Synthesis,Toxicity And Bio-activities Of Targeted Carbonyl Cobalt CO-releaseing Molecules

The carbonyl cobalt CO releasing molecule has good antitumor activity,but most of them have no selectivity to tissue and organs.As the role of cyclooxygenase COX-2 in the development of tumors have been revealed,COX-2 will become one of the most promising targets in the study of anticancer drugs.Carbonyl cobalt CORMs with COX-2 inhibitor is possible a new kind of multiple targets for anti-cancer drug types.Besides,there are large amounts of galactose receptors and glycyrrhetic acid receptors on the surface of hepatocytes,therefore,hybrid carbonyl cobalt CORMs containing galactose and glycyrrhetinic acid structure are likely to be a new type of targeted anti-cancer drugs types.Therefore,three series of targeed carbonyl cobalt CORMs were designed and synthesized,and their CO release characteristics,toxicity and antitumor activity were evaluated.The research content and results mainly include the following aspects:1.Synthesis,Toxicity and Antitumor Activity of CORM based on glycyrrhetinic acidA series of CO release molecules?CORMs?based on glycyrrhetinic acid?GA?,were synthesized and characterized by IR,NMR and ESI-MS.All the complexes were evaluated using HeLa,A549,HT-29,SMMC7721 and HepG2 cells as models.The testing results:all the complexes displayed good anti-proliferation activity against the HepG2 and SMMC-7721 liver cancer cells,and their IC₅₀ values in the range of10.07-66.06?M;compared with DDP,their activities were comparable or even better under the same condition.Among them,complex 2,3,8 and 18 exhibited higher anti-proliferation activities against HepG2 and SMMC-7721 cell lines than the others.This is resulting from lots of receptors for GA on the liver cellular membrane.In order to confirm the targeting of the complexes,the uptakes of complex 2,3,8 and 18 by HepG2,HT-29,A549 and SMMC7721 cell lines were studied.The results showed cell uptake rates of the complexes by HepG2 cells and SMMC7721 cells were much greater than by other cells under the same condition.The apoptosis of HepG2 cells was assessed after staining by DAPI,PI,Mito-Tracker Green and DCFH-DA,respectively,but the results were the same;meanwhile,the tested complexes up-regulated the expression levels of caspase-3 and Bax,down-regulated the Bcl-2 expression.Zebrafish testing results indicate that the complexes had a certain effect on zebrafish embryo survival,embryo hatching,embryonic movement,zebrafish malformation and zebrafish movement at 20?M.This suggests the complexes have a potential to be candidates for liver cancers,and it is necessary to be studied further.2.Syntheses,anti-cancer activity of CO-releasing molecules with targeting galactose receptorOn the basis of the specific recognition of galactose or sialic acid to its receptor,a series of CORMs based on carbohydrates were synthesized and evaluated.The testing results show all the complexes displayed anticancer activity.Among them,the effects of complexes 1,8 and 10 were very distinct.Complex 1 displayed higher activity against HeLa,HepG2,MCF-7 and HT-29 cells proliferation than cis-platin?DDP?,and its selectivity was far much better than DDP compared with normal cell W138.Furthermore,the uptakes of complexes 1,8 and 10 by HepG2,HT-29,A549 and RAW264.7 cell lines were studied.The uptake ratio of each cell line for complex 1was different,the order of uptake ratio in four cell lines was HepG2>HT-29>RAW264.7>A549.The HepG2 cells absorbed beyond 60%complex 1 after incubation for 8 h,while A549 only 27.8%.For complex 8,the uptake trend was similar to that of complex 1 absorbed by all the four cancer cells,but the uptake rate was lower.However,differently,complex 10 was absorbed heavily by macrophage RAW264.7,followed by HepG2;after 8h incubation later,the uptake rate of RAW264.7 was over 50%.In addition,the mechanism of action was explored,the results show complex 1up-regulated the expression levels of caspase-3 and Bax,down-regulated the Bcl-2expression,by which giving rise to HepG2 cell apoptosis.3.Synthesis,toxicity and biological activities of carbonyl cobalt CORMs with inhibiting cyclooxygenase-2A series of hybrid carbonyl cobalt CO-releasing molecules?CORMs?with inhibiting cyclooxygenase-2 were synthesized and characterized by IR,NMR and HRMS.The crystal structures of complexes 9,11,14 and 16 were determined by single-crystal X-ray diffraction.The anti-tumor experiment results showed o all the complexes displayed anticancer activity.Among them,complexes 12 and 13 which modified by selective COX-2 inhibitors displayed strong antiproliferative activity and selectivity to MCF-7cell and HT-29 cell lines,and their IC₅₀ values were 33.6-55.8?M;but compared with cis-platin?DDP?,they showed slightly lower activities.Compared with 5-Fu,their activities were comparable or even better under the same condition The complex inhibited the expression of COX-2 in HT-29 cells and MCF-7cells,and complex 12had stronger inhibitory effects than the others,which was accordance with its stronger activity against cell proliferation.In addition,the complexes displayed antihypertensive effects on spontaneously hypertensive rats,accompanying with good myocardium protection.