Protein domain-based prediction of drug/compound-target interactions and experimental validation on LIM kinases.

Predictive approaches such as virtual screening have been used in drug discovery with the objective of reducing developmental time and costs. Current machine learning and network-based approaches have issues related to generalization, usability, or model interpretability, especially due to the complexity of target proteins' structure/function, and bias in system training datasets. Here, we propose a new method "DRUIDom" (DRUg Interacting Domain prediction) to identify bio-interactions between drug candidate compounds and targets by utilizing the domain modularity of proteins, to overcome problems associated with current approaches. DRUIDom is composed of two methodological steps. First, ligands/compounds are statistically mapped to structural domains of their target proteins, with the aim of identifying their interactions. As such, other proteins containing the same mapped domain or domain pair become new candidate targets for the corresponding compounds. Next, a million-scale dataset of small molecule compounds, including those mapped to domains in the previous step, are clustered based on their molecular similarities, and their domain associations are propagated to other compounds within the same clusters. Experimentally verified bioactivity data points, obtained from public databases, are meticulously filtered to construct datasets of active/interacting and inactive/non-interacting drug/compound-target pairs (~2.9M data points), and used as training data for calculating parameters of compound-domain mappings, which led to 27,032 high-confidence associations between 250 domains and 8,165 compounds, and a finalized output of ~5 million new compound-protein interactions. DRUIDom is experimentally validated by syntheses and bioactivity analyses of compounds predicted to target LIM-kinase proteins, which play critical roles in the regulation of cell motility, cell cycle progression, and differentiation through actin filament dynamics. We showed that LIMK-inhibitor-2 and its derivatives significantly block the cancer cell migration through inhibition of LIMK phosphorylation and the downstream protein cofilin. One of the derivative compounds (LIMKi-2d) was identified as a promising candidate due to its action on resistant Mahlavu liver cancer cells. The results demonstrated that DRUIDom can be exploited to identify drug candidate compounds for intended targets and to predict new target proteins based on the defined compound-domain relationships. Datasets, results, and the source code of DRUIDom are fully-available at: https://github.com/cansyl/DRUIDom.

Synthesis of 7-Chloroquinoline Derivatives Using Mixed Lithium-Magnesium Reagents.

We have prepared a library of functionalized quinolines through the magnesiation of 7-chloroquinolines under mild conditions, employing both batch and continuous flow conditions. The preparation involved the generation of mixed lithium-magnesium intermediates, which were reacted with different electrophiles. Mixed lithium-zinc reagents allowed the synthesis of halogenated and arylated derivatives. Some of the synthesized 4-carbinol quinolines have shown interesting antiproliferative properties, their hydroxyl group being a suitable amino group bioisostere. We also report a two-step approach for optically active derivatives.

A comprehensive review of flow chemistry techniques tailored to the flavours and fragrances industries.

Due to their intrinsic physical properties, which includes being able to perform as volatile liquids at room and biological temperatures, fragrance ingredients/intermediates make ideal candidates for continuous-flow manufacturing. This review highlights the potential crossover between a multibillion dollar industry and the flourishing sub-field of flow chemistry evolving within the discipline of organic synthesis. This is illustrated through selected examples of industrially important transformations specific to the fragrances and flavours industry and by highlighting the advantages of conducting these transformations by using a flow approach. This review is designed to be a compendium of techniques and apparatus already published in the chemical and engineering literature which would constitute a known solution or inspiration for commonly encountered procedures in the manufacture of fragrance and flavour chemicals.

Rearrangement of 3-Hydroxyazetidines into 2-Oxazolines.

A novel rearrangement sequence of 3-hydroxyazetidines via a Ritter initiated cascade provides highly substituted 2-oxazolines in high yields. The reaction conditions and substrate scope of the transformation have been studied demonstrating the generality of the process. The derived products can also be functionalized in order to undergo further intramolecular cyclization leading to a new class of macrocycle. The final cyclization step was shown to be a transformation amenable to continuous flow processing allowing for a dramatic reduction in the reaction time and simple scale-up.

A One-Pot Divergent Sequence to Pyrazole and Quinoline Derivatives.

The hydroxy-pyrazole and 3-hydroxy-oxindole motifs have been utilised in several pharma and agrochemical leads but are distinctly underrepresented in the scientific literature due to the limited routes of preparation. We have developed a one-pot procedure for their synthesis starting from simple isatins. The method employs cheap and easy-to-handle building blocks and allows easy isolation.

Copper-Mediated Nitrosation: 2-Nitrosophenolato Complexes and Their Use in the Synthesis of Heterocycles.

