Ralf Mede

CORM-EDE1: A Highly Water-Soluble and Nontoxic Manganese-Based photoCORM with a Biogenic Ligand Sphere

[Mn(CO)5Br] reacts with cysteamine and 4-amino-thiophenyl with a ratio of 2:3 in refluxing tetrahydrofuran to the complexes of the type [{(OC)3Mn}2(μ-SCH2CH2NH3)3]Br2 (1, CORM-EDE1) and [{(OC)3Mn}2(μ-SC6H4-4-NH3)3]Br2 (2, CORM-EDE2). Compound 2 precipitates during refluxing of the tetrahydrofuran solution as a yellow solid whereas 1 forms a red oil that slowly solidifies. Recrystallization of 2 from water yields the HBr-free complex [{(OC)3Mn}2(μ-S-C6H4-4-NH2)2(μ-SC6H4-4-NH3)] (3). The n-propylthiolate ligand (which is isoelectronic to the bridging thiolate of 1) leads to the formation of the di- and tetranuclear complexes [(OC)4Mn(μ-S-nPr)2]2 and [(OC)3Mn(μ-S-nPr)]4. CORM-EDE1 possesses ideal properties to administer carbon monoxide to biological and medicinal tissues upon irradiation (photoCORM). Isolated crystalline CORM-EDE1 can be handled at ambient and aerobic conditions. This complex is nontoxic, highly soluble in water, and indefinitely stable therein in the absence of air and phosphate buffer. CORM-EDE1 is stable as frozen stock in aqueous solution without any limitations, and these stock solutions maintain their CO release properties. The reducing dithionite does not interact with CORM-EDE1, and therefore, the myoglobin assay represents a valuable tool to study the release kinetics of this photoCORM. After CO liberation, the formation of MnHPO4 in aqueous buffer solution can be verified.

CO-independent modification of K+ channels by tricarbonyldichlororuthenium(II) dimer (CORM-2)

Abstract Although toxic when inhaled in high concentrations, the gas carbon monoxide (CO) is endogenously produced in mammals, and various beneficial effects are reported. For potential medicinal applications and studying the molecular processes underlying the pharmacological action of CO, so‐called CO‐releasing molecules (CORMs), such as tricabonyldichlororuthenium(II) dimer (CORM‐2), have been developed and widely used. Yet, it is not readily discriminated whether an observed effect of a CORM is caused by the released CO gas, the CORM itself, or any of its intermediate or final breakdown products. Focusing on Ca2+‐ and voltage‐dependent K+ channels (KCa1.1) and voltage‐gated K+ channels (Kv1.5, Kv11.1) relevant for cardiac safety pharmacology, we demonstrate that, in most cases, the functional impacts of CORM‐2 on these channels are not mediated by CO. Instead, when dissolved in aqueous solutions, CORM‐2 has the propensity of forming Ru(CO)2 adducts, preferentially to histidine residues, as demonstrated with synthetic peptides using mass‐spectrometry analysis. For KCa1.1 channels we show that H365 and H394 in the cytosolic gating ring structure are affected by CORM‐2. For Kv11.1 channels (hERG1) the extracellularly accessible histidines H578 and H587 are CORM‐2 targets. The strong CO‐independent action of CORM‐2 on Kv11.1 and Kv1.5 channels can be completely abolished when CORM‐2 is applied in the presence of an excess of free histidine or human serum albumin; cysteine and methionine are further potential targets. Off‐site effects similar to those reported here for CORM‐2 are found for CORM‐3, another ruthenium‐based CORM, but are diminished when using iron‐based CORM‐S1 and absent for manganese‐based CORM‐EDE1. Graphical abstract Figure. No caption available.

Acetoxymethyl Concept for Intracellular Administration of Carbon Monoxide with Mn(CO)3-Based PhotoCORMs

Targeted administration of carbon monoxide with CO releasing molecules (CORMs) inside of cells proved to be very challenging. Consequently, there are only very few reports on intracellular uptake of CORMs requiring high extracellular CORM loading because an equilibrium between extra- and intracellular concentrations can be assumed. Here we present a strategy for a targeted intracellular administration of manganese(I)-based CORMs that are altered inside of cells to trap these complexes. Thereafter, carbon monoxide can be liberated by irradiation (photoCORMs). To achieve this innovative task, acetoxymethyl (AM) groups are attached at the periphery of the hydrophobic manganese(I) carbonyl complexes to not influence the CO release behavior. Inside of cells these AM substituents are cleaved by esterases yielding hydrophilic manganese(I) carbonyl compounds which are captured inside of cells. This objective is realized by using the bidentate bases 4-(acetoxymethoxycarbonyl)phenyl-bis(3,5-dimethylpyrazolyl)methane (1) and 4-(acetoxymethoxy)phenyl-bis(3,5-dimethylpyrazolyl)methane (4) at facial (OC)3 MnBr fragments yielding CORM-AM1 (2) and CORM-AM2 (5), respectively. Besides synthesis, crystal structures and spectroscopic properties we present targeted administration and intracellular accumulation of these AM-containing CORMs.