Ethyl 5-(4-Bromophenyl)-4-methyl-1H-pyrrole-2-carboxylate

This note describes a sequence converting an oxime-substituted pyrrolidine into a trisubstituted pyrrole structure. The synthetic route is based on a double chlorination of the pyrrolidine substrate followed by the base induced formation of both an imine and a nitrile oxide functionality. The latter reacts with an immobilized thiourea to yield an isothiocyanate which upon elimination generates the final pyrrole in an unprecedented cascade of events

Continuous-Flow Hofmann Rearrangement Using Trichloroisocyanuric Acid for the Preparation of 2-Benzoxazolinone

A continuous-flow preparation of 2-benzoxazolinone via the Hofmann rearrangement of salicylamide has been implemented employing trichloroisocyanuric acid as the stable and atom-economic chlorinating agent. The system was optimized to avoid solid accumulation and allow the preparation of hundreds of grams of the pure desired material over a working day. Furthermore, a trichloroisocyanuric acid (TCCA)-based chlorination of 2-benzoxazolone to the corresponding 5-chloro derivative was also carried out under batch conditions

The rapid generation of isothiocyanates in flow

Isothiocyanates are versatile starting materials for a wide range of chemical reactions. However, their high nucleophilic susceptibility means they are best prepared and used immediately. We report here on a flow platform for the fast and efficient formation of isothiocyanates by the direct conversion of easily prepared chloroximes. To expedite this chemistry a flow insert cartridge containing two immobilised reagents is used to affect the chemical transformation which typically eliminates the requirements for any conventional work-up or purification of the reaction stream

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

A Robust and Scalable Continuous Flow Process for Glycerol Carbonate

We report a robust continuous flow procedure for the synthesis of glycerol carbonate (2‐GLC) from green reagents glycerol and dimethyl carbonate (DMC), mediated by an inexpensive polymer‐supported base catalyst using methanol as co‐solvent. High conversion and selectivity were obtained, while residence times were typically shorter than 10 minutes

Flow-Assisted Synthesis: A Key Fragment of SR 142948A

We report a series of multi-step flow operations to deliver an advanced hydrazine intermediate used in the assembly of the neurotensin modulator SR 142948A. Several new reactor configurations have enabled chemical transformations that would be otherwise difficult or dangerous to perform at scale. Overall the flow approach has allowed the preparation of kilogram quantities of the required hydrazine through a short and efficient route

Continuous flow based catch and release protocol for the synthesis of alpha-ketoesters

Using a combination of commercially available mesofluidic flow equipment and tubes packed with immobilised reagents and scavengers, a new synthesis of α-ketoesters is reported

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

Discovery of a Potent Dual Inhibitor of Aromatase and Aldosterone Synthase.

Estrogen deficiency derived from inhibition of estrogen biosynthesis is a typical condition of postmenopausal women and breast cancer (BCs) patients undergoing antihormone therapy. The ensuing increase in aldosterone levels is considered to be the major cause for cardiovascular diseases (CVDs) affecting these patients. Since estrogen biosynthesis is regulated by aromatase (CYP19A1), and aldosterone biosynthesis is modulated by aldosterone synthase (CYP11B2), a dual inhibitor would allow the treatment of BC while reducing the cardiovascular risks typical of these patients. Moreover, this strategy would help overcome some of the disadvantages often observed in single-target or combination therapies. Following an in-depth analysis of a library of synthesized benzylimidazole derivatives, compound was found to be a potent and selective dual inhibitor of aromatase and aldosterone synthase, with IC values of 2.3 and 29 nM, respectively. Remarkably, the compound showed high selectivity with respect to 11β-hydroxylase (CYP11B1), as well as CYP3A4 and CYP1A2. When tested in cells, showed potent antiproliferative activity against BC cell lines, particularly against the ER+ MCF-7 cells (IC of 0.26 ± 0.03 μM at 72 h), and a remarkable pro-apoptotic effect. In addition, the compound significantly inhibited mTOR phosphorylation at its IC concentration, thereby negatively modulating the PI3K/Akt/mTOR axis, which represents an escape for the dependency from ER signaling in BC cells. The compound was further investigated for cytotoxicity on normal cells and potential cardiotoxicity against ERG and Nav1.5 ion channels, demonstrating a safe biological profile. Overall, these assays demonstrated that the compound is potent and safe, thus constituting an excellent candidate for further evaluation. [Abstract copyright: © 2023 The Authors. Published by American Chemical Society.

A simple one-pot oxidation protocol for the synthesis of dehydrohedione from Hedione

A new method for the oxidation of Hedione 1 to dehydrohedione 2, a high value intermediate in the flavour and fragrance industry, has developed based upon one pot α-chlorination-elimination sequence which can be readily scaled. The spontaneous elimination of the α-chloro in methanol was unprecedented and has allowed for the oxidation, typically performed in multiple steps/reactions, to be carried out as a one-pot protocol. A continuous flow process for performing the reaction utilising sulfuryl chloride has also demonstrated allowing for steady, safe evolution of SO2 gas during the reaction