- Oxidative regioselective amination of chromones exposes potent inhibitors of the hedgehog signaling pathway
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A transition metal-free, oxidative, regioselective cross-coupling between non-functionalized azoles and chromones at C2-position was developed. A broad reaction scope and further transformation of products were demonstrated. The biological evaluation of products revealed a novel class of hedgehog signaling pathway inhibitors. This journal is
- Samanta, Rajarshi,Narayan, Rishikesh,Bauer, Jonathan O.,Strohmann, Carsten,Sievers, Sonja,Antonchick, Andrey P.
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- Nickel-Catalyzed Decarbonylative Amination of Carboxylic Acid Esters
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The reaction of carboxylic acid derivatives with amines to form amide bonds has been the most widely used transformation in organic synthesis over the past century. Its utility is driven by the broad availability of the starting materials as well as the kinetic and thermodynamic driving force for amide bond formation. As such, the invention of new reactions between carboxylic acid derivatives and amines that strategically deviate from amide bond formation remains both a challenge and an opportunity for synthetic chemists. This report describes the development of a nickel-catalyzed decarbonylative reaction that couples (hetero)aromatic esters with a broad scope of amines to form (hetero)aryl amine products. The successful realization of this transformation was predicated on strategic design of the cross-coupling partners (phenol esters and silyl amines) to preclude conventional reactivity that forms inert amide byproducts.
- Malapit, Christian A.,Borrell, Margarida,Milbauer, Michael W.,Brigham, Conor E.,Sanford, Melanie S.
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supporting information
p. 5918 - 5923
(2020/04/08)
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- Syntheses and Evaluation of 2- or 3-(N-Cyclicamino)chromone Derivatives as Monoamine Oxidase Inhibitors
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A series of 2-(N-cyclicamino)chromone derivatives (1a–4c) and 3-(N-cyclicamino)chromone derivatives (5a–8c) were synthesized, and their monoamine oxidase (MAO) A and B inhibitory activities were studied as part of a structure–activity relationship investigation. Compounds 1a–4c showed no remarkable inhibition for MAO-A or MAO-B, whereas compounds 5a–8c (with a few exceptions) showed significant and selective inhibition of MAO-B. Of these compounds, 7c, 7-methoxy-3-(4-phenyl-1-piperazinyl)-4H-1-benzopyran-4-one inhibited MAO-B the most potently and selectively, having IC50 of 15nM and an MAO-B selectivity index of more than 6700; c.f, 50nM and 2000, respectively, for safinamide. The mode of inhibition of 7c to MAO-B was competitive and reversible. Considering the IC50 values and selectivity indices of the other synthetic compounds, the presence of the methoxy group on the chromone ring (R2) of 7c seemed to increase MAO-B inhibition. Molecular docking analysis also supports this hypothesis. Our results suggest that 3-(N-cyclicamino)-chromones are useful lead compounds for the development of MAO-B inhibitors.
- Takao, Koichi,Sakatsume, Tsukasa,Kamauchi, Hitoshi,Sugita, Yoshiaki
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p. 1082 - 1089
(2020/11/26)
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- Efficient one-pot synthesis of N-substituted 2-aminochromones, their benzo-fused derivatives, and diaminobenzodipyrandiones of two new structural classes
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N-Substituted 2-aminochromones and their benzo-fused derivatives were obtained in high yields by a new one-pot synthesis, starting from the appropriate acetamides, salicylic acid or its benzo-fused derivatives, and phosphoryl chloride. By the same reaction, from suitable dihydroxybenzenedicarboxylic acids, some compounds of two new structural classes, 2,7-diaminobenzo[1,2-b:4,5-b']dipyran-4,9-diones and 2,8-diamino-4H,6H-benzo[1,2-b:5,4-b']dipyran-4,6-diones, were synthesized. Georg Thieme Verlag Stuttgart.
- Roma, Giorgio,Piras, Daniela,Di Braccio, Mario,Grossi, Giancarlo
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experimental part
p. 849 - 857
(2010/10/02)
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- Targeting the gatekeeper residue in phosphoinositide 3-kinases
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A single residue in the ATP binding pocket of protein kinases-termed the gatekeeper-has been shown to control sensitivity to a wide range of small molecule inhibitors (Chem. Biol. 2004, 11, 691; Chem. Biol. 1999, 6, 671). Kinases that possess a small side chain at this position (Thr, Ala, or Gly) are readily targeted by structurally diverse classes of inhibitors, whereas kinases that possess a larger residue at this position are broadly resistant. Recently, lipid kinases of the phosphoinositide 3-kinase (PI3-K) family have become the focus of intense research interest as potential drug targets (Chem. Biol. 2003, 10, 207; Curr. Opin. Pharmacol. 2003, 3, 426). In this study, we identify the residue that corresponds structurally to the gatekeeper in PI3-Ks, and explore its importance in controlling enzyme activity and small molecule sensitivity. Isoleucine 848 of p110α was mutated to alanine and glycine, but the mutated kinase was found to have severely impaired enzymatic activity. A structural bioinformatic comparison of this kinase with its yeast orthologs identified second site mutations that rescued the enzymatic activity of the I848A kinase. To probe the dimensions of the gatekeeper pocket, a focused panel of analogs of the PI3-K inhibitor LY294002 was synthesized and its activity against gatekeeper mutated and wild-type p110α was assessed.