A simple protocol yielding ortho-substituted nitrosophenols from phenols is demonstrated, in the form of copper(II) bis(nitrosophenolato) complexes. The developed methodology was applied to a range of substrates, confirming the role of the copper in both the formation and protection of the challenging 1, 2-substitution pattern. Using polymer supported thiourea, the Cu could be stripped from the complexes and thus enabled the isolation or identification of the uncoordinated ligands and their decomposition products, in yields generally low in line with the intrinsic high reactivity of 2-nitrosophenols. The product complexes are useful intermediates as demonstrated in revisiting a formal [4 + 2] cycloaddition with dimethylacetylene dicarboxylate to synthesise bicyclic products in variable yields, revealing the product has a novel structure different from those previously reported in the literature.

The Synthesis and Utility of Metal-Nitrosophenolato Compounds-Highlighting the Baudisch Reaction.

The syntheses of the title compounds demonstrate a privileged introduction of a nitroso (and a hydroxyl via the Baudisch reaction) group to an aromatic ring. These complexes first appeared in the literature as early as 1939, and a range of applications has subsequently been published. However, optimisations of the preparative sequences were not considered, and as such, the reactions have seldom been utilised in recent years; indeed, there remains confusion in the literature as to how such complexes form. In this review, we aim to demystify the misunderstanding surrounding these remarkable complexes and consider their renewed application in the 21st century.

Flow Hydrodediazoniation of Aromatic Heterocycles.

Continuous flow processing was applied for the rapid replacement of an aromatic amino group with a hydride. The approach was applied to a range of aromatic heterocycles, confirming the wide scope and substituent-tolerance of the processes. Flow equipment was utilized and the process optimised to overcome the problematically-unstable intermediates that have restricted yields in previous studies relying on batch procedures. Various common organic solvents were investigated as potential hydride sources. The approach has allowed key structures, such as amino-pyrazoles and aminopyridines, to be deaminated in good yield using a purely organic-soluble system.

Indium- and Zinc-Mediated Acyloxyallylation of Protected and Unprotected Aldotetroses-Revealing a Pronounced Diastereodivergence and a Fundamental Difference in the Performance of the Mediating Metal.

The acyloxyallylation of unprotected aldoses was first demonstrated more than a decade ago as a potentially elegant two-carbon homologation of reducing sugars (upon ozonolysis); however, its application in real case syntheses remained scarce. Following up on such a successful showcase and to answer several pending questions about this attractive transformation, we engaged in an in depth methodological reinvestigation. The epimeric tetroses l-erythrose and d-threose in unprotected and protected form were successfully applied to the indium and also zinc-mediated acyloxyallylation, with the latter being a first for an unprotected sugar. The investigation largely benefited from the choice of these more exotic starting materials as it allowed unambiguous identification/quantification of the hexose-products which are available as authentic reference materials. The observed diastereoselectivities indicate a strong substrate control (stereochemistry at O2), and the influence of the reagent's structure on the selectivity was investigated in great detail. A strong facial diastereodivergence between related protected and unprotected structures was demonstrated and an unexpected, pronounced principle difference in performance between indium and zinc was revealed.

A continuous flow synthesis and derivatization of 1,2,4-thiadiazoles.

A continuous flow process is presented that enables the efficient synthesis and derivatization of 1,2,4-thiadiazole heterocycles. Special attention was given to the safe handling of the versatile yet hazardous trichloromethane sulfenylchloride reagent including its in-line quenching in order to eliminate malodourous and corrosive by-products. Based on this flow method gram quantities of 5-chloro-3-phenyl-1,2,4-thiadiazole were safely prepared allowing for further elaboration of this valuable building block by reaction with different nitrogen-, sulfur- and oxygen-based nucleophiles. This synthetic approach was subsequently applied to generate a series of bromophenyl-5-chloro-1,2,4-thiadiazoles providing a valuable entry towards further structural diversification on this important heterocyclic scaffold.

A concise flow synthesis of indole-3-carboxylic ester and its derivatisation to an auxin mimic.

An assembled suite of flow-based transformations have been used to rapidly scale-up the production of a novel auxin mimic-based herbicide which was required for preliminary field trials. The overall synthetic approach and optimisation studies are described along with a full description of the final reactor configurations employed for the synthesis as well as the downstream processing of the reaction streams.

Diastereoselective Trifluoroacetylation of Highly Substituted Pyrrolidines by a Dakin-West Process.

A robust approach allowing for the efficient trifluoroacetylation of a series of highly substituted pyrrolidines in a diastereoselective manner is reported. The transformation is based on a Dakin-West reaction of advanced pyrrolidine 2-carboxylic acid derivatives that can be assembled stereoselectively in four synthetic steps. Importantly, this work demonstrates how the introduction of lateral substituents on the pyrrolidine scaffold enables the generation of the desired trifluoroacetylation products, which was not possible previously due to the exclusive formation of trifluoromethylated oxazoles (vide infra). In the course of this work we succeeded for the first time in isolating and characterizing (HRMS, IR, 1H, 13C and 19F NMR, X-ray) different intermediates of the Dakin-West reaction allowing us to probe its mechanism.

