concentration.…”

Section: Introductionmentioning

confidence: 99%

Multiple and Variable Binding of Pharmacologically Active Bis(maltolato)oxidovanadium(IV) to Lysozyme

et al. 2022

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The interaction with proteins of metal-based drugs plays a crucial role in their transport, mechanism, and activity. For an active ML n complex, where L is the organic carrier, various binding modes (covalent and non-covalent, single or multiple) may occur and several metal moieties (M, ML, ML 2 , etc.) may interact with proteins. In this study, we have evaluated the interaction of [V IV O(malt) 2 ] (bis(maltolato)oxidovanadium(IV) or BMOV, where malt = maltolato, i.e., the common name for 3-hydroxy-2methyl-4H-pyran-4-onato) with the model protein hen egg white lysozyme (HEWL) by electrospray ionization mass spectrometry, electron paramagnetic resonance, and X-ray crystallography. The multiple binding of different V-containing isomers and enantiomers to different sites of HEWL is observed. The data indicate both noncovalent binding of cis-[VO(malt) 2 (H 2 O)] and [VO(malt)-(H 2 O) 3 ] + and covalent binding of [VO(H 2 O) 3−4 ] 2+ and cis-[VO(malt) 2 ] and other V-containing fragments to the side chains of Glu35, Asp48, Asn65, Asp87, and Asp119 and to the C-terminal carboxylate. Our results suggest that the multiple and variable interactions of potential V IV OL 2 drugs with proteins can help to better understand their solution chemistry and contribute to define the molecular basis of the mechanism of action of these intriguing molecules.

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Section: Introductionmentioning

confidence: 99%

Multiple and Variable Binding of Pharmacologically Active Bis(maltolato)oxidovanadium(IV) to Lysozyme

et al. 2022

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“…Noteworthily, BiP has been proven as an intracellular sensor of heavy metals. − Such feature possibly contributed to its sensitivity toward metallodrugs, so future designs of ICD compounds could use the scaffolds of 1a and other known ICD metal agents as the leads to start with. As the binding interaction of metal complexes with biomolecular targets could be systematically tuned by the ligand design, , it is envisioned that metal complexes could be developed as potent ICD inducers with high specificity and robust efficacy. Besides the rational design, high-throughput screenings using a wide range of small molecules against BiP (either blocking its expression or enzymatic activity) may also contribute to the discovery of novel ICD agents.…”

Section: Discussionmentioning

confidence: 99%

Target Profiling of an Iridium(III)-Based Immunogenic Cell Death Inducer Unveils the Engagement of Unfolded Protein Response Regulator BiP

et al. 2022

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Clinical chemotherapeutic drugs have occasionally been observed to induce antitumor immune responses beyond the direct cytotoxicity. Such effects are coined as immunogenic cell death (ICD), representing a “second hit” from the host immune system to tumor cells. Although chemo-immunotherapy is highly promising, ICD inducers remain sparse with vague drug–target mechanisms. Here, we report an endoplasmic reticulum stress-inducing cyclometalated Ir(III)–bisNHC complex (1a) as a new ICD inducer, and based on this compound, a clickable photoaffinity probe was designed for target identification, which unveiled the engagement of the master regulator protein BiP (binding immunoglobulin protein)/GRP78 of the unfolded protein response pathway. This has been confirmed by a series of cellular and biochemical studies including fluorescence microscopy, cellular thermal shift assay, enzymatic assays, and so forth, showing the capability of 1a for BiP destabilization. Notably, besides 1a, the previously reported ICD inducers including KP1339, mitoxantrone, and oxaliplatin were also found to engage BiP interaction, suggesting the important role of BiP in eliciting anticancer immunity. We believe that the ICD-related target information in this work will help to understand the mode of action of ICD that is beneficial to designing new ICD agents with high specificity and improved efficacy.

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“…Consequently, structural modifications could affect the kinetics of the release of the labile ligand and thus the activation process itself [ 46 ]. In this framework, the structural diversity of carboplatin and oxaliplatin results in a toxicity level that is lower than that of cisplatin, and particularly nephron- and ototoxicity [ 48 , 49 ].…”

Section: The Strategiesmentioning

confidence: 99%

Strategies for the Improvement of Metal-Based Chemotherapeutic Treatments

Cirri¹,

Bartoli²,

Pratesi³

et al. 2021

Biomedicines

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This article provides an overview of the various research approaches we have explored in recent years to improve metal-based agents for cancer or infection treatments. Although cisplatin, carboplatin, and oxaliplatin remain the cornerstones in tumor chemotherapy, the discovery and approval of novel inorganic anticancer drugs is a very slow process. Analogously, although a few promising inorganic drugs have found clinical application against parasitic or bacterial infections, their use remains relatively limited. Moreover, the discovery process is often affected by small therapeutic enhancements that are not attractive for the pharmaceutical industry. However, the availability of increasing mechanistic information for the modes of action of established inorganic drugs is fueling the exploration of various approaches for developing effective inorganic chemotherapy agents. Through a series of examples, some from our own research experience, we focus our attention on a number of promising strategies, including (1) drug repurposing, (2) the simple modification of the chemical structures of approved metal-based drugs, (3) testing novel drug combinations, and (4) newly synthesized complexes coupling different anticancer drugs. Accordingly, we aim to suggest and summarize a series of reliable approaches that are exploitable for the development of improved and innovative treatments.

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Protein Metalation by Inorganic Anticancer Drugs

Cited by 14 publications

References 93 publications

Multiple and Variable Binding of Pharmacologically Active Bis(maltolato)oxidovanadium(IV) to Lysozyme

Multiple and Variable Binding of Pharmacologically Active Bis(maltolato)oxidovanadium(IV) to Lysozyme

Target Profiling of an Iridium(III)-Based Immunogenic Cell Death Inducer Unveils the Engagement of Unfolded Protein Response Regulator BiP

Strategies for the Improvement of Metal-Based Chemotherapeutic Treatments

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