Structural Transformation Of Nature Products Curcumin And Study On Bioactivities Of Curcumin Analogs

Natural products curcumin has a variety of biological activities, including antioxidant, antitumor, antiinflammation, neuroprotection and anti-Alzheimer’s disease. However, the clinical application of curcumin has been significantly limited by its instability and poor metabolic property. Alzheimer’s disease (AD) is a chronic neurodegenerative disease. It is generally accepted that the accumulation of senile plaques (SP) containing β-amyloid plaques (Aβ plaques) is one of pivotal clinical pathological features of AD. Therefore, the development of molecule imaging probes for β-amyloid plaques, combined with modern imaging techniques would be very useful for early diagnosis of AD.In this paper, a series of curcumin analogues were synthesized by reforming the double carbonyl moiety of curcumin and then the molecular probes were screened, which can be used for early diagnosis of AD targeting senile plaque.(1) With the Computer Aided Drug Design (CADD) and relevant literatures, we progressed comprehensive structural screening with docking methods and then finally determined the structures of curcumin analogs.(2) The synthesis routes of target compounds were determined, and then a series of curcumin analogs 2a-2c,4a-4g were synthesized and characterized by1H-NMR.(3)The binding activity of curcumin analogs with target protein was detected by radioligand binding assay of receptor (RBA) experiments.The results revealed that compound 2c,4a,4d, 4f and 4g showed good affinity for Aβ protein. AD brain tissue fluorescent staining in vitro showed compound 4d has good binding with senile plaques within brain sections of postmortem AD patiens. The results of distribution experiments of 4g in major organs at different times revealed that the molecular probe could cross the blood-brain barrier with high brain initial uptake and rapid brain clearance, desirable for pharmacokinetics requirements of AD molecular probes.(4) Based on the study before and relevant literatures,some F-19 based curcumin analogs were designed for MRI probes. The research showed that the molecule could cross the blood-brain barrier but the activity of binding target protein is low. It needs further research.