- Novel, Self-Assembling Dimeric Inhibitors of Human β Tryptase
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β-Tryptase, a homotetrameric serine protease, has four identical active sites facing a central pore, presenting an optimized setting for the rational design of bivalent inhibitors that bridge two adjacent sites. Using diol, hydroxymethyl phenols or benzoyl methyl hydroxamates, and boronic acid chemistries to reversibly join two [3-(1-acylpiperidin-4-yl)phenyl]methanamine core ligands, we have successfully produced a series of self-assembling heterodimeric inhibitors. These heterodimeric tryptase inhibitors demonstrate superior activity compared to monomeric modes of inhibition. X-ray crystallography validated the dimeric mechanism of inhibition, and compounds demonstrated high selectivity against related proteases, good target engagement, and tryptase inhibition in HMC1 xenograft models. Screening 3872 possible combinations from 44 boronic acid and 88 diol derivatives revealed several combinations that produced nanomolar inhibition, and seven unique pairs produced greater than 100-fold improvement in potency over monomeric inhibition. These heterodimeric tryptase inhibitors demonstrate the power of target-driven combinatorial chemistry to deliver bivalent drugs in a small molecule form.
- Giardina, Sarah F.,Werner, Douglas S.,Pingle, Maneesh,Feinberg, Philip B.,Foreman, Kenneth W.,Bergstrom, Donald E.,Arnold, Lee D.,Barany, Francis
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p. 3004 - 3027
(2020/04/17)
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- Unraveling the anti-influenza effect of flavonoids: Experimental validation of luteolin and its congeners as potent influenza endonuclease inhibitors
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The biological effects of flavonoids on mammal cells are diverse, ranging from scavenging free radicals and anti-cancer activity to anti-influenza activity. Despite appreciable effort to understand the anti-influenza activity of flavonoids, there is no clear consensus about their precise mode-of-action at a cellular level. Here, we report the development and validation of a screening assay based on AlphaScreen technology and illustrate its application for determination of the inhibitory potency of a large set of polyols against PA N-terminal domain (PA-Nter) of influenza RNA-dependent RNA polymerase featuring endonuclease activity. The most potent inhibitors we identified were luteolin with an IC50 of 72 ± 2 nM and its 8-C-glucoside orientin with an IC50 of 43 ± 2 nM. Submicromolar inhibitors were also evaluated by an in vitro endonuclease activity assay using single-stranded DNA, and the results were in full agreement with data from the competitive AlphaScreen assay. Using X-ray crystallography, we analyzed structures of the PA-Nter in complex with luteolin at 2.0 ? resolution and quambalarine B at 2.5 ? resolution, which clearly revealed the binding pose of these polyols coordinated to two manganese ions in the endonuclease active site. Using two distinct assays along with the structural work, we have presumably identified and characterized the molecular mode-of-action of flavonoids in influenza-infected cells.
- Albi?ana, Carlos Berenguer,Brynda, Ji?í,Fanfrlík, Jind?ich,Flieger, Miroslav,Hodek, Jan,Karlukova, Elena,Ko?í?ek, Milan,Konvalinka, Jan,Machara, Ale?,Majer, Pavel,Radilová, Kate?ina,Weber, Jan,Zima, Václav
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supporting information
(2020/09/09)
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- A versatile approach for the synthesis of para -substituted arenes via palladium-catalyzed C-H functionalization and protodecarboxylation of benzoic acids
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While a great number of ortho C-H functionalization reactions have been developed and several breakthroughs have been achieved in meta C-H activation, para C-H functionalization is still in its infancy stage. In this article, a versatile strategy for the synthesis of para-substituted arenes has been developed via a tandem process consisting of palladium-catalyzed C-H functionalization and subsequent copper-catalyzed protodecarboxylation of benzoic acids. Both electron-withdrawing and electron-donating functionalities can be introduced into the para positions of arenes bearing a variety of substituents.
- Pan, Shulei,Zhou, Bo,Zhang, Yanghui,Shao, Changdong,Shi, Guangfa
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supporting information
p. 277 - 281
(2016/01/20)
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- MONOMERS CAPABLE OF DIMERIZING IN AN AQUEOUS SOLUTION, AND METHODS OF USING SAME
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Described herein are monomers capable of forming a biologically useful multimer when in contact with one, two, three or more other monomers in an aqueous media. In one aspect, such monomers may be capable of binding to another monomer in an aqueous media (e.g. in vivo) to form a multimer, (e.g. a dimer). Contemplated monomers may include a ligand moiety, a linker element, and a connector element that joins the ligand moiety and the linker element. In an aqueous media, such contemplated monomers may join together via each linker element and may thus be capable of modulating one or more biomolecules substantially simultaneously, e.g., modulate two or more binding domains on a protein or on different proteins.
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Paragraph 0442-0443
(2014/07/22)
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- Design, synthesis and biological activity of selective and orally available TF/FVIIa complex inhibitors containing non-amidine P1 ligands
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We found the novel selective and orally available non-amidine TF/FVIIa complex inhibitor 21e, 4-({[(1S)-(aminocarbonyl)-3-methylbutyl]amino}carbonyl)-2′-({[4- (aminomethyl)phenyl]amino}carbonyl)-4′-(methylamino)biphenyl-2- carboxylic acid. The derivatives
- Miura, Masanori,Seki, Norio,Koike, Takanori,Ishihara, Tsukasa,Niimi, Tatsuya,Hirayama, Fukushi,Shigenaga, Takeshi,Sakai-Moritani, Yumiko,Tagawa, Ayako,Kawasaki, Tomihisa,Sakamoto, Shuichi,Okada, Minoru,Ohta, Mitsuaki,Tsukamoto, Shin-ichi
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p. 160 - 173
(2007/10/03)
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- One-pot synthetic procedure for 2,2′-disubstituted biaryls via the Suzuki coupling reaction of aryl triflates in a biphasic solvent system
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A one-pot synthetic procedure for 2,2′-disubstituted biaryls was developed via a Suzuki cross-coupling reaction of aryl triflates in a biphasic solvent system. The effects of various bases and solvents were investigated. Results showed that the Na2/
- Miura, Masanori,Koike, Takanori,Ishihara, Tsukasa,Hirayama, Fukushi,Sakamoto, Shuichi,Okada, Minoru,Ohta, Mitsuaki,Tsukamoto, Shin-Ichi
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p. 3809 - 3820
(2007/10/03)
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- 2-FURANCARBOXYLIC ACID HYDRAZIDES AND PHARMACEUTICAL COMPOSITIONS CONTAINING THE SAME
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The present invention provides 2-furancarboxylic acid hydrazide compounds represented by General Formula(I) below, and prodrugs, physiologically acceptable salts, hydrates, solvates thereof, methods for producing them and pharmaceutical compositions containing them: wherein A is a group represented by Formula (a) or the like: (wherein either R4 or R5 represents cyano, nitro or the like, and the other represents a hydrogen atom or the like); either R1 or R2 represents a group: -D-(X)m-R6 or the like, and the other represents a group: -E-(Y)n-R7, hydrogen atom, aryl or the like; R3 is a hydrogen atom or the like; D and E independently represent aryl; X and Y independently represent 0 or the like; R6 and R7 independently represent alkyl, aryl, arylalkyl or the like; and m and n are independently 0 or 1, provided that the aryl is optionally substituted. Such compounds exhibit a potent antagonistic activity on glucagon receptor and are of use as preventive and/or therapeutic agents for symptoms and diseases in which glucagon is involved.
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