Theoretical Insights into the Mechanism of Carbon Monoxide (CO) Release from CO-Releasing Molecules

Authors

  • Dr. Sai Vikrama Chaitanya Vummaleti,

    1. Department of Drug Discovery and Development, Istituto Italiano di Tecnologia via Morego 30, 16163 Genova (Italy), Fax: (+39) 010-7170187
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  • Dr. Davide Branduardi,

    1. Department of Drug Discovery and Development, Istituto Italiano di Tecnologia via Morego 30, 16163 Genova (Italy), Fax: (+39) 010-7170187
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  • Dr. Matteo Masetti,

    1. Department of Pharmaceutical Sciences, Alma Mater Studiorum, Bologna University via Belmeloro 6, 40126 Bologna (Italy)
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  • Dr. Marco De Vivo,

    1. Department of Drug Discovery and Development, Istituto Italiano di Tecnologia via Morego 30, 16163 Genova (Italy), Fax: (+39) 010-7170187
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  • Prof. Roberto Motterlini,

    1. Department of Drug Discovery and Development, Istituto Italiano di Tecnologia via Morego 30, 16163 Genova (Italy), Fax: (+39) 010-7170187
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  • Prof. Andrea Cavalli

    Corresponding author
    1. Department of Drug Discovery and Development, Istituto Italiano di Tecnologia via Morego 30, 16163 Genova (Italy), Fax: (+39) 010-7170187
    2. Department of Pharmaceutical Sciences, Alma Mater Studiorum, Bologna University via Belmeloro 6, 40126 Bologna (Italy)
    • Department of Drug Discovery and Development, Istituto Italiano di Tecnologia via Morego 30, 16163 Genova (Italy), Fax: (+39) 010-7170187
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Abstract

We used density functional theory to investigate the capacity for carbon monoxide (CO) release of five newly synthesized manganese-containing CO-releasing molecules (CO-RMs), namely CORM-368 (1), CORM-401 (2), CORM-371 (3), CORM-409 (4), and CORM-313 (5). The results correctly discriminated good CO releasers (1 and 2) from a compound unable to release CO (5). The predicted Mn[BOND]CO bond dissociation energies were well correlated (R2≈0.9) with myoglobin (Mb) assay experiments, which quantified the formation of MbCO, and thus the amount of CO released by the CO-RMs. The nature of the Mn[BOND]CO bond was characterized by natural bond orbital (NBO) analysis. This allowed us to identify the key donor–acceptor interactions in the CO-RMs, and to evaluate the Mn[BOND]CO bond stabilization energies. According to the NBO calculations, the charge transfer is the major source of Mn[BOND]CO bond stabilization for this series. On the basis of the nature of the experimental buffers, we then analyzed the nucleophilic attack of putative ligands (L′=HPO42−, H2PO4, H2O, and Cl) at the metal vacant site through the ligand-exchange reaction energies. The analysis revealed that different L′-exchange reactions were spontaneous in all the CO-RMs. Finally, the calculated second dissociation energies could explain the stoichiometry obtained with the Mb assay experiments.

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