Photocatalytic Radical Coupling of Organoborates with α-Halogenated Electron-Poor Olefins.

Herein, we report the visible-light-mediated addition of organoborates to α-halogenated electron-poor olefins enabled by an environmentally benign metal-free catalyst. The method accommodates a variety of boronic acid derivatives as well as alkenes and delivers the corresponding saturated α-halo-derivatives in up to 90% yields. The obtained products are high-value building blocks in organic synthesis, allowing for a variety of follow-up transformations.

The 115 Year Old Multicomponent Bargellini Reaction: Perspectives and New Applications.

Despite its uniqueness, the Bargellini multicomponent reaction remains barely known by the most part of chemists. This can be ascribed to the fact that this transformation has not been adequately reviewed in the classic books of named reactions in organic chemistry. Nevertheless, several works on this reaction have been carried out over the years, many of them were written in Italian in the period 1929-1966. In this review article we extensively cover, in a chronological order, the most important applications of the Bargellini reaction reported to date, with the hope that this knowledge-sharing will help chemists to properly use this multicomponent transformation and imagine novel reactivities based on it.

Synthesis, Docking and Biological Evaluation of a Novel Class of Imidazothiazoles as IDO1 Inhibitors.

IDO1, a key dioxygenase in tryptophan-kynurenine metabolism, appeared in the last 10 years at the vanguard of druggable targets in cancer therapy due to its well-established role both in immune escape and inflammatory neovascularization. Among the pool of IDO1 inhibitors that have entered clinical trials, none have reached approval. The identification of novel inhibitors endowed with better clinical profile, together with the further comprehension of the interactions with residues in IDO1 active site, are still a need. In this context, we have synthesized a novel class of imidazothiazole derivatives as IDO1 inhibitors and identified three compounds with inhibitory potency in the low micromolar range. This report strengthens the role played by pocket C in the active site of IDO1, providing novel directions in the design of IDO1 inhibitors.

A multicomponent approach in the discovery of indoleamine 2,3-dioxygenase 1 inhibitors: Synthesis, biological investigation and docking studies.

Indoleamine 2,3-dioxygenase plays a crucial role in immune tolerance and has emerged as an attractive target for cancer immunotherapy. In this study, the Passerini and Ugi multicomponent reactions have been employed to assemble a small library of imidazothiazoles that target IDO1. While the p-bromophenyl and the imidazothiazole moieties have been kept fixed, a full SAR study has been performed on the side-chain, leading to the discovery of nine compounds with sub-micromolar IC50 values in the enzyme-based assay. Compound 7d, displaying a α-acyloxyamide substructure, is the most potent compound, with an IC50 value of 0.20 µM, but a low activity in a cell-based assay. Compound 6o, containing a α-acylaminoamide moiety, shows an IC50 value of 0.81 µM in the IDO1-based assay, a full biocompatibility at 10 µM, together with a modest inhibitory activity in A375 cells. Molecular docking studies show that both 7d and 6o display a unique binding mode in the IDO1 active site, with the side-chain protruding in an additional pocket C, where a crucial hydrogen bond is formed with Lys238. Overall, this work describes an isocyanide based-multicomponent approach as a straightforward and versatile tool to rapidly access IDO1 inhibitors, providing a new direction for their future design and development.

Arynes and isocyanides: Two close-knit partners in multicomponent reactions.

Despite benzyne has been known since 1940, this fascinating species has received much attention only over the last decades. The renaissance of interest in aryne chemistry is ascribable to the seminal discovery that arynes can be generated in situ from stable and commercially available precursors under mild and neutral conditions. Thanks to their high reactivity, arynes are key intermediates in countless chemical transformations ranging from cycloadditions to insertions and, among all these approaches, multicomponent reactions (MCRs) are currently standing out in this field. In particular, this short article is focused on MCRs involving the concomitant use of benzyne and isocyanides. Furthermore, the first overview on aryne MCRs triggered by α-isocyanoacetamides is presented.

