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Characterization of a versatile organometallic pro-drug (CORM) for experimental CO based therapeutics.

ABSTRACT: The complex fac-[Mo(CO)(3)(histidinate)]Na has been reported to be an effective CO-Releasing Molecule in vivo, eliciting therapeutic effects in several animal models of disease. The CO releasing profile of this complex in different settings both in vitro and in vivo reveals that the compound can readily liberate all of its three CO equivalents under biological conditions. The compound has low toxicity and cytotoxicity and is not hemolytic. CO release is accompanied by a decrease in arterial blood pressure following administration in vivo. We studied its behavior in solution and upon the interaction with proteins. Reactive oxygen species (ROS) generation upon exposure to air and polyoxomolybdate formation in soaks with lysozyme crystals were observed as processes ensuing from the decomposition of the complex and the release of CO.

SUBMITTER: Seixas JD

PROVIDER: S-EPMC3618497 | biostudies-literature | 2013 May

REPOSITORIES: biostudies-literature

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Characterization of a versatile organometallic pro-drug (CORM) for experimental CO based therapeutics.

Seixas João D JD Mukhopadhyay Abhik A Santos-Silva Teresa T Otterbein Leo E LE Gallo David J DJ Rodrigues Sandra S SS Guerreiro Bruno H BH Gonçalves Ana M L AM Penacho Nuno N Marques Ana R AR Coelho Ana C AC Reis Patrícia M PM Romão Maria J MJ Romão Carlos C CC

Dalton transactions (Cambridge, England : 2003) 20130501 17

The complex fac-[Mo(CO)(3)(histidinate)]Na has been reported to be an effective CO-Releasing Molecule in vivo, eliciting therapeutic effects in several animal models of disease. The CO releasing profile of this complex in different settings both in vitro and in vivo reveals that the compound can readily liberate all of its three CO equivalents under biological conditions. The compound has low toxicity and cytotoxicity and is not hemolytic. CO release is accompanied by a decrease in arterial bloo ...[more]

PMID: 23223860

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Project description:Carbon monoxide (CO) is an endogenous signaling molecule with demonstrated pharmacological effects. For studying CO biology, there is a need for sensitive and selective fluorescent probes for CO as research tools. In developing such probes, CO gas and/or commercially available metal-carbonyl-based "CO-releasing molecules" (CORMs) have been used as CO sources. However, new findings are steadily emerging that some of these commonly used CORMs do not release CO reliably in buffers commonly used for studying such CO probes and have very pronounced chemical reactivities of their own, which could lead to the erroneous identification of "CO probes" that merely detect the CORM used, not CO. This is especially true when the CO-sensing mechanism relies on chemistry that is not firmly established otherwise. Cu2+ can quench the fluorescence of an imine-based fluorophore, DPHP, presumably through complexation. The Cu2+-quenched fluorescence was restored through the addition of CORM-3, a Ru-based CORM. This approach was reported as a new "strategy for detecting carbon monoxide" with the proposed mechanism being dependent on CO reduction of Cu2+ to Cu1+ under near-physiological conditions ( Anal. Chem. 2022, 94, 11298-11306). The study only used CORM-3 as the source of CO. CORM-3 has been reported to have very pronounced redox reactivity and is known not to release CO in an aqueous solution unless in the presence of a strong nucleophile. To assess whether the fluorescent response of the DPHP-Cu(II) cocktail to CORM-3 was truly through detecting CO, we report experiments using both pure CO and CORM-3. We confirm the reported DPHP-Cu(II) response to CORM-3 but not pure CO gas. Further, we did not observe the stated selectivity of DPHP for CO over sulfide species. Along this line, we also found that a reducing agent such as ascorbate was able to induce the same fluorescent turn-on as CORM-3 did. As such, the DPHP-Cu(II) system is not a CO probe and cannot be used to study CO biology. Corollary to this finding, it is critical that future work in developing CO probes uses more than a chemically reactive "CO donor" as the CO source. Especially important will be to confirm the ability of the "CO probe" to detect CO using pure CO gas or another source of CO.

Dataset Information

Characterization of a versatile organometallic pro-drug (CORM) for experimental CO based therapeutics.

Publications

Characterization of a versatile organometallic pro-drug (CORM) for experimental CO based therapeutics.

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