Inhibicija dipeptidil peptidaze-4 heterocikličnim jedinjenjima in vitro
AuthorTomović, Katarina T.
Committee membersKocić, Gordana
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Dipeptidyl peptidase-4 is a target in diabetes therapy. The impact of mono-, bi- and tricyclic derivatives of imidazole, thiazole, pyridine, pyran, pyrimidine and morpholine on the activity of recombinant human dipeptidyl peptidase-4 was evaluated by spectrophotometric method in vitro compared with sitagliptin and diprotin A as reference inhibitors, clarifying the mechanism of inhibition and structureactivity relationship of the most effective inhibitors. Derivatives of benzimidazol-2-imine, bis(benzimidazol-2-yl)amine, 6- (phenylcarbonyl)-[1,3]thiazolo[3,2-a]benzimidazol-3-one, benzo[4,5]thieno[2,3-d]pyrimidin-4-amine and -phthalimide inhibited dipeptidyl peptidase-4 with IC50 < 200 μM. 2-(2-(3-Chlorobenzyl)-5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3- d]pyrimidin-4-yl)isoindoline-1,3-dione was about two times less effective than diprotin A, with noncompetitive type of inhibition, what might be explained by absence of interactions with Glu205, Glu206 and S1 pocket of dipeptidyl peptidase-4.... 1-Propyl-N-(1-propyl-1H-benzimidazol-2-yl)-1H-benzimidazol-2- amine and 1-methyl-N-(1-propyl-1H-benzimidazol-2-yl)-1Hbenzimidazol- 2-amine showed about three and one and a half times higher effectivenes, respectively, while 1-ethyl-N-(1-propyl-1Hbenzimidazol- 2-yl)-1H-benzimidazol-2-amine was about three times less effective than diprotin A. The S2 extensive subsite of dipeptidyl peptidase-4 participates in interactions with these structures, what presumably contributes to their higher activity. Besides dipeptidyl peptidase-4, 2-[2-imino-5-nitro-3-(2-oxo-2- phenylethyl)-2,3-dihydro-1H-benzimidazol-1-yl]-1-phenylethanone and 2-(4-fluorobenzylidene)-6-(phenylcarbonyl)[1,3]thiazolo[3,2- a]benzimidazol-3(2H)-one inhibited xanthine oxidase in vitro with IC50 < 150 μM, in spectrophotometric assay. Potential pronounced cardiovascular protective effects of dual dipeptidyl peptidase-4 and xanthine oxidase inhibitors were considered. Effective benzo[4,5]thieno[2,3-d]pyrimidine derivatives and dual inhibitors were not cytotoxic to a greater extent at concentrations below 250 μM, assessed on Caco-2 cells by MTT assay. The significance and mechanisms of multiple biochemical effects of dipeptidyl peptidase-4 inhibition and pleiotropis effects of existing and new, including those found in this dissertation, inhibitors were considered in order to assess possible broadening of range of indications, pointing to protective effects in cardiovascular and renal pathology by affecting mediators of inflammation, oxidative stress, fibrosis and apoptosis, to beneficial effects on postischemic angiogenesis mediated by prevention of stromal cell-derived factor-1 cleavage, and to pulmonary hypertension as possible indication of inhibitors effective in irreversible phase of remodeling.
Faculty:Универзитет у Нишу, Медицински факултет
- Obtaining, physicochemical characterization, analysis and biological activity of pharmacologically active compounds (RS-172044)