Objective. Scientific evidence is lacking for the antiarthritic efficacy of turmeric dietary supplements that are being promoted for arthritis treatment. Therefore, we undertook studies to determine the antiarthritic efficacy and mechanism of action of a well-characterized turmeric extract using an animal model of rheumatoid arthritis (RA).Methods. The composition of commercial turmeric dietary supplements was determined by highperformance liquid chromatography. A curcuminoidcontaining turmeric extract similar in composition to these supplements was isolated and administered intraperitoneally to female Lewis rats prior to or after the onset of streptococcal cell wall-induced arthritis. Efficacy in preventing joint swelling and destruction was determined clinically, histologically, and by measurement of bone mineral density. Mechanism of action was elucidated by analysis of turmeric's effect on articular transcription factor activation, microarray analysis of articular gene expression, and verification of the physiologic effects of alterations in gene expression. Results.A turmeric fraction depleted of essential oils profoundly inhibited joint inflammation and periarticular joint destruction in a dose-dependent manner. In vivo treatment prevented local activation of NF-B and the subsequent expression of NF-B-regulated genes mediating joint inflammation and destruction, including chemokines, cyclooxygenase 2, and RANKL. Consistent with these findings, inflammatory cell influx, joint levels of prostaglandin E 2 , and periarticular osteoclast formation were inhibited by turmeric extract treatment.Conclusion. These translational studies demonstrate in vivo efficacy and identify a mechanism of action for a well-characterized turmeric extract that supports further clinical evaluation of turmeric dietary supplements in the treatment of RA.The use of botanical remedies for arthritis treatment is promoted in the US by the lay press and high-profile medical practitioners (1,2). Interest in the use of nonpharmaceutical arthritis treatments has grown with the withdrawal of Food and Drug Administrationapproved antiinflammatory drugs (3). However, scientific data are almost uniformly lacking concerning the antiarthritic efficacy and mechanism of action of popular botanical remedies (4,5). The rational medicinal use of botanical dietary supplements is further complicated by the fact that the composition of over-the-counter botanical dietary supplements is not strictly regulated (4,5). Unfortunately, in the medical literature, the chemical composition and biologic activity of botanicals that are tested for antiarthritic efficacy are frequently also not well characterized (6-9). Therefore, benchmarks are lacking for assessing the potential suitability of commercially available botanical supplements or phytomedicines. 3452Turmeric is one such botanical supplement whose use against arthritis, supported almost exclusively by its traditional, centuries-old use as an antiinflammatory agent in Ayurvedic medicine, has been heavily prom...

A phosphepine catalyst mediates enantioselective [3+2] cycloadditions of allenes with a variety of β‐substituted α,β‐unsaturated enones to produce highly functionalized cyclopentenes that contain two contiguous stereocenters (see scheme). Surprisingly, opposite regioisomers are produced as compared to reactions with β‐unsubstituted enones.

The development of effective methods for the asymmetric synthesis of b-lactones is an important challenge for a variety of reasons.[1] Numerous biologically active b-lactone-containing natural and unnatural products have been described, including Xenical (tetrahydrolipstatin), an anti-obesity drug developed by Roche. [2,3] Furthermore, b-lactones serve as useful intermediates in an array of fields, including materials science and synthetic organic chemistry. [1,4] The strain of the four-membered lactone provides an opportunity for a range of functionalizations; for example, nucleophiles can react either at the carbonyl group through an addition-elimination sequence or at a CÀO single bond through an S N 2 process. Thus, a number of recent total syntheses, such as those of (À)-laulimalide, [5] (À)-malyngolide, [6] and trapoxin B, [7] have exploited enantiopure b-lactones as intermediates.One attractive route to b-lactones is the overall [2+2] cycloaddition of a ketene with an aldehyde [Eq. (1)]. Chiral nucleophiles and chiral Lewis acids have both been shown to catalyze this process, sometimes with outstanding enantioselectivity (the postulated mechanism for the nucleophilecatalyzed cycloaddition is illustrated in Scheme 1). [8][9][10][11] To date, all reports of asymmetric catalysis of this transformation have described reactions of ketene itself (H 2 C=C=O) or of monosubstituted ketenes. Expanding the scope of such processes to include disubstituted ketenes would furnish access to a,a-disubstituted b-lactones, an important class of synthetic targets. [12] We have been exploring the utility of planar-chiral DMAP and PPY derivatives (for example, 1) as catalysts for a range of transformations, [13] including an asymmetric Staudinger synthesis of b-lactams that likely proceeds by a pathway analogous to that depicted in Scheme 1 (DMAP = 4-(dimethylamino)pyridine, PPY = 4-pyrrolidin-1-ylpyridine). [14] We were intrigued by the possibility that these nucleophilic catalysts might also be useful for b-lactone synthesis. This sort of an "extension" from reactions of imines to reactions of aldehydes is not as straightforward as may appear; for example, in the case of cinchona alkaloid-based catalysts, an excellent method for enantioselective b-lactam synthesis from monosubstituted ketenes was reported several years ago, [15] whereas general conditions for b-lactone synthesis from monosubstituted ketenes, which require a Lewis acid co-catalyst, have only been developed very recently. [16] In this Communication, we demonstrate that PPY derivative 1 serves as an effective catalyst for [2+2] cycloadditions of disubstituted ketenes with aldehydes to furnish the first catalytic asymmetric route to a,a-disubstituted b-lactones.In our earlier study, we established that 1 catalyzes a Staudinger-type cycloaddition of ketenes with imines to efficiently afford b-lactams with good enantioselectivity (76-98 % yield; 81-98 % ee).[14] However, when we apply these conditions to the corresponding reaction of ketenes with aldehydes, we obta...

The histone acetyltransferases, CREB binding protein (CBP) and EP300, are master transcriptional co-regulators that have been implicated in numerous diseases, such as cancer, inflammatory disorders, and neurodegeneration. A novel, highly potent, orally bioavailable EP300/CBP histone acetyltransferase (HAT) inhibitor, CPI-1612 or 17, was developed from the lead compound 3. Replacement of the indole scaffold of 3 with the aminopyridine scaffold of 17 led to improvements in potency, solubility, and bioavailability. These characteristics resulted in a 20-fold lower efficacious dose for 17 relative to lead 3 in a JEKO-1 tumor mouse xenograft study.

Complementary palladium-catalyzed methods for direct arylation of oxazole with high regioselectivity (>100:1) at both C-5 and C-2 have been developed for a wide range of aryl and heteroaryl bromides, chlorides, iodides, and triflates. C-5 arylation is preferred in polar solvents with phosphines 5 or 6, whereas C-2 arylation is preferred by nonpolar solvents and phosphine 3. This represents the first general method for C-5 selective arylation of oxazole and should see broad applicability in the synthesis of biologically active molecules. Additionally, potential mechanisms for these two competing arylation processes are proposed on the basis of mechanistic observations.