Discovery of 8-Membered Ring Sulfonamides as Inhibitors of Oncogenic Mutant Isocitrate Dehydrogenase 1.

Evidence suggests that specific mutations of isocitrate dehydrogenases 1 and 2 (IDH1/2) are critical for the initiation and maintenance of certain tumor types and that inhibiting these mutant enzymes with small molecules may be therapeutically beneficial. In order to discover mutant allele-selective IDH1 inhibitors with chemical features distinct from existing probes, we screened a collection of small molecules derived from diversity-oriented synthesis. The assay identified compounds that inhibit the IDH1-R132H mutant allele commonly found in glioma.

Chemical perturbation of an intrinsically disordered region of TFIID distinguishes two modes of transcription initiation.

Intrinsically disordered proteins/regions (IDPs/IDRs) are proteins or peptide segments that fail to form stable 3-dimensional structures in the absence of partner proteins. They are abundant in eukaryotic proteomes and are often associated with human diseases, but their biological functions have been elusive to study. In this study, we report the identification of a tin(IV) oxochloride-derived cluster that binds an evolutionarily conserved IDR within the metazoan TFIID transcription complex.

Niche-Based Screening in Multiple Myeloma Identifies a Kinesin-5 Inhibitor with Improved Selectivity over Hematopoietic Progenitors.

Novel therapeutic approaches are urgently required for multiple myeloma (MM). We used a phenotypic screening approach using co-cultures of MM cells with bone marrow stromal cells to identify compounds that overcome stromal resistance. One such compound, BRD9876, displayed selectivity over normal hematopoietic progenitors and was discovered to be an unusual ATP non-competitive kinesin-5 (Eg5) inhibitor.

Small-molecule screening identifies inhibition of salt-inducible kinases as a therapeutic strategy to enhance immunoregulatory functions of dendritic cells.

Genetic alterations that reduce the function of the immunoregulatory cytokine IL-10 contribute to colitis in mouse and man. Myeloid cells such as macrophages (MΦs) and dendritic cells (DCs) play an essential role in determining the relative abundance of IL-10 versus inflammatory cytokines in the gut. As such, using small molecules to boost IL-10 production by DCs-MΦs represents a promising approach to increase levels of this cytokine specifically in gut tissues.

Palladium-catalyzed chemoselective allylic substitution, Suzuki-Miyaura cross-coupling, and allene formation of bifunctional 2-B(pin)-substituted allylic acetate derivatives.

A formidable challenge at the forefront of organic synthesis is the control of chemoselectivity to enable the selective formation of diverse structural motifs from a readily available substrate class. Presented herein is a detailed study of chemoselectivity with palladium-based phosphane catalysts and readily available 2-B(pin)-substituted allylic acetates, benzoates, and carbonates. Depending on the choice of reagents, catalysts, and reaction conditions, 2-B(pin)-substituted allylic acetates and derivatives can be steered into one of three reaction manifolds: allylic substitution, Suzuki-Miyaura cross-coupling, or elimination to form allenes, all with excellent chemoselectivity.

Breaking Conjugation: Unusual Regioselectivity with 2-Substituted Allylic Substrates in the Tsuji-Trost Reaction.

η-Allyl palladium complexes are key intermediates in Tsuji-Trost allylic substitution reactions. It is well known that (η-1-aryl-3-alkyl substituted allyl)Pd intermediates result in nucleophilic attack at the alkyl substituted terminus. In contrast, the chemistry of (η-1,2,3-trisubstituted allyl)Pd intermediates is relatively unexplored.

Synthesis of piperlogs and analysis of their effects on cells.

Piperlongumine (PL) is a naturally occurring small molecule previously shown to induce cell death preferentially in cancer cells relative to non-cancer cells. An initial effort to synthesize analogs highlighted the reactivities of both of piperlongumine's α,β-unsaturated imide functionalities as key features determining PL's cellular effects. In this study, a second-generation of analogs was synthesized and evaluated in cells to gain further insight into how the reactivity, number, and orientation of PL's reactive olefins contribute to its ability to alter the physiology of cells.

Stereoselective vinylation of aryl N-(2-pyridylsulfonyl) aldimines with 1-alkenyl-1,1-heterobimetallic reagents.

Vinylation of aryl N-(2-pyridylsulfonyl) aldimines with versatile 1-alkenyl-1,1-borozinc heterobimetallic reagents is disclosed. In situ hydroboration of air-stable B(pin)-alkynes followed by chemoselective transmetalation with dimethylzinc and addition to aldimines provides B(pin)-substituted allylic amines in 53-93% yield in a one-pot procedure. The addition step can be followed by either B-C bond oxidation to provide α-amino ketones (71-98% yield) or Suzuki cross-coupling to furnish trisubstituted 2-arylated (E)-allylic amines (51-73% yield).

Palladium-catalyzed allylic substitution with (η6-arene-CH2Z)Cr(CO)(3)-based nucleophiles.

Although the palladium-catalyzed Tsuji-Trost allylic substitution reaction has been intensively studied, there is a lack of general methods to employ simple benzylic nucleophiles. Such a method would facilitate access to "α-2-propenyl benzyl" motifs, which are common structural motifs in bioactive compounds and natural products. We report herein the palladium-catalyzed allylation reaction of toluene-derived pronucleophiles activated by tricarbonylchromium.

Diastereoselective aziridination of 2-B(pin)-substituted allylic alcohols: an efficient approach to novel organoboron compounds.

We report that 2-B(pin)-substituted allylic alcohols are good substrates for diastereoselective aziridinations in the presence of PhI(OAc)(2) and N-aminophthalimide. Under the aziridination conditions, the valuable B-C bond remains intact, affording a variety of novel boron-substituted aziridines in good yields and excellent diastereoselectivities. Oxidation of the aziridine B-C bond enables generation of syn-1,3-aminohydroxy-2-ketones with high diastereoselectivity.

Allylic substitution versus Suzuki cross-coupling: capitalizing on chemoselectivity with bifunctional substrates.

One catalyst, two reactions; a tale of chemoselectivity: Given the choice between an allylic acetate and a vinylboronate ester, palladium preferentially reacts with the allylic acetate giving the allylic substitution product. In the presence of an aryl bromide and base, Suzuki cross-coupling subsequently ensues to afford allylic amines.

Applications of 1-alkenyl-1,1-heterobimetallics in the stereoselective synthesis of cyclopropylboronate esters, trisubstituted cyclopropanols and 2,3-disubstituted cyclobutanones.

1-Alkenyl-1,1-heterobimetallics are potentially very useful in stereoselective organic synthesis but are relatively unexplored. Introduced herein is a practical application of 1-alkenyl-1,1-heterobimetallic intermediates in the synthesis of versatile cyclopropyl alcohol boronate esters, which are valuable building blocks. Thus, hydroboration of 1-alkynyl-1-boronate esters with dicyclohexylborane generates 1-alkenyl-1,1-diboro species.

Tandem reactions for streamlining synthesis: enantio- and diastereoselective one-pot generation of functionalized epoxy alcohols.

[Reaction: see text] In 1980, Sharpless and Katsuki introduced the asymmetric epoxidation of prochiral allylic alcohols (the Sharpless-Katsuki asymmetric epoxidation), which enabled the rapid synthesis of highly enantioenriched epoxy alcohols. This reaction was a milestone in the development of asymmetric catalysis because it was the first highly enantioselective oxidation reaction. Furthermore, it provided access to enantioenriched allylic alcohols that are now standard starting materials in natural product synthesis.