17 e⁻rhenium dicarbonyl CO-releasing molecules on a cobalamin scaffold for biological application

Abstract

Cyanocobalamin (B(12)) offers a biocompatible scaffold for CO-releasing 17-electron dicarbonyl complexes based on the cis-trans-[Re(II)(CO)(2)Br(2)](0) core. A Co-C≡N-Re conjugate is produced in a short time and high yield from the reaction of [Et(4)N](2)[Re(II)Br(4)(CO)(2)] (ReCORM-1) with B(12). The B(12)-Re(II)(CO)(2) derivatives show a number of features which make them pharmaceutically acceptable CO-releasing molecules (CORMs). These cobalamin conjugates are characterized by an improved stability in aqueous aerobic media over the metal complex alone, and afford effective therapeutic protection against ischemia-reperfusion injury in cultured cardiomyocytes. The non-toxicity (at μM concentrations) of the resulting metal fragment after CO release is attributed to the oxidation of the metal and formation in solution of the ReO(4)(-) anion, which is among the least toxic of all of the rare inorganic compounds. Theoretical and experimental studies aimed at elucidating the aqueous chemistry of ReCORM-1 are also described.

Live-Fibroblast IR Imaging of a Cytoprotective PhotoCORM Activated with Visible Light

“…About one million cells were plated per Petri dish of 4.5 cm 2 area and kept proliferating to near confluence at 37 ºC in the presence of 95% air and 5% CO2 as described earlier. 7 Thereafter, the medium was exchanged in order to establish the following experimental conditions. and considered significant when two-tailed p < 0.05.…”

“…22 Within the CORM field we started to develop CO releasing molecules conjugated to biocompatible scaffolds, [23][24][25] with a focus on vitamin B 12 , and we have recently introduced a cyanocobalamin (B 12 ) Re-based CORM coordinated to the axial cyano group of the vitamin (B 12 -ReCORM-2 in chart 1). 7 The molecule shows cytoprotective effects on an ischemiareperfusion injury model of neonatal rat cardiomyocytes (NRCs) but atomic absorption spectroscopy (AAS) measurements indicated no cellular uptake of the molecule. 7,26 We believe there are two possible explanations for this observation.…”

“…7 The molecule shows cytoprotective effects on an ischemiareperfusion injury model of neonatal rat cardiomyocytes (NRCs) but atomic absorption spectroscopy (AAS) measurements indicated no cellular uptake of the molecule. 7,26 We believe there are two possible explanations for this observation. On one hand it is possible that the CO-releasing profile of B 12 -ReCORM-2 (t ½ of CO release = 20-30 min depending on conditions) does not allow sufficient time for the intracellular accumulation of the molecule.…”

“…To date the majority of CORMs are transition metal (TM) carbonyl complexes which under different stimuli are able to deliver CO to diseased or inflamed tissues in order to initiate and promote therapeutic effects at the site of disease. CO release in these molecules may be triggered by different strategies which include simple CO dissociation [4][5][6] , redox or ligand exchange mediated processes [7][8][9][10][11][12] , enzymatic triggering 13,14 or the use of electromagnetic radiation. [15][16][17] In general, at present, CORMs are not designed to target a specific receptor or intracellular target and their potential utility is credited to their fundamental ability to liberate CO.…”

Vitamin B12–Metal Conjugates for Targeted Chemotherapy and Diagnosis: Current Status and Future Prospects

“…[35] The same group have recently reported on some constitutional isomers of vitamin B 12 -rhenium conjugates based on a {fac-Re I (CO) 3 } unit attached either to the Co III cyano group (compound 13) or to the 5′-site of ribose (compound 14; Figure 8). [36] Intriguingly, contrary to what had previously been observed for 12, [35] synchrotron infrared spectromicroscopy measurements provided evidence that cellular uptake takes place in the cases both of 13 and of 14. In particular, conjugate 14 was shown to accumulate in 3T3 fibroblasts preferentially in proximity to the cell nucleus.…”