scholarly journals Thiol-to-amine cyclization reaction enables screening of large libraries of macrocyclic compounds and the generation of sub-kilodalton ligands

2019 ◽  
Vol 5 (8) ◽  
pp. eaaw2851 ◽  
Author(s):  
S. S. Kale ◽  
M. Bergeron-Brlek ◽  
Y. Wu ◽  
M. G. Kumar ◽  
M. V. Pham ◽  
...  
Keyword(s):  
Drug Development ◽  
Structure Analysis ◽  
Drug Targets ◽  
Macrocyclic Ligands ◽  
Cyclization Reaction ◽  
Thrombin Inhibitor ◽  
Macrocyclic Compounds ◽  
Cyclization Reactions ◽  
X Ray ◽  
High Yields

Macrocyclic compounds are an attractive modality for drug development, but the limited availability of large, structurally diverse macrocyclic libraries hampers the discovery of leads. Here, we describe the discovery of efficient macrocyclization reactions based on thiol-to-amine ligations using bis-electrophiles, their application to synthesize and screen large libraries of macrocyclic compounds, and the identification of potent small macrocyclic ligands. The thiol-to-amine cyclization reactions showed unexpectedly high yields for a wide substrate range, which obviated product purification and enabled the generation and screening of an 8988 macrocycle library with a comparatively small effort. X-ray structure analysis of an identified thrombin inhibitor (Ki = 42 ± 5 nM) revealed a snug fit with the target, validating the strategy of screening large libraries with a high skeletal diversity. The approach provides a route for screening large sub-kilodalton macrocyclic libraries and may be applied to many challenging drug targets.

Synthesis and properties of some icosahedral carborane B,B'-dithiols

1980 ◽  
Vol 45 (6) ◽  
pp. 1775-1779 ◽  
Author(s):  
Jaromír Plešek ◽  
Zbyněk Janoušek ◽  
Stanislav Heřmánek
Keyword(s):  
Structure Analysis ◽  
Mass Spectra ◽  
X Ray ◽  
High Yields ◽  
Excess Sulfur

Reaction of icosahedral carboranes with excess sulfur over AlCl3 converts in high yields o-carborane to 9,12-, and m-carborane to 9,10- and 5(4),9-dithiols which were transformed by CH2Br2 to the appropriate cyclic thioformal derivatives. Reaction of 9,12(HS)2-1,2-C2B10H10 with acetone and AlCl3 afforded a cyclic thioketal, the structure of which was confirmed by X-ray structure analysis. All structures were proposed on the ground of 1H-, 11B-NMR and mass spectra.

Darstellung und Struktur kationischer η2-Thiocarbenkomplexe von Molybdän und Wolfram / Synthesis and Structure of Cationic η2-Thiocarbene Complexes of Molybdenum and Tungsten

1990 ◽  
Vol 45 (6) ◽  
pp. 921 ◽  
Author(s):  
N. Ullrich ◽  
C. Stegmair ◽  
H. Keller ◽  
E. Herdtweck ◽  
F. R. Kreißl
Keyword(s):  
Structure Analysis ◽  
Triple Bond ◽  
Mass Spectra ◽  
Electrophilic Attack ◽  
X Ray ◽  
High Yields ◽  
New Compounds ◽  
Carbyne Complexes ◽  
And Tungsten

The reaction of dimethyl(methylthio)sulfonium tetrafluoroborate [(CH3)2S–SCH3][BF4] with η/5-cyclopentadienyl(dicarbonyl)carbyne complexes of molybdenum and tungsten Cp(CO)2M ≡ C–R (M = Mo, W; R = CH3, C6H5, C6H4CH3) 1c, 2a–d results in an electrophilic attack of the SCH3 moiety at the metal carbon triple bond, providing orange to red, diamagnetic, cationic η2-thiocarbene complexes 3c, 4a–d in high yields. The new compounds were identified by X-ray structure analysis, NMR, IR and mass spectra.

