Syntheses, Toxicity, Anti-inflammatory, Bio-distribution And Metblosim Of Carbonyl Metal CO-Releasing Molecules Containing Cobalt

Many studies have shown that carbonyl metal CO release molecules(CORMs) like endogenous CO has extensive pHarmacological activities such as anti-inflammatory, vasodilation. The carbonyl metal CO-releasing molecules containing cobalt showed strong inhibition of tumor cell proliferation. As COX2 have been revealed in cancer gradually and COX2 will become one of potential targets in anticancer drug research. The hybrid molecules CO-releasing containing cobalt is a kind of inhibitor COX2 and is possible a new kind of multiple targets for anti-inflammatory and anti-cancer drug types.Based on the concept, we summarized the work about carbonyl metal CO release molecules(CORMs) of our lab and we obeyed principle of prodrug and synthesized 17 hybrid molecules CORMs containing cobalt with acetyl salicylic acid, ibuprofen, glycyrrhetinic acid and 5- fluorouracil and characterized all the complexes by many manners like FT-IR, H1-NMR, ESI-MS, X-ray and so on, then investigated them properties from toxicity, anti-inflammatory, bio-distribution and metblosim.The results as fellow.(1) We tested and obtained the half-lives of all CO-releasing molecules containing cobalt in range of 8.1-71.8 min and their logP in range of 1.56-1.96.(2) The toxicity of all the complexes were detected by the MTT method. All the complexes have anticaner activities. The Hela cell line IC50 were 36.2-131.0 μM, the Hepg2 IC50 in range of 39.2-139.0 μM. At the same time, we chose complexes 1, 9 and teseted their effects on the cell apoptosis, cell cycle, ROS, and mitchondrial membrane in Hela cells. The results showed complexes 1, 9 can induce Hela “late apoptosis”, block Hela cells in G2 / M pHase, increase ROS in the Hela cells and change mitchondrial membrane. Oral toxicity values LD50 were 1500-3000 mg kg-1; after cosecutive administrations, they can affect functional and pHysiological of livers and kindy.(3) The anti-inflammatory results showed that all of them can reduce intracellular nitrite level, complexes 1 and 3 showed stronger activity than complex 12. Their anti-inflammatory activity mainly contributes the CO molecules originated from the CORMs, which confirmed by comparison with the corresponding ligand.(4) Detected distribution of complexes in mice blood and other important tissues and organs and results showed that complexes can not cross the blood-brain barrier.(5) We use FT-IR, ESI-MS and XPS means to investigate metabolism of complexes. FT- IR results showed no metal carbonyl in urine and complexes can gradually release CO in vivo. XPS results showed that cobalt atoms were oxidated to CoⅡ and CoⅢ and excreted with the urine eventually.