MicroCycle: An Integrated and Automated Platform to Accelerate Drug Discovery.

We herein describe the development and application of a modular technology platform which incorporates recent advances in plate-based microscale chemistry, automated purification, in situ quantification, and robotic liquid handling to enable rapid access to high-quality chemical matter already formatted for assays. In using microscale chemistry and thus consuming minimal chemical matter, the platform is not only efficient but also follows green chemistry principles. By reorienting existing high-throughput assay technology, the platform can generate a full package of relevant data on each set of compounds in every learning cycle. The multiparameter exploration of chemical and property space is hereby driven by active learning models. The enhanced compound optimization process is generating knowledge for drug discovery projects in a time frame never before possible.

Which boronic acids are used most frequently for synthesis of bioactive molecules?

Boronic acids are essential building blocks used for the synthesis of bioactive molecules, the generation of chemical libraries and the exploration of structure-activity relationships. As a result, more than ten thousand boronic acids are commercially available. Medicinal chemists are therefore facing a challenge; which of them should they select to maximize information obtained by the synthesis of new target molecules. The present article aims to help them to make the right choices. The boronic acids used frequently in the synthesis of bioactive molecules were identified by mining several large molecular and reaction databases and their properties were analyzed. Based on the results a diverse set of boronic acids covering well the bioactive chemical space was selected and is suggested as a basis for library design for the efficient exploration of structure-activity relationships. A Boronic Acid Navigator web tool which helps chemists to make their own selection is also made available at https://bit.ly/boronics.

The most common linkers in bioactive molecules and their bioisosteric replacement network.

Structures of the large majority of bioactive molecules are composed of several rings that are decorated by substituents and connected by linkers. While numerous cheminformatics studies focusing on rings and substituents are available, practically nothing has been published about the third important structural constituent of bioactive molecules - the linkers. The current study attempts to fill this gap. The most common linkers present in bioactive molecules are identified, their properties analyzed and a method for linker similarity search introduced. The bioisosteric replacement network of linkers is generated based on a large corpus of structure-activity data from medicinal chemistry literature. The results are presented in a graphical form and the underlying data are also made available for download. This analysis is intended to help medicinal chemists to better understand the role of linkers, particularly heterocyclic rings in bioactive molecules and to select an optimal set of linkers in their future project.

Ring replacement recommender: Ring modifications for improving biological activity.

Analysis of structure-activity data from a large corpus of medicinal chemistry literature identified a set of ring replacements that have a significant chance of improved biological activity. A database of these replacements for 245 common heterocyclic rings is provided. Based on the analysis of the whole data set, 80 diverse substituted rings are suggested for use in an early stage of hit optimization and in the design of focused libraries with the goal to explore structure-activity relationships and quickly improve the biological activity of the explored series. An easy to use Ring Replacement Recommender web tool, allowing medicinal chemists to interactively explore the recommended ring substitutions, is available at https://bit.ly/ringreplacement.

Chemoenzymatic conversion of amides to enantioenriched alcohols in aqueous medium.

One-pot reactions that combine non-enzymatic and biocatalytic transformations represent an emerging strategy in chemical synthesis. Some of the most powerful chemoenzymatic methodologies, although uncommon, are those that form a carbon-carbon (C-C) bond and a stereocenter at one of the reacting carbons, thereby streamlining traditional retrosynthetic disconnections. Here we report the one-pot, chemoenzymatic conversion of amides to enantioenriched alcohols. This transformation combines a nickel-catalyzed Suzuki-Miyaura coupling of amides in aqueous medium with an asymmetric, biocatalytic reduction to provide diarylmethanol derivatives in high yields and enantiomeric excesses. The synthetic utility of this platform is underscored by the formal syntheses of both antipodes of the pharmaceutical orphenadrine, which rely on ketoreductase enzymes that instill complementary stereoselectivities. We provide an explanation for the origins of stereoselectivity based on an analysis of the enzyme binding pockets.

Mizoroki-Heck Cyclizations of Amide Derivatives for the Introduction of Quaternary Centers.

We report non-decarbonylative Mizoroki-Heck reactions of amide derivatives. The transformation relies on the use of nickel catalysis and proceeds using sterically hindered tri- and tetrasubstituted olefins to give products containing quaternary centers. The resulting polycyclic or spirocyclic products can be obtained in good yields. Moreover, a diastereoselective variant of this method gives access to an adduct bearing vicinal, highly substituted sp3 stereocenters. These results demonstrate that amide derivatives can be used as building blocks for the assembly of complex scaffolds.

