Synthesis, Characterization And Organ Protection Of Dipeptide-containing Carbon Monoxide Release Molecules

CO Releasing Molecules (CO-RMs) exist many defects:high poisonousness, poor solubility, the CO release uncontrollable, etc. To overcome the shortcomings of CO-RMs, we developed Fischer Carbene carbonyl coordination with five CO [(CO)5CrC(CH3)L] as lead structure, the natural amino as small peptide(L)(Pep-CORM). We synthesized fifteen Pep-CORM la-2g. The standard myoglobin assay reveals the property of CO release, we found that the precise-control-release by adjusting the light intensity. Biological activity test showed the low toxicity, revealing that it has good protective effect in organ preservation and organ transplantation. This thesis is composed of following three parts:1. We developed the efficient synthesis method of fifteen Pep-CORM 1 a-2g, and all compounds have been characterized by spectroscopy methods, showing that the structures are consistent with expected. Single crystal structures of compounds la and 2b were analyzed by X-ray diffraction, revealed that the inner coordination sphere were five CO and carbene C ligands. We tested the CO-releasing under different conditions by standard myoglobin assay. The CO release can be in a controlled manner by 365nm at room temperature. The compounds have certain toxicity by testing the RAW264.7 and KB cells, and 100 uM of Pep-CORM could obviously inhibit the cell growth.2. Firstly, we investigated the release process by TGAn IRn NMR and Ms. TGA analysis showing that five CO deviated away firstly (130-150’C), then rejected the samll peptide linked to Carbene carbon, which coordinated with the central metal(412-456℃). The lost parts were burnt to be small gas molecules; At last, the residues were incomplete combustion C and Cr2O3. Compounds released CO gradually irradiated by 365nm, then small H2O or solvent replaced the metal vacancy by the leaving CO in the photo-dissociation process. Interestingly, we found that the peptide ligand was stable chelating the central metal during the photo-dissociation process.3. We tested the CO-releasing ability in vitro organ preservation solution. We carried out related biological experiments to explore the physiological role. In a lethal renal ischemia-reperfusion injury (IRI) model in mice, we detected the CO concentration in kidey (2500 ppb/g) was higher than the liver (1250 ppb/g), and all higher than control group (CORM-2). For further exploration of anti-IRI property, we conducted H&M experiments, the epidermal cells of renal tubules of CORM-la group were in better condition than the Sham group, PBS group and i-CORM-la group, which has good property of protecting the ischemia-reperfusion injury (IRI).