Syntheses and Structures of a Class of Bridged Bis(Amidinate)s and Derivatives

2018 ◽  
Vol 42 (5) ◽  
pp. 239-243 ◽  
Author(s):  
Fen-Hua Wang ◽  
Song Wang ◽  
Jiang-Sheng Huang ◽  
Jun Zhang ◽  
Chun-Mei Ding
Keyword(s):  
Crystal Structure ◽  
Structure Analysis ◽  
Crystal Structure Analysis ◽  
Aromatic Rings ◽  
Hydrogen Atoms ◽  
X Ray ◽  
Different Types ◽  
Butyl Amine ◽  
High Yields ◽  
Very High

A series of different types of ‘bridge’ linked bis(amidinate)s have been prepared. Reactions of a variety of linked diamines with pivaloyl chloride yielded the corresponding diamides in very high yields. Conversion of the diamides to the diimine chloride is achieved with PCl5 in CH2Cl2. Reactions of the diimine chloride with aniline or t-butyl amine yielded the bis(amidinate)s in good yields, while reaction with pyrrolyl sodium or 2,5-dimethyl pyrrolyl potassium afforded the corresponding derivatives. Their structures were characterised by NMR and HRMS, and some products were further characterised by X-ray crystal structure analysis. It was found that the locations of the hydrogen atoms within the two amidine fragments vary. The structures showed that in the phenylene-linked bis(amidinate)s, the hydrogen atoms were attached to different nitrogen atoms in the amidine groups, and in the cyclohexylene-linked bis(amidinate)s or their derivatives, the C=N of the amidine groups were conjugated with the aromatic rings.

scholarly journals Using X-ray Diffraction Techniques for Biomimetic Drug Development, Formulation, and Polymorphic Characterization

Biomimetics ◽  
2020 ◽  
Vol 6 (1) ◽  
pp. 1
Author(s):  
Israel Rodríguez ◽  
Ritika Gautam ◽  
Arthur D. Tinoco
Keyword(s):  
Drug Development ◽  
Drug Targets ◽  
Amorphous Materials ◽  
Solid Dispersions ◽  
Amorphous Solid ◽  
Drug Approval ◽  
Active Pharmaceutical Ingredient ◽  
Drug Formulation ◽  
X Ray Diffraction ◽  
X Ray

Drug development is a decades-long, multibillion dollar investment that often limits itself. To decrease the time to drug approval, efforts are focused on drug targets and drug formulation for optimal biocompatibility and efficacy. X-ray structural characterization approaches have catalyzed the drug discovery and design process. Single crystal X-ray diffraction (SCXRD) reveals important structural details and molecular interactions for the manifestation of a disease or for therapeutic effect. Powder X-ray diffraction (PXRD) has provided a method to determine the different phases, purity, and stability of biological drug compounds that possess crystallinity. Recently, synchrotron sources have enabled wider access to the study of noncrystalline or amorphous solids. One valuable technique employed to determine atomic arrangements and local atom ordering of amorphous materials is the pair distribution function (PDF). PDF has been used in the study of amorphous solid dispersions (ASDs). ASDs are made up of an active pharmaceutical ingredient (API) within a drug dispersed at the molecular level in an amorphous polymeric carrier. This information is vital for appropriate formulation of a drug for stability, administration, and efficacy purposes. Natural or biomimetic products are often used as the API or the formulation agent. This review profiles the deep insights that X-ray structural techniques and associated analytical methods can offer in the development of a drug.

Absolute Stereochemistry of (-)-Wieland-Miescher Ketone as Established by the X-ray Crystallographic and CD Exciton Chirality Methods

1992 ◽  
Vol 57 (7) ◽  
pp. 1459-1465 ◽  
Author(s):  
Nobuyuki Harada ◽  
Tatsuo Sugioka ◽  
Hisashi Uda ◽  
Takeo Kuriki
Keyword(s):  
Structure Analysis ◽  
Absolute Configuration ◽  
X Ray ◽  
The Absolute ◽  
Absolute Stereochemistry

The 8aR absolute stereochemistry of Wieland-Miescher ketone (-)-I was established by the X-ray structure analysis of its bis(4-bromobenzoate) derivatives (1R,6R,8aR)-(+)-IV and (1R,6S,8aR)-(-)-V. The absolute configuration of (-)-I was corroborated further by the application of the CD exciton chirality method to bis(4-bromobenzoates) (+)-IV and (-)-V.

