- Probing Embryonic Development Enables the Discovery of Unique Small-Molecule Bone Morphogenetic Protein Potentiators
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We report on the feasibility to harness embryonic development in vitro for the identification of small-molecule cytokine mimetics and signaling activators. Here, a phenotypic, target-agnostic, high-throughput assay is presented that probes bone morphogenetic protein (BMP) signaling during mesodermal patterning of embryonic stem cells. The temporal discrimination of BMP- and transforming growth factor-β (TGFβ)-driven stages of cardiomyogenesis underpins a selective, authentic orchestration of BMP cues that can be recapitulated for the discovery of BMP activator chemotypes. Proof of concept is shown from a chemical screen of 7000 compounds, provides a robust hit validation workflow, and afforded 2,3-disubstituted 4H-chromen-4-ones as potent BMP potentiators with osteogenic efficacy. Mechanistic studies suggest that Chromenone 1 enhances canonical BMP outputs at the expense of TGFβ-Smads in an unprecedented manner. Pharmacophoric features were defined, providing a set of novel chemical probes for various applications in (stem) cell biology, regenerative medicine, and basic research on the BMP pathway.
- Antonchick, Andrey P.,Bertrand, Jessica,Halver, Jonas,Müller, Eva,Puthanveedu, Mahesh,Riege, Daniel,Schade, Dennis,Sievers, Sonja,Waldmann, Herbert,Wesseler, Fabian
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supporting information
p. 3978 - 3990
(2022/02/16)
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- Electrochemical C-H Halogenations of Enaminones and Electron-Rich Arenes with Sodium Halide (NaX) as Halogen Source for the Synthesis of 3-Halochromones and Haloarenes
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Without employing an external oxidant, the simple synthesis of 3-halochromones and various halogenated electron-rich arenes has been realized with electrode oxidation by employing the simplest sodium halide (NaX, X = Cl, Br, I) as halogen source. This electrochemical method is advantageous for the simple and mild room temperature operation, environmental friendliness as well as broad substrate scope in both C-H bond donor and halogen source components.
- Lin, Yan,Jin, Jun,Wang, Chaoli,Wan, Jie-Ping,Liu, Yunyun
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p. 12378 - 12385
(2021/09/07)
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- Synthesis of 3-halochromones with simple KX halogen sources enabled by: In situ halide oxidation
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On the basis of a designated in situ oxidation tactic, the synthesis of 3-halochromones has been realized for the first time by using simple KX (X = Br, I) salts as halogen sources. Instead of the free radical process, the control experiments indicate that the reported reactions proceed through a halogenium intermediate. Compared to the known synthetic methods relying on molecular halogen, haloid acid or N-halosuccinimide as the halogen source, the present method is attractive due to its higher atom economy and being more friendly to the operator, thus providing a practical complimentary approach to the preparation of useful halochromone compounds.
- Lin, Yan,Liu, Yunyun,Wan, Jie-Ping
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p. 8120 - 8124
(2020/06/09)
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- A Benazepine isoprenoid flavone compound and its preparation method and application
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The invention relates to a piperazine ring-containing isoflavone-like compound as well as a preparation method and application thereof. The preparation method comprises the following steps: dissolving2-hydroxyacetophenone and N,N-dimethylformamide dimethy
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- METHODS FOR PRECISION THERAPEUTIC TARGETING OF HUMAN CANCER CELL MOTILITY AND KITS THEREOF
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Disclosed are methods for identifying an agent of interest that alters binding or activity of a client protein to a chaperone and kits thereof.
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- Metal-free, green and efficient oxidative α halogenation of enaminones by halo acid and DMSO
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Metal free oxidative halogenation of N-aryl enaminones has been demonstrated using a DMSO-halo acid combination under mild reaction conditions. This strategy allows a facile halogenation of enaminones through α functionalization leading to a broad range o
- Sorabad, Ganesh Shivayogappa,Maddani, Mahagundappa Rachappa
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supporting information
p. 6563 - 6568
(2019/05/10)
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- Transition-metal-free decarboxylative bromination of aromatic carboxylic acids
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Methods for the conversion of aliphatic acids to alkyl halides have progressed significantly over the past century, however, the analogous decarboxylative bromination of aromatic acids has remained a longstanding challenge. The development of efficient methods for the synthesis of aryl bromides is of great importance as they are versatile reagents in synthesis and are present in many functional molecules. Herein we report a transition metal-free decarboxylative bromination of aromatic acids. The reaction is applicable to many electron-rich aromatic and heteroaromatic acids which have previously proved poor substrates for Hunsdiecker-type reactions. In addition, our preliminary mechanistic study suggests that radical intermediates are not involved in this reaction, which is in contrast to classical Hunsdiecker-type reactivity. Overall, the process demonstrates a useful method for producing valuable reagents from inexpensive and abundant starting materials.