- Alaimo, Peter J.,Knight, Zachary A.,Shokat, Kevan M.
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p. 2825 - 2836
(2007/10/03)
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- Selective benzopyranone and pyrimido[2,1-α]isoquinolin-4-one inhibitors of DNA-dependent protein kinase: Synthesis, structure-activity studies, and radiosensitization of a human tumor cell line in vitro
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A diverse range of chromen-2-one, chromen-4-one and pyrimidoisoquinolin-4- one derivatives was synthesized and evaluated for inhibitory activity against the DNA repair enzyme DNA-dependent protein kinase (DNA-PK), with a view to elucidating structure-activity relationships for potency and kinase selectivity. DNA-PK inhibitory activity varied widely over the series of compounds evaluated (IC50 values ranged from 0.19 to >10 μM), with excellent activity being observed for the 7,8-benzochromen-4-one and pyrimido[2,1-a] isoquinolin-4-one templates. By contrast, inhibitors based on the benzochromen-2-one (coumarin) or 2-aryl-7,8-benzochromen-4-one (flavone) scaffolds were less potent. Crucially, these studies revealed a very constrained structure-activity relationship at the 2-position of the benzopyranone and pyrimido[2,1-a]-isoquinolin-4-one pharmacophore, with only a 2-morpholino or 2-(2′-methylmorpholino) group being tolerated at this position. More detailed biological studies conducted with the most potent inhibitor NU7163 (48; IC50 = 0.19 μM) demonstrated ATP-competitive DNA-PK inhibition, with a Ki value of 24 nM, and 48 exhibited selectivity for DNA-PK compared with the related enzymes ATM, ATR, mTOR, and PI 3-K (p110alpha). Compound 48 sensitized the HeLa human tumor cell line to the cytotoxic effects of ionizing radiation in vitro, a dose modification factor of 2.3 at 10% survival being observed with an inhibitor concentration of 5 μM. This study identified these structural classes as novel DNA-PK inhibitors and delineated initial structure-activity relationships against DNA-PK.
- Griffin, Roger J.,Fontana, Gabriele,Golding, Bernard T.,Guiard, Sophie,Hardcastle, Ian R.,Leahy, Justin J. J.,Martin, Niall,Richardson, Caroline,Rigoreau, Laurent,Stockley, Martin,Smith, Graeme C. M.
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p. 569 - 585
(2007/10/03)
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- Isoform-specific phosphoinositide 3-kinase inhibitors from an arylmorpholine scaffold
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Phosphoinositide 3-kinases (PI3-Ks) are an ubiquitous class of signaling enzymes that regulate diverse cellular processes including growth, differentiation, and motility. Physiological roles of PI3-Ks have traditionally been assigned using two pharmacological inhibitors, LY294002 and wortmannin. Although these compounds are broadly specific for the PI3-K family, they show little selectivity among family members, and the development of isoform-specific inhibitors of these enzymes has been long anticipated. Herein, we prepare compounds from two classes of arylmorpholine PI3-K inhibitors and characterize their specificity against a comprehensive panel of targets within the PI3-K family. We identify multiplex inhibitors that potently inhibit distinct subsets of PI3-K isoforms, including the first selective inhibitor of p110β/p110δ (IC50 p110β = 0.13 μM, p110δ = 0.63 μM). We also identify trends that suggest certain PI3-K isoforms may be more sensitive to potent inhibition by arylmorpholines, thereby guiding future drug design based on this pharmacophore.
- Knight, Zachary A.,Chiang, Gary G.,Alaimo, Peter J.,Kenski, Denise M.,Ho, Caroline B.,Coan, Kristin,Abraham, Robert T.,Shokat, Kevan M.
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p. 4749 - 4759
(2007/10/03)
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- Antiatherosclerotic and antithrombotic 1-benzopyran-4-ones and 2-amino-1,3-benzoxazine-4-ones
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This invention relates to compounds of Formula I STR1 which are useful in association with a pharmaceutical carrier as antiatherosclerotic agents. In addition, various compounds of Formula I are useful inhibitors of cell proliferation.
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- A cyclodehydration route to 2-aminochromones
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Cyclodehydration of a series of salicylacetamides with triflic anhydride efficiently provided the corresponding 2-aminochromone. The use of polyphosphoric ester for this process was somewhat less effective.
- Morris,Wishka,Fang
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p. 849 - 858
(2007/10/02)
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