Fluorine-Substituted Building Blocks

In the previous issue, we presented the set of building blocks which had at least one fluorine substituent. This issue continues representation of fluorine-substituted building blocks emphasizing compounds derived from original scaffolds designed by Enamine chemists.

Understanding the importance of the fluoro-organic compounds for the pharmaceutical industry, we put much effort in adapting known and developing new synthetic methodologies allowing introducing fluorine by the use of different fluorine reagents.

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Conformationally restricted diamines and amino alcohols

The primary structure of a peptide can be formally considered as a oligoethylenediamine molecular platform to which the side chains and carbonyl oxygen atoms are attached through single and double bonds respectively. This backbone is conformationally restrained at the amide bonds and has some rotational degrees of freedom at single C-C and C-N bonds. The later become restricted upon the formation of the secondary structures stabilized by multiple hydrogen bonds. The fragments of 1,3-, 1,4-, 1,5- and 1,6-diamines are found in peptides containing aspargine, glutamine, tryptophane, histidine, lysine and arginine. Apparently some structural, conformational and functional features of peptides can be reproduced by designed derivatives of synthetic conformationally restrained diamines.

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Functionalised Sulfonyl halides – Linkers

This issue of Enamine Product Focus introduces a family of functionalized building blocks called linkers. The term “linker” has been used in medicinal chemistry to define different substances. To avoid ambiguity we will use here the following meaning: a compound is viewed as a linker if it has two or more chemically orthogonal functionalities on an inert, flexible or rigid scaffold. Functional groups could be used to connect (or “link”) fragments responsible for the interaction with biological target – this is applicable both for HTS libraries design and in Fragment-Based Drug Discovery (FBDD). For the latter approach to drug discovery, the design of linkers is particularly critical.

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Amino acids selection

Amino acids are the building blocks which are widespread in the Nature. Even of the limited number of the genetically-coded α-amino acids the Nature composes practically unlimited number of proteins. The “success” of proteins in sustaining life and regulating biochemical processes prompted chemists over the world to mimic their structure and function in search for new drug candidates – peptidomimetics. It is therefore not surprising that the selection of the natural proteinogenic amino acids was substantially enriched by creating new, unnatural amino acids, specially designed to improve pharmacokinetic and pharmacodynamic properties of the peptidomimetics and other biologically active compounds based on them.

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Conformationally rigid amino acids

"The α-amino acids, molecules of which have restricted conformational flexibility, are widely used in design of peptidomimetics, peptide models, and in systematic search for biologically active compounds. Among these amino acids, a distinct class of compounds can be highlighted, namely - conformationally rigid amino acids (CRA). Certain torsion angles, which describe the conformation of a polypeptide chain at the CRA, are "fixed" that allows predicting and controlling it to some extent. Many structural studies show that the CRA residues can dictate certain conformation of the peptide chain around them, consequently, they can stabilize or destabilize certain peptide secondary structure elements.

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