Synthesis and Biological Evaluation of Curcumin Analogs as Antiplatelet Inhibitor

Abstract

The curcuminoid natural products have long been recognized for their medicinal properties and utilized for the treatment of many diseases. Curcuminoids are the major constituents of turmeric (Curcuma longa L.) and some other Curcuma species, including a number of other plant species. Curcuminoids include curcumin (~77%), demethoxycurcumin (~18%), and bisdemethoxycurcumin (~5%), and they exhibit many interesting biological activities such as antioxidant, anti-inflammatory, anticancer, and antiplatelet activities. The cause of thrombosis is commonly associated with platelet aggregation. The effect of curcumin has been reported to reduce platelet aggregation and to increase prostacyclin (PGI2) as the main factor, and it inhibited the induction of platelet aggregation for adenosine diphosphate (ADP), epinephrine (adrenaline), and collagen. Platelets play a main role in hemostasis in the main defense mechanism in biological systems (in vivo). However, hyper-activated platelets increase thrombosis and could develop various cardiovascular diseases such as coronary artery disease, myocardial infarction, and stroke. Conventional anti-platelet drugs such as aspirin, clopidogrel bisulfate, and abciximab have already been proven to treat and prevent cardiovascular diseases, but these drugs also have side effects like bleeding. We decided to use curcumin and its analogs as starting materials in order to prevent side effects. However, curcumin has poor absorption in vivo, thus we studied improving its physical properties. It remains unknown whether the activity of curcumin is based on its presumably promiscuous scaffold, or if it results from the Michael acceptor properties of the α,β-unsaturated 1,3-diketone moiety central to its structure. The keto-enol tautomerism and E/Z enol stereoisomerism of curcumin result in dynamic equilibria of isomers, which hinder the evaluation of the structure-activity relationships (SARs) of substituted curcumins. We studied the relationship between curcumin-derived pyrazoles of the 1,3-dicarbonyl with various hydrazines and curcuminester of the phenol position. Curcumin-derived pyrazoles were synthesized in order to minimize the metal chelation properties of curcumin. We designed and synthesized new curcumin derivatives. First, known compounds (curcumin, bisdemethoxycurcumin, curcumin-derived pyrazole, and bisdemethoxycurcumin-derived pyrazole) were separated Figure 1. Approaches of curcumin analogs.