An aryne-based three-component access to α-aroylamino amides.

Aryne chemistry has recently received widespread attention and isocyanides have been reported as efficient nucleophilic partners in a set of multicomponent transformations. In this study, we demonstrate that tertiary α-monosubstituted α-isocyanoacetamides are efficaciously coupled with water and benzyne to offer a direct and metal-free access to densely functionalized α-benzoylamino amides, without competing with the intramolecular cyclization to 5-aminooxazoles. Despite the formation of the aryl anion as a key intermediate, the reaction displays a stereoconservative course, allowing for the preparation of enantiomerically pure α-benzoylamino amides. Finally, the synthetic utility of the reported MCR was exemplified by the preparation of proglumide, a cholecystokinin antagonist.

The multicomponent Passerini reaction as a means of accessing diversity in structure, activity and properties: Soft and hard vanilloid/cannabinoid modulators.

A growing body of evidence points to the existence of a crosstalk between the endovanilloid (EV)- and the endocannabinoid (EC) systems, leading to the concept of a single system based on a shared set of endogenous ligands and regulation mechanisms. The EV/EC system encompasses the ion channel TRPV1, the G protein coupled receptors CB1 and CB2, their endogenous ligands and the enzymes for biosynthesis and inactivation. Disorders in which the EV/EC interaction is involved are inflammation, pain, neurodegenerative diseases and disorders of bones and skin. In the present paper, with the aim of targeting the EV/EC system, the Passerini reaction is used in a diversity-oriented approach to generate a series of α-acyloxycarboxamides bearing different substructures that resemble endogenous ligands. Compounds have been screened for activity on TRPV1, CB1 and CB2 and metabolic stability in skin cells, liver subcellular fractions and plasma. This protocol allowed to generate agents characterized by a diverse activity on TRPV1, CB1 and CB2, as well as heterogeneous metabolic stability that could allow different routes of administration, from soft drugs for topical treatment of skin diseases to hard drugs for systemic use in inflammation and pain. Compared to natural mediators, these compounds have a better drug-likeness. Among them, 41 stands out as an agonist endowed with a well-balanced activity on both TRPV1 and CB2, high selectivity over TRPM8, TRPA1 and CB1, metabolic stability and synthetic accessibility.

Identification of a Compound Inhibiting Both the Enzymatic and Nonenzymatic Functions of Indoleamine 2,3-Dioxygenase 1.

Indoleamine 2,3-dioxygenase 1 (IDO1) plays a key role in tumor immune escape. Besides being a metabolic enzyme that catalyzes the first step of tryptophan catabolism, it also acts as a signal-transducing protein, whose partnering with tyrosine phosphatase Src homology 2 (SH2) domain-containing protein tyrosine phosphatase substrate (SHPs) and phosphatidylinositol-3-kinase (PI3K) regulatory subunit p85 promotes the establishment of a sustained immunosuppressive phenotype. While IDO1 inhibitors typically interfere with its enzymatic activity, we aimed to discover a more effective modulator capable of blocking not only the enzymatic but also the signaling-mediated functions of IDO1. By virtual screening, we identified the compound VS-15, which selectively binds the heme-free form of IDO1, inhibits its enzymatic activity, and reduces the IDO1-mediated signaling pathway by negatively interfering with its partnership with SHPs and PI3K regulatory subunit p85 as well as with the IDO1 anchoring to the early endosomes in tumor cells. Moreover, VS-15 counteracts the TGF-ß-mediated immunosuppressive phenotype in dendritic cells and reduces the level of inhibition of T cell proliferation by suppressive monocytes isolated from patients affected by pancreatic cancer. Herein, we describe the discovery and characterization of a small molecule with an unprecedented mechanism of action, capable of inhibiting both the enzymatic and nonenzymatic activities of IDO1 by binding to its apo-form. These results pave the way for the development of next-generation IDO1 inhibitors with a unique competitive advantage over the currently available modulators, thereby opening therapeutic opportunities in cancer immunotherapy.

