The Synthesis And Activity Screening In Vitro Of Novel Mercaptosuccinic Acid Derivatives As Matrix Metalloproteinase Inhibitors

MMPS is one of the hydrolysis enzyme that Zn2+、Ca2+reliable on and it’s aevolution highly conserved in the nature, it’s able to degrade almost all ingredient inECM, also it participate the degradation and inhibitor of connective tissue. Moreover,it can interaction with all growth factor and cytokines in the extracellularmicroenvironment. so as to play a important role in the physiological process ofwound healing, bone absorption, pregnancy, childbirth and mammary gland atrophyetc and relative tissue remodeling process. In addition, MMPS also play a vital rolein rheumatoid arthritis,osteoarthritis, corneal ulcer, periodontal disease,atherosclerosis, myocardial infarction, neurodegenerative diseases, invasion andmetastasis of the tumor, which have pathological process with a characteristic ofexcessive destruction of EMC, since1980,After Litotta found the collagendegradation process of the basement membrane align with the metastasis potential ofthe neoplasms, MMPs has rapidly become of hot topic in the process of invasion andmetastasis of tumor, tumorigenesis, tumor growth and angiogenesis of tumor, itpromote the development of the anti-tumor ie,MMPs inhibitor. Therefore expressionand activity of inhibit of MMPs has become of new approach to control the growthand metastasis of malignant. In conclusion, A high efficiency, high selectivity andhigh availability MMPIS will have a wide application prospects.The common characteristics of the MMPIs structure is contain the ZBG, suchas Hydroxamate、mercaptans、phosphoric acid etc;Large hydrophobic group P1’, cancombine with S1’-loop of MMPs, and is also the foundation of the selectivity ofMMPIs;Hydrogen bonding receptors, such as sulfonyl, dibenzyloxyphosphoiyl,propylene acyl,-S,-O,-C=O, etc. The novel MMPIs is mainly to modify P1’regions which contains heteroatom groups. Benzothiazole is a kind of uniquepowerful anti-cancer,the study found that the drugs which contains benzothiazolenucleus have special killing effection on tumor cells. In addition, it has a low toxicity,no pollution, high efficiency, diversity of structure change, etc,so it has been widely used in anti-tumor drugs research.This article based on the analysis of the3D structure of active site、the designof the structure of the drug (SBDD), traditional structure-activity relationship (SAR)and the biological activities of benzothiazole,on which design and synthesis a seriesof2-amino-6-instead of benzothiazole as P1’hydrophobic groups;and thiol,carbonylas ZBG, the chemical structure has been confirmed by IR,1H-NMR and ESI-MS,which shows they are all new compounds. We also make a activity screening in vitro(K562cell inhibition rate, the inhibition of matrix metalloproteinases), of them B1[N1-(6-Chloro-benzothiazol-2-yl)-2-mercapto-N4-(phenyl)-succinamide] have betterinhibition effect on K562cells (IC50=16.16uM) which5-FU is only (IC50=54.0uM,D2have a weekly inhibition effect. In vitro inhibition of gelatinases experimentsdemonstrate that the B4[N1-(6-Chloro-benzothiazol-2-yl)-2-mercapto-N4-(4-methoxy-phenyl)-succinamide],C2[N4-(4-chlorophenyl)-2-mercapto-N1-(6-methyl-benzothiazol-2-yl)-succinamide] have strong inhibition activity, and C1, C3enzymeactivity is weaker..