Divergent Reactivity of Thioalkynes in Lewis Acid Catalyzed Annulations with Donor-Acceptor Cyclopropanes.

Efficient methods for the convergent synthesis of (poly)cyclic scaffolds are urgently needed in synthetic and medicinal chemistry. Herein, we describe new annulation reactions of thioalkynes with phthalimide-substituted donor-acceptor cyclopropanes, which gave access to highly substituted cyclopentenes and polycyclic ring systems. With silyl-thioalkynes, the Lewis acid catalyzed [3+2] annulation reaction with donor-acceptor cyclopropanes took place to afford 1-thio-cyclopenten-3-amines. On the other hand, an unprecedented polycyclic compound was formed with alkyl-thioalkynes through a reaction pathway directly involving the phthalimide group. The two transformations proceeded in good yields and tolerated a large variety of functional groups.

1-Alkynyltriazenes as Functional Analogues of Ynamides.

The chemical reactivity of 1-alkynyltriazenes has been investigated and is found to parallel the reactivity of ynamides. The similarity in reactivity of these two classes of compounds is demonstrated by addition reactions with acids, by cycloaddition reactions with ketenes, tetracyanoethene, and cyclopropanes, as well as by intramolecular cyclization reactions. The presence of reactive triazene groups in the products enables subsequent transformations. Overall, our results suggest that 1-alkynyltriazenes should become valuable reagents in synthetic organic chemistry.

[4 + 2]-Annulations of aminocyclobutanes.

The first [4 + 2]-annulation between aminocyclobutanes and aldehydes to access tetrahydropyranyl amines is reported. With phthalimido cyclobutane dicarboxylates and aromatic aldehydes, tetrahydropyrans were obtained in 53-92% yield and 3:1-17:1 dr using scandium triflate or iron trichloride as catalyst. The use of thymine- or fluorouracil-substituted cyclobutanes gave direct access to six-membered ring nucleoside analogues. Finally, the [4 + 2]-annulation between aminocyclobutanes and enol ethers led to the corresponding cyclohexylamines.

Taming hypervalent bonds and strained rings for catalysis and synthesis.

Improving the synthesis of complex organic molecules is essential for progress in many fields such as medicine, agrochemicals or materials. Since 2007, our laboratory has been focusing on the development of non-classical bond disconnections based on the use of small, energy-loaded organic molecules: hypervalent iodine reagents and strained rings. In this overview article, we report our progress since 2011 in these areas. The use of cyclic hypervalent iodine reagents has been extended to the C2-selective alkynylation of indoles, the domino cyclization alkynylation of allenes, the alkynylation of thiols and the azidation of carbonyl compounds. Amino-substituted aminocyclopropanes and aminocyclobutanes were used in [3+2] and [4+2] annulations to access nitrogen-rich building blocks, including nucleoside analogues. The first example of dynamic kinetic [3+2] annulation of aminocyclopropanes with both enol ethers and aldehydes was also reported.

Synthesis of (carbo)nucleoside analogues by [3+2] annulation of aminocyclopropanes.

(Carbo)nucleoside derivatives constitute an important class of pharmaceuticals, yet there are only few convergent methods to access new analogues. Here, we report the first synthesis of thymine-, uracil-, and 5-fluorouracil-substituted diester donor-acceptor cyclopropanes and their use in the indium- and tin-catalyzed [3+2] annulations with aldehydes, ketones, and enol ethers. The obtained diester products could be easily decarboxylated and reduced to the corresponding alcohols. The method gives access to a broad range of new (carbo)nucleoside analogues in only four or five steps and will be highly useful for the synthesis of libraries of bioactive compounds.

Novel in vivo active anti-malarials based on a hydroxy-ethyl-amine scaffold.

A novel series of anti-malarials, based on a hydroxy-ethyl-amine scaffold, initially identified as peptidomimetic protease inhibitors is described. Combination of the hydroxy-ethyl-amine anti-malarial phramacophore with the known Mannich base pharmacophore of amodiaquine (57) resulted in promising in vivo active novel derivatives.