- Quibell, Jacob M.,Perry, Gregory J. P.,Cannas, Diego M.,Larrosa, Igor
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p. 3860 - 3865
(2018/04/26)
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- Precision therapeutic targeting of human cancer cell motility
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Increased cancer cell motility constitutes a root cause of end organ destruction and mortality, but its complex regulation represents a barrier to precision targeting. We use the unique characteristics of small molecules to probe and selectively modulate cell motility. By coupling efficient chemical synthesis routes to multiple upfront in parallel phenotypic screens, we identify that KBU2046 inhibits cell motility and cell invasion in vitro. Across three different murine models of human prostate and breast cancer, KBU2046 inhibits metastasis, decreases bone destruction, and prolongs survival at nanomolar blood concentrations after oral administration. Comprehensive molecular, cellular and systemic-level assays all support a high level of selectivity. KBU2046 binds chaperone heterocomplexes, selectively alters binding of client proteins that regulate motility, and lacks all the hallmarks of classical chaperone inhibitors, including toxicity. We identify a unique cell motility regulatory mechanism and synthesize a targeted therapeutic, providing a platform to pursue studies in humans.
- Xu, Li,Gordon, Ryan,Farmer, Rebecca,Pattanayak, Abhinandan,Binkowski, Andrew,Huang, Xiaoke,Avram, Michael,Krishna, Sankar,Voll, Eric,Pavese, Janet,Chavez, Juan,Bruce, James,Mazar, Andrew,Nibbs, Antoinette,Anderson, Wayne,Li, Lin,Jovanovic, Borko,Pruell, Sean,Valsecchi, Matias,Francia, Giulio,Betori, Rick,Scheidt, Karl,Bergan, Raymond
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- A domino reaction of 3-chlorochromones with aminoheterocycles. Synthesis of pyrazolopyridines and benzofuropyridines and their optical and ecto-5′-nucleotidase inhibitory effects
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A new and efficient domino reaction of 3-chlorochromones with electron-rich aminoheterocycles was developed which allows for a convenient synthesis of a variety of pyrazolo[3,4-b]pyridines, pyrrolo[2,3-b]pyridines, pyrido[2,3-d]pyrimidines and benzofuro[3,2-b]pyridines. The products exhibit strong fluorescence. In addition, they exhibit significant ecto-5′-nucleotidase inhibition properties and cytotoxic behavior.
- Miliutina, Mariia,Janke, Julia,Hassan, Sidra,Zaib, Sumera,Iqbal, Jamshed,Lecka, Joanna,Sévigny, Jean,Villinger, Alexander,Friedrich, Aleksej,Lochbrunner, Stefan,Langer, Peter
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p. 717 - 732
(2018/02/09)
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- INHIBITION OF CANCER CELL MOTILITY
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Provided herein are compositions and methods for inhibiting cancer cell motility and/or metastasis. In particular embodiments, KBU2046 (or an analog thereof) and one or more additional therapies (e.g., cancer therapies (e.g., hormone therapies and chemotherapies) are provided to inhibit cancer cell motility, inhibit metastasis, and/or treat cancer (e.g., prostate cancer, lung cancer, breast cancer, colon cancer, etc.).
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- PPh3·HBr-DMSO: A Reagent System for Diverse Chemoselective Transformations
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The broad applicability of the hitherto unexplored reagent combination PPh3·HBr-DMSO is exemplified with multiple highly diverse one-step transformations to synthetically useful building blocks, such as flavones, 4H-thiochromen-4-ones, α-hydroxy ketones, 1,4-naphthoquinones (including vitamin K3), 2-bromo-3-substituted-1H-1-indenones, 2-methylthio-1H-1-indenones, 3-butyne-1,2-dione, and 4-pentene-2,3-diones. The simple and mild reaction conditions make the reagent superior in terms of yield and substrate scope in comparison with the existing alternatives.