Exploring Flow Procedures for Diazonium Formation.

The synthesis of diazonium salts is historically an important transformation extensively utilized in dye manufacture. However the highly reactive nature of the diazonium functionality has additionally led to the development of many new reactions including several carbon-carbon bond forming processes. It is therefore highly desirable to determine optimum conditions for the formation of diazonium compounds utilizing the latest processing tools such as flow chemistry to take advantage of the increased safety and continuous manufacturing capabilities. Herein we report a series of flow-based procedures to prepare diazonium salts for subsequent in-situ consumption.

Flow carbonylation of sterically hindered ortho-substituted iodoarenes.

The flow synthesis of ortho-substituted carboxylic acids, using carbon monoxide gas, has been studied for a number of substrates. The optimised conditions make use of a simple catalyst system compromising of triphenylphosphine as the ligand and palladium acetate as the pre-catalyst. Carbon monoxide was introduced via a reverse "tube-in-tube" flow reactor at elevated pressures to give yields of carboxylated products that are much higher than those obtained under normal batch conditions.

Catalytic Chan-Lam coupling using a 'tube-in-tube' reactor to deliver molecular oxygen as an oxidant.

A flow system to perform Chan-Lam coupling reactions of various amines and arylboronic acids has been realised employing molecular oxygen as an oxidant for the re-oxidation of the copper catalyst enabling a catalytic process. A tube-in-tube gas reactor has been used to simplify the delivery of the oxygen accelerating the optimisation phase and allowing easy access to elevated pressures. A small exemplification library of heteroaromatic products has been prepared and the process has been shown to be robust over extended reaction times.

Batch and Flow Synthesis of Pyrrolo[1,2-a]-quinolines via an Allene-Based Reaction Cascade.

An efficient reaction cascade delivering a series of pyrrolo[1,2-a]quinolines bearing phosphonate or phosphine oxide moieties is presented. This sequence exploits the in situ transformation of propargylic alcohols into transient allenes by means of a strategic [2,3]-sigmatropic rearrangement followed by trapping of the resulting allenes by an adjacent pyrrole ring. Furthermore, the initial small scale batch process was successfully translated into a continuous flow process allowing efficient preparation of selected pyrrolo[1,2-a]quinolines on multigram scale without any safety concerns due to the reaction's inherent exothermic profile.

Synthesis of 1,3,6-Trisubstituted Azulenes.

We have developed a short, general synthetic route to 1,3,6-trisubstituted azulenes. The key intermediate, 6-methylazulene, was synthesized from readily available and inexpensive starting materials in 63% yield over two steps. The methyl group of 6-methylazulene was then used as a synthetic handle to introduce different substituents at the 6-position via two different methods. Subsequently, the 1- and 3-positions were substituted with additional functional handles, such as formyl, chloromethylketone, and iodide. The efficiency of the synthetic route was demonstrated by preparing a collection of three different products with the best demonstrated yield 33% over seven steps.

Total syntheses of natural products containing spirocarbocycles.

The structures of natural products from a variety of sources contain spirocycles, two rings that share a common atom. The spiro motif is finding increasing inclusion in drug candidates, and as a structural component in several promising classes of chiral ligands used in asymmetric synthesis. Total syntheses of products containing all-carbon spirocycles feature several common methods of ring closure which we examine in this review.

A monolith immobilised iridium Cp* catalyst for hydrogen transfer reactions under flow conditions.

An immobilised iridium hydrogen transfer catalyst has been developed for use in flow based processing by incorporation of a ligand into a porous polymeric monolithic flow reactor. The monolithic construct has been used for several redox reductions demonstrating excellent recyclability, good turnover numbers and high chemical stability giving negligible metal leaching over extended periods of use.

Flow synthesis of ethyl isocyanoacetate enabling the telescoped synthesis of 1,2,4-triazoles and pyrrolo-[1,2-c]pyrimidines.

The efficient flow synthesis of important heterocyclic building blocks based on the 1,2,4-triazole and pyrrolo[1,2-c]pyrimidine scaffold has been achieved. Crucially, a telescoped continuous flow process was developed based on the reaction of N-formylglycine with triphosgene to deliver a stream of ethyl isocyanoacetate in situ, which subsequently yielded the desired heterocyclic entities in a telescoped reaction. Additionally, the functionalisation of the pyrrolo[1,2-c]pyrimidine core via subsequent SEAr reactions was studied revealing insight into a 'halogen dance' phenomenon associated with these medicinally relevant architectures.