CDK8/19 inhibition triggers a switch from mitosis to endomitosis in cord blood megakaryocytes.

Neonatal and adult megakaryocytes differ in proliferative capacity and ploidy levels, and neonatal and adult platelets differ in function, gene expression, and protein content. The mechanisms underlying these differences are incompletely understood. CDK8 and CDK19 are transcriptional kinases part of the CDK-mediator complex, which regulates gene transcription in a cell-specific manner.

Potent Uncompetitive Inhibitors of Nicotinamide -Methyltransferase (NNMT) as In Vivo Chemical Probes.

NNMT uses SAM as a cofactor to catalyze the methylation of nicotinamide, producing 1-methylnicotinamide. Recent studies have shown that NNMT upregulation in cancer-associated fibroblasts (CAFs) is required to maintain the CAF phenotype in high-grade serous carcinoma. These observations suggest that NNMT should be evaluated as a therapeutic target, especially in cancer.

Asymmetric Total Synthesis of C9'--Sinefungin.

The natural nucleoside (+)-sinefungin, structurally similar to cofactor -adenosyl--methionine, inhibits various SAM-dependent methyltransferases (MTs). Access to sinefungin analogues could serve as the basis for the rational design of small molecule methyltransferase inhibitors. We developed a route to the unnatural C9' epimer of sinefungin that employed a diastereoselective Overman rearrangement to install the key C6' amino stereocenter.

High-Affinity Alkynyl Bisubstrate Inhibitors of Nicotinamide -Methyltransferase (NNMT).

Nicotinamide -methyltransferase (NNMT) is a metabolic enzyme that methylates nicotinamide (NAM) using cofactor -adenosylmethionine (SAM). NNMT overexpression has been linked to diabetes, obesity, and various cancers. In this work, structure-based rational design led to the development of potent and selective alkynyl bisubstrate inhibitors of NNMT.

Catalytic Allylic Oxidation to Generate Vinylogous Acyl Sulfonates from Vinyl Sulfonates.

Regioselective formation of vinylogous acyl sulfonates was accomplished via the allylic oxidation of the corresponding vinyl sulfonates. The reaction progressed through the agency of catalytic iron(III) chloride catalysis with tert-Butyl hydroperoxide (TBHP) as the stoichiometric oxidant. Tolerance of other functional groups, including some other allylic and benzylic sites, was observed.

STAT3 Inhibitory Activity of Structurally Simplified Withaferin A Analogues.

Signal transducer and activator of transcription 3 (STAT3) is a component of the JAK/STAT pathway. Therapeutic inhibition of STAT3 has been of high interest, as its aberrant activation has been linked to cancer, inflammation, and other human diseases. The withanolide family natural product withaferin A (1) inhibits STAT3 activation.

Identification of Mediator Kinase Substrates in Human Cells using Cortistatin A and Quantitative Phosphoproteomics.

Cortistatin A (CA) is a highly selective inhibitor of the Mediator kinases CDK8 and CDK19. Using CA, we now report a large-scale identification of Mediator kinase substrates in human cells (HCT116). We identified over 16,000 quantified phosphosites including 78 high-confidence Mediator kinase targets within 64 proteins, including DNA-binding transcription factors and proteins associated with chromatin, DNA repair, and RNA polymerase II.

Mediator kinase inhibition further activates super-enhancer-associated genes in AML.

Super-enhancers (SEs), which are composed of large clusters of enhancers densely loaded with the Mediator complex, transcription factors and chromatin regulators, drive high expression of genes implicated in cell identity and disease, such as lineage-controlling transcription factors and oncogenes. BRD4 and CDK7 are positive regulators of SE-mediated transcription. By contrast, negative regulators of SE-associated genes have not been well described.

Total Synthesis of (-)-Nemorosone and (+)-Secohyperforin.

A general strategy for the synthesis of polycyclic polyprenylated acylphloroglucinols is described in which a scalable, Lewis acid catalyzed epoxide-opening cascade cyclization is used to furnish common intermediate 4. The utility of this approach is exemplified by the total syntheses of both ent-nemorosone and (+)-secohyperforin, which were each accomplished in four steps from this intermediate.

Broad-range inhibition of enterovirus replication by OSW-1, a natural compound targeting OSBP.

Enteroviruses, e.g., polio-, coxsackie- and rhinoviruses, constitute a large genus within the Picornaviridae family of positive-strand RNA viruses and include many important pathogens linked to a variety of acute and chronic diseases.

Itraconazole inhibits enterovirus replication by targeting the oxysterol-binding protein.

