Design, Synthesis And Screening Of The Compounds Reversing Arterial Stiffening Of Aging And Diabetes Based On AGEs Cross-link

We designed new drugs reversing arterial stiffening in aging and diabetes targeted AGEs crosslinks. According to the proposed mechanism of breaking of AGEs crosslinks and ALT711's structure characteristics, we designed new lead optimization visual combinatorial libraries, and visually screened the libraries by calculating the charge using MOPAC. The results led to compound ZW1 with high cleavage in vivo and in vitro. We also build lead discovery visual combinatorial libraries, and defined different chemical space of the compounds in libraries.Based on our design, 2, 11, 10, 18 compounds belong to selenazole, selenophen, thiophene and imidazole[2,1-b]selenazole respectively have been synthesized and the structure of 41 compounds have been identified by IR, 'HNMR.and MS. A novel one-pot synthesis which avoided high-toxic and unstable starting material, selenourea and was easy to operate had been used in synthesis of 2-amino-l, 3-selenazoles; a new one-pot method of synthesis of imidazole[2,l-b]selenazole had been also developed. Both were feasible in parallel synthesis of combinatorial libraries.The results in vitro assay indicated that the breaking ratio of 20 compounds at 0.1mmol and 17 compounds at O.lmmol was higher than that of ALT711's. The in vivo study with compound ZW1 had resulted in improvement in the elasticity of stiffened vascular and increment of the solubility of diabetic tail tendon collagen.The relationship between the structure and activities of the compounds have been studied by Ab initio calculation. The QSAR model of imidazole[2,l-b]selenazole showed that there was a good multivariate linear relationship between the activity and the charge of C9,N10 and Se14 ; the QSAR model of others showed that the activities will increase attributing to the L or the charge of C2.The knowledge-based quantitative structure and activities relationships were used to predict the cleavage ability of AGEs crosslinks breakers. One of the Kbase QSARmodels showed that there was a good multivariate linear relationship between the activity and four major indices; the other one showed that four major fragments could enhance the activity of AGEs cleavage. 18 compounds' cleavage could be accurately predicted by the model. Both QSAR models could be used in synthetic strategies during lead optimization and new vitual libraries prediction.Overall, the design, synthesis and screening of AGEs Cross-links breakers have been researched . The new compound ZW1 have potent ability of decreasing AGEs crosslinks in diabetic rat, improving the existing vascular and myocardial stiffness and was worth to further research as a candidate new drug.