Deuterium in drug discovery: progress, opportunities and challenges.

Substitution of a hydrogen atom with its heavy isotope deuterium entails the addition of one neutron to a molecule. Despite being a subtle change, this structural modification, known as deuteration, may improve the pharmacokinetic and/or toxicity profile of drugs, potentially translating into improvements in efficacy and safety compared with the non-deuterated counterparts. Initially, efforts to exploit this potential primarily led to the development of deuterated analogues of marketed drugs through a 'deuterium switch' approach, such as deutetrabenazine, which became the first deuterated drug to receive FDA approval in 2017. In the past few years, the focus has shifted to applying deuteration in novel drug discovery, and the FDA approved the pioneering de novo deuterated drug deucravacitinib in 2022. In this Review, we highlight key milestones in the field of deuteration in drug discovery and development, emphasizing recent and instructive medicinal chemistry programmes and discussing the opportunities and hurdles for drug developers, as well as the questions that remain to be addressed.

Correction to "An Unexpected Deuterium-Induced Metabolic Switch in Doxophylline".

[This corrects the article DOI: 10.1021/acsmedchemlett.2c00166.].

First-in-Class Dual Hybrid Carbonic Anhydrase Inhibitors and Transient Receptor Potential Vanilloid 1 Agonists Revert Oxaliplatin-Induced Neuropathy.

Here, we report for the first time a series of compounds potentially useful for the management of oxaliplatin-induced neuropathy (OINP) able to modulate the human Carbonic Anhydrases (hCAs) as well as the Transient Receptor Potential Vanilloid 1 (TRPV1). All compounds showed effective in vitro inhibition activity toward the main hCAs involved in such a pathology, whereas selected items reported moderate agonism of TRPV1. X-ray crystallographic experiments assessed the binding modes of the two enantiomers (R)-37a and (S)-37b within the hCA II cleft. Although the tails assumed diverse orientations, no appreciable effects were observed for their hCA II affinity. Similarly, the activity of (R)-39a and (S)-39b on TRPV1 was not influenced by the stereocenters. In vivo evaluation of the most promising derivatives (R)-12a, (R)-37a, and the two enantiomers (R)-39a, (S)-39b revealed antihypersensitivity effects in a mouse model of OINP with potent and persistent effect up to 75 min after administration.

An Unexpected Deuterium-Induced Metabolic Switch in Doxophylline.

Precision deuteration has become part of the medicinal chemist's toolbox, but its usefulness can be undermined by unpredictable metabolic switch effects. Herein we report the deuteration of doxophylline, a drug used in the treatment of asthma and COPD that undergoes extensive oxidative metabolism. Labeling of the main metabolic soft spots triggered an unexpected multidirectional metabolic switch that, while not improving the pharmacokinetic parameters, changed the metabolic scenario and, in turn, the pharmacodynamic features in two murine models of lung injury.

A Versatile and Sustainable Multicomponent Platform for the Synthesis of Protein Degraders: Proof-of-Concept Application to BRD4-Degrading PROTACs.

The use of small molecules to induce targeted protein degradation is increasingly growing in the drug discovery landscape, and protein degraders have progressed rapidly through the pipelines. Despite the advances made so far, their synthesis still represents a significant burden and new approaches are highly demanded. Herein we report an unprecedented platform that leverages the modular nature of both multicomponent reactions and degraders to enable the preparation of highly decorated PROTACs. As a proof of principle, our platform has been applied to the preparation of potential BRD4-degrading PROTACs, resulting in the discovery of a set of degraders endowed with high degradation efficiency. Compared to the existing methods, our approach offers a versatile and cost-effective means to access libraries of protein degraders and increase the chance of identifying successful candidates.

STIM1 and ORAI1 mutations leading to tubular aggregate myopathies are sensitive to the Store-operated Ca2+-entry modulators CIC-37 and CIC-39.

