Thalidomide (1) is a sedative and/or hypnotic drug, which was used from the late 1950's to the early 1960's, but was withdrawn from the market due to its severe teratogenicity. [1][2][3] In spite of this tragedy, thalidomide research was not halted, because of the drug's effectiveness against various kinds of diseases, including leprosy and AIDS.2-4) Thalidomide was relaunched for the treatment of Hansen's disease in 1998 in the U.S., with special precautions for usage.In order to explain the pleiotropic effects of thalidomide, we have postulated that thalidomide is a multi-target drug, and we have been engaged in structural development studies of thalidomide as a scaffold. 2,3,[5][6][7][8][9][10][11][12][13][14][15][16][17] This systematic search has yielded tumor necrosis factor (TNF)-a production regulators, 2,3,5-7) androgen receptor antagonists, 2,3,8,9) peptidase inhibitors, 3,10-13) glucosidase inhibitors, 15,16) and thymidine phosphorylase inhibitors. 16) We suspected that cyclooxygenase (COX) might be another molecular target of thalidomide, since thalidomide is effective against colon and prostate cancers and possesses anti-angiogenic activity. 17,18) Prostaglandin and thromboxane biosynthesis involves the conversion of arachidonic acid to prostaglandin H 2 (PGH 2 ), a reaction catalyzed by the sequential actions of COX and prostaglandin endoperoxidase synthase (PGHS).19) Three isoforms of COX (COX-1, COX-2, and COX-3) are known to date, of which COX-1, and COX-2 have been well investigated. COX-1 is constitutively expressed in many organs or tissues, while COX-2 is inducible with various stimuli. Overexpression of COX-2 has been detected in various tumors and its role in carcinogenesis and angiogenesis has been well documented. [20][21][22] Therefore, COX-2 is thought to be a promising therapeutic target for cancer. [20][21][22] Attempts have been made to apply COX-2 inhibitors, such as celecoxib and sulindac, for chemoprevention of various cancers, including colon and prostate cancers. 23,24) Thalidomide suppresses lipopolysaccaride-induced expression of COX-2. 25,26) In addition, we have recently demonstrated that thalidomide directly inhibits COX-1/COX-2 with efficacy comparable to that of aspirin.27) Much research has been done on the development of COX-2-selective inhibitors, including QSAR studies, but almost all of it deals with medium-sized molecules having a molecular weight of more than 300. Our earlier work on the COX-inhibiting activity of thalidomide afforded a new scaffold for small-molecular COX inhibitors (molecular weight of less than 300), which should be suitable for many kinds of structural development.As a part of our continuing research directed toward the structural development of thalidomide as a multi-template for lead discovery, we report here novel COX inhibitors derived from thalidomide, focusing on COX-1-and COX-2-inhibitory activities.
Results and DiscussionThe compounds discussed in this study were prepared by standard procedures, and the structures were confirmed by 1 H...
