Curcumin (diferuloyl methane, Chart 1) is a major constituent found in the spice tumeric, which is a dried powder from the rhizomes of Curcuma longa L. Several in vitro and in vivo studies demonstrated suppression, retardation, or inversion of carcinogenesis.1-3) Furthermore, it also exhibits anti-inflammatory, antioxidant, antiviral, and anti-infectious activities and wound healing properties. [4][5][6][7][8] Inhibition of arachidonic acid metabolism by curcumin has been suggested to be a key mechanism for its anticarcinogenic action. The enzyme cyclooxygenase (COX) catalyzes the first two steps in the biosynthesis of prostaglandins (PGs) from the substrate arachidonic acid. At least two forms of this enzyme exist. 9,10) One of these forms, COX-1, is constitutively expressed and is responsible for maintaining normal physiologic function and the PGs produced by this enzyme play a protective role. The other known form of the enzyme, cyclooxygenase-2 (COX-2), is an inducible form and its expression is affected by various stimuli such as mitogens, oncogenes, tumor promoters, and growth factors. 10) COX-2 has been detected in various tumors and its role in carcinogenesis and angiogenesis has been well documented. Therefore, COX-2 is thought to be a promising therapeutic target for cancer. However, current clinical studies of a COX-2-selective inhibitor, rofecoxib (Vioxx), for preventing recurrence of colorectal polyps in patients with a history of colorectal adenomas were discontinued and the drug was withdrawn from the market because its use was associated with an increased incidence of cardiovascular events, such as heart attack and stroke.
11)Very recently, experimental results have also indicated a possible involvement of the other isoform of COX, COX-1, in angiogenesis, thereby providing the rationale for the development of selective COX-1 inhibitors.12,13) These data were also confirmed by in vitro studies in isolated ovine COX-1 and COX-2 enzymes which showed that curcumin and its analogues tetrahydrocurcumin and trimethoxydibenzoylmethane had significantly higher inhibitory effects on the peroxidase activity of COX-1 than that of COX-2.2) Furthermore, a recent report by Gupta et al. 14) has also indicated that COX-1 is overexpressed in a significant number of ovarian cancers. We therefore investigated whether novel curcumin analogues might achieve an even better and more selective COX-1 inhibition than curcumin. Thus, seven analogues of curcumin were synthesized using standard chemical methods. Each analogue (except the intermediate 2) was then tested for COX-1 and COX-2 inhibition in an in vitro model and the resulting inhibition values compared with that of the clinically established selective COX-2 inhibitor celecoxib. Also molecular docking studies were performed to investigate the ligand-protein interactions responsible for the biological data found.
Results and DiscussionThe chemical synthesis of the curcumin analogues was carried out following two known pathways. Their basic principle is the same, b...
