Cover Feature: Synthesis of Functionalized Difluorocyclopropanes: Unique Building Blocks for Drug Discovery (Chem. Eur. J. 47/2018)

AbstractA three-step approach to the synthesis of sp3-enriched β-fluoro sulfonyl chlorides starting from alkenes is reported. The method was successfully applied to a wide range of acyclic and cyclic substrates, bearing either an exocyclic or an endocyclic double bond. The procedure worked with a wide range of substrates and tolerated a number of functional and protecting groups. Moreover, the target cyclic compounds were obtained as single cis diastereomers on a multigram scale. The title compounds are promising building blocks for drug discovery that can be used to obtain sp3-enriched β-fluoro and α,β-unsaturated sulfonamides.

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Synthetically Accessible Virtual Inventory (SAVI)

10.26434/chemrxiv.12185559 ◽

2020 ◽

Author(s):

Hitesh Patel ◽

Wolf Ihlenfeldt ◽

Philip Judson ◽

Yurii S. Moroz ◽

Yuri Pevzner ◽

...

Keyword(s):

Drug Discovery ◽

Chemical Synthesis ◽

Programming Languages ◽

Expert Knowledge ◽

Scoring Systems ◽

Building Blocks ◽

Single Step

We have made available a database of over 1 billion compounds predicted to be easily synthesizable. They have been created by a set of transforms based on an adaptation and extension of the CHMTRN/PATRAN programming languages describing chemical synthesis expert knowledge, which originally stem from the LHASA project. The chemoinformatics toolkit CACTVS was used to apply a total of 53 transforms to about 150,000 readily available building blocks (enamine.net). Only single-step, two-reactant syntheses were calculated for this database even though the technology can execute multi-step reactions. The possibility to incorporate scoring systems in CHMTRN allowed us to subdivide the database of 1.75 billion compounds in sets according to their predicted synthesizability, with the most-synthesizable class comprising 1.09 billion synthetic products. Properties calculated for all SAVI products show that the database should be well-suited for drug discovery. It is being made publicly available for free download from https://cactus.nci.nih.gov/download/savi_download/.

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Glycosylated α-Azido Amino Acids: Versatile Intermediates in the Synthesis of Neoglycoconjugates

Synlett ◽

10.1055/s-0036-1591902 ◽

2018 ◽

Vol 29 (07) ◽

pp. 904-907 ◽

Cited By ~ 2

Author(s):

Trinidad Velasco-Torrijos ◽

Róisín O’Flaherty

Keyword(s):

Amino Acids ◽

Drug Discovery ◽

Building Blocks ◽

Sensor Development ◽

Galactosyl Ceramide

A series of glycosylated α-azido amino acids was synthesized as precursors for neoglycoconjugates, a class of important biomolecules for drug discovery, and sensor development. The synthetically challenging 1,2-cis α-galactosylated species described herein were designed as building blocks in the synthesis of analogues of α-galactosyl ceramide, a potent immunomodulator. A benzyl-protected 1,2,3-triazolyl α-galactosyl-l-serine derivative was prepared using copper azide alkyne cycloaddition to showcase the potential of glycosylated α-azido amino acids in neoglycoconjugate design.

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Diastereoselective Synthesis of 2-Phenyl-3-(trifluoromethyl)piperazines as Building Blocks for Drug Discovery

The Journal of Organic Chemistry ◽

10.1021/jo500832j ◽

2014 ◽

Vol 79 (12) ◽

pp. 5887-5894 ◽

Cited By ~ 16

Author(s):

María Sánchez-Roselló ◽

Oscar Delgado ◽

Natalia Mateu ◽

Andrés A. Trabanco ◽

Michiel Van Gool ◽

...

Keyword(s):

Drug Discovery ◽

Building Blocks ◽

Diastereoselective Synthesis

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Glycosamino Acids: Building Blocks for Combinatorial Synthesis—Implications for Drug Discovery

Angewandte Chemie International Edition ◽

10.1002/1521-3773(20020118)41:2<230::aid-anie230>3.0.co;2-l ◽

2002 ◽

Vol 41 (2) ◽

pp. 230 ◽

Cited By ~ 179

Author(s):

Frank Schweizer

Keyword(s):

Drug Discovery ◽

Building Blocks ◽

Combinatorial Synthesis

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The Generated Databases (GDBs) as a Source of 3D-shaped Building Blocks for Use in Medicinal Chemistry and Drug Discovery

CHIMIA International Journal for Chemistry ◽

10.2533/chimia.2020.241 ◽

2020 ◽

Vol 74 (4) ◽

pp. 241-246 ◽

Cited By ~ 2

Author(s):

Kris Meier ◽

Sven Bühlmann ◽

Josep Arús-Pous ◽

Jean-Louis Reymond

Keyword(s):

