Product Focus

Bifunctional building blocks are of special interest for drug design and organic synthesis due to three reasons, at least. First, these compounds can be used to tether two molecular fragments responsible for binding to the biological target, thus they can act as linkers. Second, if one functional group is not engaged in connection between the core of building block and the rest of a molecule being constructed, then it can participate in important interaction with a biological target. Finally, many bifunctional building blocks can undergo cyclization reactions, allowing rapid advance toward prospective heterocyclic units.

This issue of Enamine Product Focus represents a family of Building Blocks possessing sulfone moiety as a part of a cyclic unit. All the building blocks processing cyclic sulfone moiety have some common features that make the design of potential drug candidates particularly efficient.

A concept of bioisosterism has attracted much attention in recent years. The success of this strategy in developing new substances which are therapeutically attractive has observed a significant growth in distinct therapeutic classes, being amply used to discover new analogs of commercially attractive therapeutic innovations, and also as a tool useful in the molecular modification.

A lead compound with a desired pharmacological activity may have undesirable characteristics that limit its bioavailability, or structural features which adversely influence its metabolism and excretion from the body. Bioisosterism represents one of the approaches used by the medicinal chemists for rational modification of lead compounds into safer and more clinically effective agents.

This issue of Enamine Product Focus represents a family of Building Blocks containing Hydrazine unit. Several aspects of utilizing the hydrazine building blocks for the design of potential drug candidates can be outlined. Despite hydrazines themselves are rarely thought as promising drug candidates, some successful examples of drugs possessing hydrazine moiety can be found, e. g. antiparkinsonic agent Carbidopa (Lodosyn®), antidepressant Phenelzine (Nardil®) or vasodilator Hydralazine (Apresoline®).

The synthesis of functional organic compounds for different applications largely relies on laborious approaches involving an extensive usage of protecting groups. Nowadays chemoselective routes to the construction of complex molecules are becoming a good alternative because they shorten the length of multistep syntheses by excluding protecting groups and, as a consequence, lead to increased overall yields.

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.

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.

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.

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.

"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.

Recently 3-amino-tetrahydrothiophen-1,1-dioxides have drawn significant attention of a major drug developers. A few publications have been released earlier, corroborating rather high potential of this pharmacophoric moiety.

In the last decade, development of new drugs increasingly requires the use of chiral building blocks for hit-to-lead optimization, and even on early stages - in search for efficient hit compounds. The main fundamental reason for this lies in the fact that almost all the biological targets are chiral, and the drug-receptor interaction requires strict match of chirality. The formal reason results from strengthening the regulatory guidance for submitting new drug applications in Europe and USA which concern chirality issues.

We synthesize chiral ligands for metal-based catalysts used in asymmetric synthesis:

• Chiral chelating diphosphines, phosphine-phosphinites, both known and specially designed for your purpose. These ligands are used in Rhodium or Ruthenium complexes capable to catalyse asymmetric hydrogenation of prochiral C=C and C=O bonds, hydrosilylation, hydroformylation (see, for example: Asymmetric Synthesis, (Ed.: J. D. Morrison), Academic Press, Orlando, 1985; R. Noyori, Asymmetric Catalysis in Organic Synthesis, Wiley, New York, 1994; Comprehensive Asymmetric Catalysis, (Eds.: E. N. Jacobsen, A. Pfaltz, H. Yamamoto), Springer, Heidelberg, 1999, Vol. I-III. Catalytic Asymmetric Synthesis, (Ed.: I. Ojima), Wiley-VCH, New York, 2000).

Enamine Company would like to present new Building Blocks containing CONH₂ or NHCONH₂ groups in side chains. These compounds also bear other functional groups allowing easy transformations to desired screening compounds with primary amide and ureide moieties.

Quite often hydrogen bonding interaction of a ligand amide group with a protein has its functional consequences. To a great extend protein - ligand binding occurs via hydrogen bonding. In the search for new hits and leads it is very important in combinatorial synthesis to use the least possible number of synthetic steps. Reactions of sulfonic acid chlorides are well studied and quite often used in nucleophilic substitution reaction.

Current reagent is an effective and facile generator of difluorocarbene. Phenyl(trifluoromethyl)mercury is a stable, crystalline solid which releases CF₂ under mild, nonbasic reaction conditions. The compound is hydrolytically stable and can be handled under standard laboratory conditions. The reaction of PhHgCF₃ and 3 molar equiv of anhydrous sodium iodide in benzene medium in the presence of olefins serves excellently in the synthesis of gem-difluorocyclopropanes. High products yields could be obtained in reaction times of about 15hr at 80-85°C.

Piperazines are essential elements in drug design. Currently MDL© Drug Data Report database contains over 11 800 structures bearing the piperazine moiety. Enamine would like to present our set of exclusive "small" piperazines - compounds with low molecular weight (below 190 Da).