b S Supporting Information M ultidrug resistance (MDR) continues to be a serious problem in cancer therapy and is one of the limiting factors in the development and application of antitumor drugs. Doxorubicin is a chemotherapeutic drug widely used for the treatment of various solid tumors. However, its efficacy is often limited by the development of MDR, which has been linked to the up-regulation of P-glycoprotein (P-gp) in cancer cells.1 It is known that tumor progression often is accompanied by increased COX-2 expression, and selective COX-2 inhibitors prevent the formation of multiple tumor types in experimental animals.2 In fact, it is also known that MDR caused by multidrug resistance associated protein 1 (MRP-1) is modulated by nonsteroidal antiinflammatory drugs (NSAIDs), nonselective COX inhibitors such as indomethacin 1a, or COX-2 selective inhibitors. 3,4 Mazzanti reported that the MDR phenotype might be associated with the expression of COX-2 in a human hepatocellular carcinoma cell line.5 Cho showed a mechanism by which COX inhibitors exerted an enhancing effect on the cytotoxic effect of doxorubicin via direct inhibition of P-gpATPase activity in human esophageal squamous cell carcinoma cell lines.6 However, it is less certain whether COX-1 and/or COX-2 activity is directly related to the MDR property of cancer cells. Indomethacin (1a, Figure 1) is a clinically useful NSAID with an indole structure, which inhibits both COX-1 and COX-2. In indomethacin, the two stable forms, the s-trans form and the s-cis form, around the amide bond are known (Figure 1). The COX inhibitory activities are closely related to the conformation of indomethacin itself. It has been reported that the bioactive conformations of indomethacin in complexes with COX-1 and COX-2 are the s-trans form 7 and the s-cis form, 8 respectively (4COX.pdb and 1PGG.pdb). We thought that the introduction of an alkyl substituent other than a methyl group at the 2-position of indomethacin might restrict its conformation in the s-cis or s-trans form, respectively, due to steric repulsion or πÀπ stacking interaction by the introduced substituent with the N-4-chlorobenzoyl side chain. When the substituent at the 2-position (R) is an alkyl group bulkier than methyl, the s-cis form can be more stable than the s-trans form due to steric repulsion. However, introduction of a phenyl substituent at the 2-position may make the s-trans form more stable due to πÀπ stacking (Figure 2). That these conformationally restricted analogues may be selectively active toward COX-1 or COX-2 offers some insight into the relationship between the COX-1 and/or COX-2 inhibitory effect and the MDR property of cancer cells. Since we have just developed a novel synthetic method for various substituted indoles using a combination of isomerization and enamide-ene metathesis, 9,10 consequently we decided to design and synthesize the indomethacin analogues 1bÀd substituted at the 2-position. 11The present study was carried out to investigate whether the COX activity of a series ...

A steric and electronic effect on enamide/ene metathesis, a novel preparation of 2-substituted indoles and 3-substituted indoles using enamide-ene metathesis as a key reaction, and its application to the synthesis of indomethacin are described.

We designed and synthesized conformationally restricted analogues and regioisomers of the nonsteroidal anti-inflammatory drug indomethacin. Evaluation of the inhibitory effects of these compounds on COX, P-glycoprotein, and multidrug resistance indicated that NSAIDS modulation of multidrug-resistant P-glycoprotein and multidrug-resistant protein-1 is not associated with COX-1 and COX-2 inhibitory activities.

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