Itraconazole (ITZ) is a well-known antifungal agent that also has anticancer activity. In this study, we identify ITZ as a broad-spectrum inhibitor of enteroviruses (e.g.

A unified strategy for the synthesis of 7-membered-ring-containing Lycopodium alkaloids.

A unique subset of the Lycopodium alkaloid natural products share a 7-membered-ring substructure and may potentially arise from a common biosynthetic precursor. To both explore and exploit these structural relationships, we sought to develop a unified biosynthetically inspired strategy to efficiently access these complex polycyclic alkaloids through the use of a cascade sequence. In pursuit of these goals, the first total synthesis of (+)-fastigiatine (2) was accomplished via a series of cascade reactions; we describe herein a full account of our efforts.

Synthesis of the C4-epi-lomaiviticin B core reveals subtle stereoelectronic effects.

An efficient synthesis of the C4-epi-lomaiviticin B core is reported. The synthesis features a diastereoselective anionic formal furan Diels-Alder reaction and a stereoselective oxidative enolate dimerization. During the investigation, subtle yet critical stereoelectronic effects imparted by the C4-stereocenter were observed.

The small molecule dispergo tubulates the endoplasmic reticulum and inhibits export.

The mammalian endoplasmic reticulum (ER) is an organelle that maintains a complex, compartmentalized organization of interconnected cisternae and tubules while supporting a continuous flow of newly synthesized proteins and lipids to the Golgi apparatus. Using a phenotypic screen, we identify a small molecule, dispergo, that induces reversible loss of the ER cisternae and extensive ER tubulation, including formation of ER patches comprising densely packed tubules. Dispergo also prevents export from the ER to the Golgi apparatus, and this traffic block results in breakdown of the Golgi apparatus, primarily due to maintenance of the constitutive retrograde transport of its components to the ER.

Enantioselective total synthesis of hyperforin.

A modular, 18-step total synthesis of hyperforin is described. The natural product was quickly accessed using latent symmetry elements, whereby a group-selective, Lewis acid-catalyzed epoxide-opening cascade cyclization was used to furnish the bicyclo[3.3.

Total syntheses of HMP-Y1, hibarimicinone, and HMP-P1.

Total syntheses of HMP-Y1, atrop-HMP-Y1, hibarimicinone, atrop-hibarimicinone, and HMP-P1 are described using a two-directional synthesis strategy. A novel benzyl fluoride Michael-Claisen reaction sequence was developed to construct the complete carbon skeleton of HMP-Y1 and atrop-HMP-Y1 via a symmetrical, two-directional, double annulation. Through efforts to convert HMP-Y1 derivatives to hibarimicinone and HMP-P1, a biomimetic mono-oxidation to desymmetrize protected HMP-Y1 was realized.

Gram-scale synthesis of the A'B'-subunit of angelmicin B.

A gram-scale enantiospecific synthesis of the A'B'-subunit of angelmicin B is reported. The synthesis involves a Lewis acid catalyzed contrasteric Diels-Alder reaction and a tandem silyl zincate 1,6-addition/enolate oxidation sequence.

Synthesis of the N-(tert-butyloxycarbonyl)-O-triisopropylsilyl-D-pyrrolosamine Glycal of Lomaiviticin A & B via Epimerization of L-Threonine.

An efficient synthesis of the N-(tert-butyloxycarbonyl)-O-triisopropylsilyl-D-pyrrolosamine glycal of lomaiviticin A (1) and lomaiviticin B (2) is described. The synthesis is highlighted by the epimerization of the L-threonine-derived oxazolidine 10 to oxazolidine 11. This key epimerization reaction, which serves to establish the correct relative configuration of the carbohydrate unit, was made possible only after conformational analysis indicated that substituted oxazolidines may adopt conformations that preclude enolization.

Total synthesis of (+)-fastigiatine.

The first total synthesis of the Lycopodium alkaloid (+)-fastigiatine has been accomplished in 15 steps and 30% overall yield from known compounds. Noteworthy transformations include a convergent fragment coupling via a nucleophilic cyclopropane opening, a highly diastereoselective formal [3 + 3]-cycloaddition, and a transannular Mannich reaction to construct the core of the natural product.

Enantioselective synthesis of (+)-cephalostatin 1.

This Article describes an enantioselective synthesis of cephalostatin 1. Key steps of this synthesis are a unique methyl group selective allylic oxidation, directed C-H hydroxylation of a sterol at C12, Au(I)-catalyzed 5-endo-dig cyclization, and a kinetic spiroketalization.