The discovery of the biological effects of carbon monoxide (CO) in recent years strongly suggests that CO could find applications as a therapeutic agent. CO is a highly toxic gas when used at industrial doses, due in part to its binding affinity to hemoglobin. Since hemoglobin binds CO with the highest affinity in vivo, it also constitutes a major barrier to the delivery of CO to tissues in need of therapy. A method of delivering CO that can bypass hemoglobin is the use of pro-drugs or CO carriers, called CO-releasing molecules (CO-RMs) that become activated and release CO in tissues in need of treatment. Organometallic carbonyl complexes are best suited to play the role of CO carriers, and indeed the natural CO carrier molecules hemoglobin and myoglobin belong to this class of chemical compounds. Here we describe the preparation of novel molybdenum CO-RMs of general formula Mo(CO) 3 (CNCR′R″CO 2 R‴) 3 (R′, R″ = H, Me, i Pr, CH 2 Ph, CO 2 Li, −CH 2 CH 2 −, −CH 2 (CH 2 ) 3 CH 2 −; R‴ = H, Li), which present favorable druglike characteristics, have low toxicity, and demonstrate specific CO delivery to the liver in the treatment of acetaminophen (APAP)-induced acute liver failure in mice.
The reduction of (Et(4)N)[Re(III)Br(4)(CO)(2)] (1) by 0.5 equiv of tetrakis-dimethylaminoethylene in acetonitrile yields directly the air-stable, 17-electron Re(II) synthon (Et(4)N)(2)[Re(II)Br(4)(CO)(2)] (2) in nearly quantitative yield. The versatility of 2 as a synthon for Re(II) chemistry was demonstrated by substitution reactions of [Re(II)Br(4)(CO)(2)](2-) with different mono-, bi-, and tridentate ligands. The resulting Re(II) complexes form highly crystalline compounds, and the solid state structures of the neutral trans-cis-[Re(II)Br(2)(CO)(2)(X)(n)] species (where X = imidazole, pyridine, or phenanthroline) could be determined. All complexes are stable under aerobic conditions, both as solids and in solution, and showed fully reversible one-electron Re(II) --> Re(I) reductions between ca. -70 and -120 mV. Carbonyl stretching frequencies (nu(CO)) of this new family of Re(II) complexes are observed in the 1990 cm(-1) (A(1)) and 1830 (E(g)) cm(-1) regions. With complex 2, a wide variety of fundamental but so far unknown Re(II) complexes become accessible via facile substitution reactions.
Water- and air-stable complexes comprising the cis-[Re(CO)(2)](+) core can be synthesized from the (Et(4)N)[ReBr(2)(NCCH(3))(2)(CO)(2)] precursor . Complex showed distinctly different chemical and electronic behaviour compared to [ReBr(3)(CO)(3)](2-). Substituting the two bromides in with imidazole-like ligands or alpha,alpha'-diimines gave new complexes with potential applications in bioinorganic chemistry and photochemistry. The two acetonitrile ligands are very stably bound and could not be replaced. Under CO pressure, the uncommon complex mer-[ReBr(NCCH(3))(2)(CO)(3)] was formed from . The reaction of with the tetradentate ligand bis(2-pyridylmethyl)glycine (BPG) finally induced a four fold substitution at the metal center to form a [Re(CO)(2)(L(4))](+)-type complex.
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