In Vitro Effect Of Nitric Oxide-donor Derivatives Of Apigenin And Luteolin On Diabetic Vascular Complications

Diabetes mellitus (DM) is a chronic, incurable metabolic disorder defined by thedysregulation of glucose homeostasis, and the development of both acute andlong-term complications. DM is a leading cause of morbidity and mortality in theworld, particularly from complications such as macrovascular complications,neuropathy, nephropathy, retinopathy, and cataractogenesis. However, pathogenesisof DM is very complex, multifatorial, and not fully understood. The clinal researchshown that single-target drugs were difficult to prefectly prevent and treat DM,therefore, we propose to offer a concept of “multi-target drugs design” for thedevelopment and design of new drug for preventive and therapeutic drugs for diabeticcomplications.Apigenin and luteolin, two polyphenolic compounds available in food products ofplant origin, belongs to the flavone subclass of flavonoids. Preclinical studies haveshown that they possesses a variety of pharmacological activities, includinganti-diabetic, by reducing glucose levels, antioxidant, anti-inflammatory, andanticancer activities. NO as a gaseous signalling molecule participates in a plethora ofphysiological processes in vivo. NO not only is vasodilator, it also regulation of bloodpressure, suppresses migration and proliferation of vascular smooth muscles cells,scaving harmful free radical, promote proliferation and migration of endothelialprogenitor cells, repair endothelial dysfunction to reduce the complications ofdiabetes.Our recent studies discovered that O~7-nitrooxybutyl chrysin exhibited in vitroinhibitory activities against aldose reductase and advanced glycation end-productformation. Therefore, we postulated that NO donor hybrids (organic nitrates orfuroxan) that incorporating active parts of apigenin and luteolin may be more potentthan any of the initial compounds alone, and these combining compounds asmultitarget drugs could spply synergetic effect to prevent and treat diabeticcomplications. In this study, a total of28new derivatives, incluing2different types of6seriesapigenin or luteolin compounds were designed and synthesized which were notinvolved in the paper. All of derivatives were characterized by means of1H NMR andMALDI-TOF.The result compounds discovered pharmacological activities in all active test ofthe paper. Among the tested compounds A1, La1, Lb1, and Lc1can released lowconcentrations NO, and these compounds exhibited significant in vitro inhibitoryactivities of α-Glucosidase and aldose reductase, activities of antioxidant, andinhibited advanced glycation end-product formation. These results indicated that thesecompounds as multitarget active compounds could reduce blood glucose level andcontrol four iteral of pathogenesis of vascular complications to prevent and treatdiabetic complications.