Design, Synthesis And Bioactivity Of NO Donor DPP-4 Inhibitors

Diabetes, a metabolic disorder disease, is considered as one of the most serious human chronic diseases at present. And the incidental complications are the major causes of human disability and death. Since the complexity of its pathogenesis is embodied in that many pathways would occur in the lesion process, and different paths would cause the occurrence of different target points, so modern research shoμld focus on how to choose safe and effective target point to decrease blood glucose and repair pancreas islet, and protect angiocarpy. Dipeptide base peptidase-4(DPP-4) inhibitor is a incretin-based and new oral hypoglycemic agent that can improve α and β cell dysfunction through increasing the level of GLP-1(endogenous active glucagon-like peptide 1) and GIP(glucose-dependent insulin secretion polypeptide).Quinoxalinones are benzo-nitrogen heterocyclic compounds derivated from quinocalinone ring, which have the effect of antitumor, lowering blood sugar and so on. Since it can serve as the pharmacohore of many drugs, taking it as the mother nucleus to connect certain functional groups, makes it possible to obtain the pharmacological activity that we expect. Therefore, we designed DPP-4 inhibitors by taking quinoxalinones as the matrix, making it have the inhibitory activity of DPP-4 and strengthening its capability to lower blood sugar. NO, a vital messenger in human body, which has the effect of scavenging free radicals, dilating blood vessels, promoting endothelial progenitor cell growth, function restoration and other various physical function, plays an extremely imprtant role in diabetes vascular comlications. Integrating DPP-4 inhibitor and NO donor can get a new NO donor type quinoxalinone derivative, which has both the effects of lowering blood sugar and DPP-4 activity inhibition of quinoxalinone and the fuctions of scavenging free radicals, dilating blood vessels, promoting endothelial progenitor cell growth and function restoration generated when NO donor release NO in the body, so as to achieve the goal of comprehensive disease treatment. As important contemporary malignant diseases, studies have shown that quinoxalinone by reversing the multidrug resistance(MDR), cytotoxicity and inhibition of tumor cell proliferation of these three ways to play its role in the treatment of tumors, In this thesis,though cytotoxicity(MTT) test to study its anti-tumor activity of a preliminary screening.Three quinxalinone parent nucleus were synthesized in this thesis design, and on base of this, 20 quinxalinone derivatives,9 target compound and 9 NO donor type quinoxalinone derivatives were obtained by modifying. All the compounds have new structure and structures of all the derivatives have been characterized through 1H NMR and MALDI-TOF.The target compounds have experienced DPP-4 inhibitory activity test, NO release assay The experimental resμlts show that all the compounds can inhibit DPP-4 enzyme activity in vitro, and NO donor type quinoxalinone derivatives can release a certain amount of NO in vitro. all compounds have a cytotoxic cytotoxicity and some of the compounds stronger than 5-FU. Pharmacologically active compounds synthesized showed it to have a certain anti-diabetic and anti-tumor effect, it can be used as a potential lead compound versatile study provide a reference antidiabetic and anti-tumor.