Osteoarthritis (OA) is a degenerative joint disease that involves the destruction of articular cartilage and eventually leads to disability. Molecules that promote the selective differentiation of multipotent mesenchymal stem cells (MSCs) into chondrocytes may stimulate the repair of damaged cartilage. Using an image-based high-throughput screen, we identified the small molecule kartogenin, which promotes chondrocyte differentiation (median effective concentration = 100 nM), shows chondroprotective effects in vitro, and is efficacious in two OA animal models. Kartogenin binds filamin A, disrupts its interaction with the transcription factor core-binding factor β subunit (CBFβ), and induces chondrogenesis by regulating the CBFβ-RUNX1 transcriptional program. This work provides new insights into the control of chondrogenesis that may ultimately lead to a stem cell-based therapy for osteoarthritis.

Platensimycin (1) (Scheme 1) is a novel antibiotic lead compound recently discovered by Merck scientists from a strain of Streptomyces platensis. 1a,b The potential medicinal applications 1c,d and challenging structure motif, especially the cage-like tetracyclic core with several stereogenic centers, made this compound very attractive as a target for chemical synthesis. To this end, total synthesis of its racemic form was first reported by Nicolaou and co-workers, 2a and later they also reported corresponding asymmetric versions. 2b More recently, two other routes to the tetracyclic core structure (±)-9 2c,d and synthesis of a related structure 2e have been reported. Whereas these reported routes all utilized intramolecular etherification reactions 2a between the alcohol motifs and the alkene parts as key steps, an alternative intramolecular Robinson annulation approach seems to be more straightforward. Herein, we describe our efforts in the enantioselective synthesis of the key cage-like tetracyclic core structure of platensimycin.

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While bond formation processes have traditionally garnered the attention of the chemical community, methods facilitating bond-breaking remain relatively undeveloped. We report a novel, transition metal-free oxidative C-C bond cleavage process for a broad range of ester and dicarbonyl compounds involving carbanion addition to nitrosobenzene. ReactIR experiments on the nitrosobenzenemediated oxidative decarboxylation of esters indicate the reaction proceeds via fragmentation of a previously unobserved oxazetidin-4-one heterocycle, characterized by an intense IR stretching frequency at 1846 cm -1 . These mechanistic studies have allowed further expansion of this protocol to ketone cleavage reactions of a diverse array of β-ketoester and 1,3-diketone substrates. The conceptual and mechanistic insights offered by this study are likely to provide a platform for further development of bond-breaking methodologies.Synthetic organic chemistry is concerned with the assembly of complex chemical structures from relatively simple starting materials. Not surprisingly, processes facilitating the formation of new chemical bonds encompass a preponderance of the literature. 1 However, the inverse process of C-C bond cleavage, while synthetically desirable in many cases, poses a great challenge due to the inherent strength of the C-C bond. 2,3 Accordingly, relatively few procedures have been reported for this transformation and those that have usually rely on transition metal catalysis. 4 In the present work, we describe a powerful, one step oxidative C-C bond cleavage methodology for a broad range of ester and dicarbonyl substrates utilizing nitrosobenzene as oxidant. Moreover, mechanistic studies using ReactIR spectrometry have allowed the first spectral observation of the oxazetidin-4-one ring system. This methodology marks a breakthrough over related multi-step and metal-mediated procedures, providing a highly robust oxidative C-C bond cleavage protocol for a diverse array of carbonyl compounds. 5,6Given our long standing work in Diels-Alder chemistry, we became interested in C-C bond cleavage methodology in the context of developing a highly versatile asymmetric ketene equivalent. 7 In preliminary studies toward an asymmetric route to bicyclo[2.2.1]hept-5-ene-2-yamamoto@uchicago.edu. NIH Public Access NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript one derivatives it was found that treatment of N-hydroxy methyl ester 2 with LiOH provided bicyclic ketone 4 in 75% yield over two steps (after acidic hydrolysis of the imines). 8,9Interestingly, under identical conditions N-hydroxy ethyl ester 5 gave the corresponding product 6 in only 16% yield. By increasing the lability of the ester it was found that direct addition of nitrosobenzene to the lithium enolate of phenyl ester 7 at -78 °C provided the corresponding N-phenyl imines 6, accompanied by evolution of CO 2 , within 5 minutes in 91% yield in one step (Scheme 1).The markedly contrasting results obtained between the related ethyl, methyl, and...

The first total synthesis of (+)-luteoalbusins A and B is described. Highly regio- and diastereoselective chemical transformations in our syntheses include a Friedel-Crafts C3-indole addition to a cyclotryptophan derived diketopiperazine, a late-stage diketopiperazine dihydroxylation and C11-sulfidation sequence, in addition to congener-specific polysulfane synthesis and cyclization to the corresponding epipolythiodiketopiperazine. We also report the cytoxicity of both alkaloids, and closely related derivatives, against A549, HeLa, HCT116 and MCF7 human cancer cell lines.