scholarly journals Preparative-scale HPLC Resolution of Metallacyclic η3-Allyltricarbonyliron Complexes and Determination of the Absolute Configuration by X-Ray Crystal Structure Analysis

1999 ◽  
Vol 23 (9) ◽  
pp. 578-579
Author(s):  
Rainer Schobert ◽  
Hermann Pfab ◽  
Jutta Böhmer ◽  
Frank Hampel ◽  
Andreas Werner
Keyword(s):  
Crystal Structure ◽  
Silica Gel ◽  
Structure Analysis ◽  
Absolute Configuration ◽  
Crystal Structure Analysis ◽  
Preparative Scale ◽  
X Ray ◽  
The Absolute

Racemates of (η3-allyl)tricarbonyliron lactone complex Fe(CO)3{η1:η3-C(O)XCH2CHCMeCH2} 1a (X = O) and (η3-allyl)tricarbonyliron lactam complex 2a (X = NMe) are resolved on a preparative scale by HPLC on cellulose tris(3,5-dimethylphenyl)carbamate/silica gel RP-8 and the absolute configuration of (-)-2a is determined by X-ray crystal structure analysis.

scholarly journals NMR, X-Ray and MS Investigations of Ethyl 2-Aroyl-and Ethyl 2-Arylcarbamoyl-4,5- dimethyl-1,2,3,6-tetrahydropyridazine-1- carboxylates: Flexible Multidentate Ligands

1999 ◽  
Vol 23 (3) ◽  
pp. 186-187
Author(s):  
Erkki Kolehmainen ◽  
Katri Laihia ◽  
Maija Nissinen ◽  
Kalevi Pihlaja ◽  
Alexander Perjéssy ◽  
...  
Keyword(s):  
Structure Analysis ◽  
Multidentate Ligands ◽  
X Ray ◽  
C Nmr

The 1H and 13C NMR spectral assignments of ethyl 2-aroyl-4,5-dimethyl-1,2,3,6-tetrahydropyridazine-1-carboxylates (1a-1h) and ethyl 2-arylcarbamoyl-4,5-dimethyl-1,2,3,6-tetrahydropyridazine-1-carboxylates (2a-2k) are given based on DQF COSY, 1H,13C HMQC and 1H,13C HMBC-measurements; the dynamics of the tetrahydropyridazine ring has been studied by 1H, 1H EXSY-technique and the structure of one congener (4′-methylphenyl-derivative, 2a) has been confirmed by X-ray structure analysis.

scholarly journals Rapid four-component synthesis of dihydropyrano[2,3-c]pyrazoles using nano-eggshell/Ti(IV) as a highly compatible natural based catalyst

BMC Chemistry ◽  
2021 ◽  
Vol 15 (1) ◽  
Author(s):  
Arefeh Dehghani Tafti ◽  
Bi Bi Fatemeh Mirjalili ◽  
Abdolhamid Bamoniri ◽  
Naeimeh Salehi
Keyword(s):  
Thermo Gravimetric Analysis ◽  
Reaction Times ◽  
Diffraction Field ◽  
Gravimetric Analysis ◽  
X Ray Diffraction ◽  
X Ray ◽  
Solvent Free Conditions ◽  
High Yields ◽  
Work Up

AbstractNano-eggshell/Ti(IV) as a novel naturally based catalyst was prepared, characterized and applied for the synthesis of dihydropyrano[2,3-c]pyrazole derivatives. The characterization of nano-eggshell/Ti(IV) was performed using Fourier Transform Infrared spectroscopy, X-ray Diffraction, Field Emission Scanning Electron Microscopy, Energy-Dispersive X-ray Spectroscopy, and Thermo Gravimetric Analysis. Dihydropyrano[2,3-c]pyrazoles were synthesized in the presence of nano-eggshell/Ti(IV) via a four component reaction of aldehydes, ethyl acetoacetate, malononitrile and hydrazine hydrate at room temperature under solvent free conditions. The principal affairs of this procedure are mild condition, short reaction times, easy work-up, high yields, reusability of the catalyst and the absence of toxic organic solvents.

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