Theoretical Insights into the Mechanism of Carbon Monoxide (CO) Release from CO‐Releasing Molecules |
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Authors: | Dr. Sai Vikrama Chaitanya Vummaleti Dr. Davide Branduardi Dr. Matteo Masetti Dr. Marco De Vivo Prof. Roberto Motterlini Prof. Andrea Cavalli |
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Affiliation: | 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) |
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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? 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? 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? CO bond stabilization energies. According to the NBO calculations, the charge transfer is the major source of Mn? 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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Keywords: | CO release density functional calculations kinetics ligand effects natural bond orbitals |
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