- Mal, Kanchan,Kaur, Amanpreet,Haque, Fazle,Das, Indrajit
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p. 6400 - 6410
(2015/06/30)
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- Synthesis of functionalized 2-salicyloylfurans, furo[3,2-b]chromen-9-ones and 2-benzoyl-8H-thieno[2,3-b]indoles by one-pot cyclizations of 3-halochromones with β-ketoamides and 1,3-dihydroindole-2-thiones
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Functionalized 2-salicyloylfurans and 2-benzoyl-8H-thieno[2,3-b]indoles were prepared under mild conditions by reaction of 3-halochromones with β-ketoamides and 1,3-dihydroindole-2-thiones, correspondently. The subsequent oxidative cyclization of the products resulted in formation of the corresponding furo[3,2-b]chromen-9-ones. These molecules could also be directly prepared from 3-halochromones using a one-pot protocol. The cyclization reactions reported herein are mechanistically surprising as they proceed via the oxygen and not via the (more nucleophilic) nitrogen atom of the β-ketoamide. This journal is
- Savych, Iryna,Gl?sel, Tim,Villinger, Alexander,Sosnovskikh, Vyacheslav Ya.,Iaroshenko, Viktor O.,Langer, Peter
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p. 729 - 750
(2015/02/19)
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- Efficient synthesis of chromones with alkenyl functionalities by the heck reaction
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The usefulness of the Heck reaction in the field of chromones has been demonstrated. Bromochromones with the halogen atom in their rings A and B were reacted with various terminal alkenes to give hitherto unknown alkenyl-substituted chromones. Reactivity of the substrates was found to markedly depend on the position of the bromine atom. Under phosphine-free conditions using a phase-transfer catalyst additive (tetrabutylammonium bromide), shorter reaction periods and usually higher yields were obtained.
- Patonay, Tams,Vasas, Attila,Kiss-Szikszai, Attila,Silva, Artur M. S.,Cavaleiro, Jos A. S.
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p. 1582 - 1593
(2011/08/04)
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- Catalytic asymmetric alkylation of substituted isoflavanones
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The asymmetric alkylation of isoflavanones (3-aryl-chroman-4-ones) and protected 3-phenyl-2,3-dihydroquinolin-4(1H)-ones catalyzed by a novel cinchonidine-derived phase transfer catalyst E is reported. This functionalization occurs at the unactivated C3 methine to afford novel products that can easily be functionalized to generate more complex fused ring systems. The process accommodates a variety of isoflavanones and activated electrophiles and installs a stereogenic quaternary center in high yield and with good-to-excellent selectivity. Isoflavanones are a privileged class of natural products with a broad spectrum of biological activities including insecticidal, antimicrobial, antibacterial, estrogenic, antitumor, and anti-HIV activity. 1 Isoflavanones are also precursors for more complex natural products such as pterocarpans and rotenones.1 Given their therapeutic promise, selective strategies to access new classes of isoflavanones and related structures has high value.2 The functionalization of the C3 position could promote beneficial interactions with biological targets of interest. Specifically, an alkylation at C3 can rapidly access new members of the general class of biologically active homoisoflavanones.3
- Nibbs, Antoinette E.,Baize, Amanda-Lauren,Herter, Rachel M.,Scheidt, Karl A.
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supporting information; experimental part
p. 4010 - 4013
(2009/12/05)
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- A remarkably simple one-step procedure for the preparation of α-bromo-α,β-unsaturated carbonyl compounds
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An easy and convenient one-step procedure for the conversion of α,β-unsaturated carbonyl compounds into their corresponding bromo-enones using NBS-Et3N·3HBr in the presence of potassium carbonate in dichloromethane at 0°C to room temperature under very mild conditions in high yields and significantly shorter times, is reported. Georg Thieme Verlag Stuttgart.
- Jyothi, Divya,Hariprasad
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experimental part
p. 2309 - 2311
(2009/12/08)
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- A convenient halogenation of α,β-unsaturated carbonyl compounds with OXONE and hydrohalic acid (HBr,HCl)
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Mixtures of OXONE and hydrobromic acid or hydrochloric acid afford solutions of bromine or chlorine, respectively, α-Bromo- or α-chloro-α,β-unsaturated carbonyl compounds were prepared by addition of hydrobromic acid or hydrochloric acid to the mixture of
- Kim, Kyoung-Mahn,Park, In-Hwan
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p. 2641 - 2644
(2007/10/03)
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- Substituted 4H-1-Benzopyran-4-ones (Chromones): Synthesis via Palladium-catalysed Coupling of their Halogeno Derivatives with Alkenes
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Activation of bromochromones has been achieved by Pd0 insertion into the carbon-halogen bond.The resultant species undergo coupling with alkenes leading to vinylated chromones.Vinylation occurs regiospecifically at the original site of bromination and therefore provides a method for the clean introduction of substituents into the chromone ring system.An anomalous reaction of a dibrominated chromone leading to a ring-opened product is described.
- Davies, Stephen G.,Mobbs, Bryan E.,Goodwin, Christopher J.
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p. 2597 - 2604
(2007/10/02)
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