Mo(VI) Potential Metallodrugs : Explaining the Transport and Cytotoxicity by Chemical Transformations
Mohanty, Monalisa (National Institute of Technology Rourkela)
Sahu, Gurunath (National Institute of Technology Rourkela)
Banerjee, Atanu (National Institute of Technology Rourkela)
Lima, Sudhir (National Institute of Technology Rourkela)
Patra, Sushree Aradhana (National Institute of Technology Rourkela)
Crochet, Aurélien (University of Fribourg)
Sciortino, Giuseppe (Institut d'Investigacions Químiques de Catalunya)
Sanna, Daniele (Consiglio Nazionale delle Ricerche. Istituto di Chimica Biomolecolare)
Ugone, Valeria (Consiglio Nazionale delle Ricerche. Istituto di Chimica Biomolecolare)
Garribba, Eugenio (Università di Sassari. Dipartimento di Medicina, Chirurgia e Farmacia)
Dinda, Rupam (National Institute of Technology Rourkela)

Data:	2022
Resum:	The transport and cytotoxicity of molybdenum-based drugs have been explained with the concept of chemical transformation, a very important idea in inorganic medicinal chemistry that is often overlooked in the interpretation of the biological activity of metal-containing systems. Two monomeric, [MoO2(L1)(MeOH)] (1) and [MoO2(L2)(EtOH)] (2), and two mixed-ligand dimeric MoVIO2 species, [{MoO2(L1-2)}2(μ-4,4'-bipy)] (3-4), were synthesized and characterized. The structures of the solid complexes were solved through SC-XRD, while their transformation in water was clarified by UV-vis, ESI-MS, and DFT. In aqueous solution, 1-4 lead to the penta-coordinated [MoO2(L1-2)] active species after the release of the solvent molecule (1 and 2) or removal of the 4,4'-bipy bridge (3 and 4). [MoO2(L1-2)] are stable in solution and react with neither serum bioligand nor cellular reductants. The binding affinity of 1-4 toward HSA and DNA were evaluated through analytical and computational methods and in both cases a non-covalent interaction is expected. Furthermore, the in vitro cytotoxicity of the complexes was also determined and flow cytometry analysis showed the apoptotic death of the cancer cells. Interestingly, μ-4,4'-bipy bridged complexes 3 and 4 were found to be more active than monomeric 1 and 2, due to the mixture of species generated, that is [MoO2(L1-2)] and the cytotoxic 4,4'-bipy released after their dissociation. Since in the cytosol neither the reduction of MoVI to MoV/IV takes place nor the production of reactive oxygen species (ROS) through Fenton-like reactions of 1-4 with H2O2 occurs, the mechanism of cytotoxicity should be attributable to the direct interaction with DNA that happens with a minor-groove binding which results in cell death through an apoptotic mechanism.
Drets:	Tots els drets reservats.
Llengua:	Anglès
Document:	Article ; recerca ; Versió acceptada per publicar
Matèria:	SDG 3 - Good Health and Well-being
Publicat a:	Inorganic chemistry, Vol. 61, Issue 10 (March 2022) , p. 4513-4532, ISSN 1520-510X

DOI: 10.1021/acs.inorgchem.2c00113
PMID: 35213131

Postprint 14 p, 973.2 KB

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