Drug Discovery ◽

Medicinal Chemistry ◽

Organic Molecules ◽

Chemical Space ◽

Building Blocks ◽

Chiral Molecules ◽

Hydrogen Atoms ◽

Quaternary Centers ◽

Medical Needs ◽

Unmet Medical Needs

Drug discovery is in constant need of new molecules to develop drugs addressing unmet medical needs. To assess the chemical space available for drug design, our group investigates the generated databases (GDBs) listing all possible organic molecules up to a defined size, the largest of which is GDB-17 featuring 166.4 billion molecules up to 17 non-hydrogen atoms. While known drugs and bioactive compounds are mostly aromatic and planar, the GDBs contain a plethora of non-aromatic 3D-shaped molecules, which are very useful for drug discovery since they generally have more desirable absorption, distribution, metabolism, excretion and toxicity (ADMET) properties. Here we review GDB enumeration methods and the selection and synthesis of GDB molecules as modulators of ion channels. We summarize the constitution of GDB subsets focusing on fragments (FDB17), medicinal chemistry (GDBMedChem) and ChEMBL-like molecules (GDBChEMBL), and the ring system database GDB4c as a rich source of novel 3D-shaped chiral molecules containing quaternary centers, such as the recently reported trinorbornane.

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An Approach to 1,1-Disubstituted Pyrazolylcyclopropane Building Blocks

SynOpen ◽

10.1055/s-0036-1588544 ◽

2017 ◽

Vol 01 (01) ◽

pp. 0084-0090 ◽

Cited By ~ 1

Author(s):

Pavel Nosik ◽

Oleksiy Artamonov ◽

Sergey Ryabukhin ◽

Oleksandr Grygorenko

Keyword(s):

Drug Discovery ◽

Building Blocks ◽

Lithium Diisopropylamide ◽

Early Drug

An approach to isomeric 1,1-disubstituted pyrazolylcyclopropanes that relies on lithium diisopropylamide (LDA) mediated bis-alkylation of the corresponding pyrazolylacetonitriles is developed. The building blocks obtained can be considered as lead-like bioisosteres of arylpyrazole and pyrazolecarboxamide moieties and are thus useful for early drug discovery projects.

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Synthesis of Spirocyclic Pyrrolidines: Advanced Building Blocks for Drug Discovery

Chemistry - A European Journal ◽

10.1002/chem.201704330 ◽

2017 ◽

Vol 23 (66) ◽

pp. 16695-16695 ◽

Cited By ~ 1

Author(s):

Bohdan A. Chalyk ◽

Maryna V. Butko ◽

Oksana O. Yanshyna ◽

Konstantin S. Gavrilenko ◽

Tetiana V. Druzhenko ◽

...

Keyword(s):

Drug Discovery ◽

Building Blocks

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Enantioselective Carboetherification/Hydrogenation for the Synthesis of Amino Alcohols via a Catalytically-Formed Chiral Auxiliary

10.26434/chemrxiv.12855218.v1 ◽

2020 ◽

Cited By ~ 1

Author(s):

Luca Buzzetti ◽

Mikus Purins ◽

Phillip D. G. Greenwood ◽

Jerome Waser

Keyword(s):

Drug Discovery ◽

Asymmetric Catalysis ◽

Chemical Reactions ◽

Building Blocks ◽

Amino Alcohols ◽

Chiral Auxiliary ◽

Alternative Strategy ◽

Chiral Auxiliaries ◽

Palladium Catalyzed ◽

Fast Access

Chiral auxiliaries and asymmetric catalysis are the workhorses of enantioselective transformations, but they still remain limited either in terms of efficiency or generality. Herein, we present an alternative strategy for controlling the stereoselectivity of chemical reactions. Asymmetric catalysis is used to install a transient chiral auxiliary starting from achiral precursors, which then directs diastereoselective reactions. We apply this strategy to a palladium-catalyzed carboetherification/hydrogenation sequence on propargylic amines, providing fast access to enantioenriched chiral amino alcohols, important building blocks for medicinal chemistry and drug discovery. All stereoisomers of the product could be accessed by the choice of ligand and substituent on the propargylic amine, leading to a stereodivergent process.

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Taking chance out of drug discovery

The Biochemist ◽

10.1042/bio03106040 ◽

2009 ◽

Vol 31 (6) ◽

pp. 40-42

Author(s):

Simon Pearce

Keyword(s):

Drug Discovery ◽

Research And Development ◽

Phenyl Ring ◽

Reactive Intermediates ◽

Building Blocks ◽

Bioactive Molecules ◽

Discovery Process ◽

Drug Discovery Process ◽

Drug Discovery And Development ◽

Compound Screening

Searching for bioactive molecules, using rapid compound screening, fragment-based design and unique building blocks, should not be like looking for a needle in a haystack. This article describes a range of innovative and diverse screening compounds for drug discovery and development. Available at both research and development scales, the line includes special products associated with new heterocyclic and phenyl ring-based chemical building blocks, including an exclusive and expanding range of reactive intermediates specifically designed for lead optimization, as well as a growing fragment collection. I explain how these products and services are helping to accelerate the search for bioactive molecules and are shortening the drug discovery process by reducing the element of chance.

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