Gain-of-function mutations on STIM1 and ORAI1 genes are responsible for an increased store-operated calcium entry, and underlie the characteristic symptoms of three overlapping ultra-rare genetic disorders (i.e tubular aggregate myopathy, Stormorken syndrome, York platelet syndrome) that can be grouped as tubular aggregate myopathies. These mutations lead to a wide spectrum of defects, which usually include muscle weakness and cramps. Negative modulators of store-operated Ca2+-entry targeting wild-type STIM1 and ORAI1 have entered clinical trials for a different array of disorders, including pancreatitis, COVID-19, cancer, and autoimmune disorders and, while efficacy data is awaited, safety data indicates tolerability of this STIM1/ORAI1 mutations are amenable to pharmacological intervention. If this were so, given that there are no approved treatments or clinical trials ongoing for these rare disorders, it could be envisaged that these agents could also rehabilitate tubular aggregate myopathy patients. In the present contribution we characterized the Ca2+-entry patterns induced by eleven STIM1 and three ORAI1 mutations in heterologous systems or in patient-derived cells, i.e. fibroblasts and myotubes, and evaluated the effect of CIC-37 and CIC-39, two novel store-operated calcium entry modulators. Our data show that all STIM1 and ORAI1 gain-of-function mutations tested, with the possible exception of the R304Q STIM1 mutation, are amenable to inhibition, albeit with slightly different sensitivities, paving the way to the development of SOCE modulators in tubular aggregate myopathies.

CIC-39Na reverses the thrombocytopenia that characterizes tubular aggregate myopathy.

Store-operated Ca2+-entry is a cellular mechanism that governs the replenishment of intracellular stores of Ca2+ upon depletion caused by the opening of intracellular Ca2+-channels. Gain-of-function mutations of the 2 key proteins of store-operated Ca2+-entry, STIM1 and ORAI1, are associated with several ultra-rare diseases clustered as tubular aggregate myopathies. Our group has previously demonstrated that a mouse model bearing the STIM1 p.I115F mutation recapitulates the main features of the STIM1 gain-of-function disorders: muscle weakness and thrombocytopenia. Similar findings have been found in other mice bearing different mutations on STIM1. At present, no valid treatment is available for these patients. In the present contribution, we report that CIC-39Na, a store-operated Ca2+-entry inhibitor, restores platelet number and counteracts the abnormal bleeding that characterizes these mice. Subtle differences in thrombopoiesis were observed in STIM1 p.I115F mice, but the main difference between wild-type and STIM1 p.I115F mice was in platelet clearance and in the levels of platelet cytosolic basal Ca2+. Both were restored on treatment of animals with CIC-39Na. This finding paves the way to a pharmacological treatment strategy for thrombocytopenia in tubular aggregate myopathy patients.

Activation of TRPV4 channels reduces migration of immortalized neuroendocrine cells.

Calcium is a universal signal, and its capacity to encode intracellular messages via spatial, temporal and amplitude characteristics allows it to participate in most cellular events. In a specific context, calcium plays a pivotal role in migration, although its role has not been elucidated fully. By using immortalized gonadotropin-releasing hormone-secreting neurons (GN11), we have now investigated the role of TRPV4, a member of the vanilloid family of Ca(2+) channels, in neuronal migration. Our results show that TRPV4 channels are present and functional in GN11 cells and their localization is polarized and enriched in lamellipodial structures. TRPV4 activation leads to a retraction of the lamellipodia and to a decrease in migratory behaviour; moreover cells migrate slower and in a more random manner. We therefore provide evidence for a new regulation of gonadotropin-releasing hormone neurons and a new role for calcium at the leading edge of migratory cells.

Replacement of the double bond of antitubulin chalcones with triazoles and tetrazoles: Synthesis and biological evaluation.

In the chalcone scaffold, it is thought that the double bond is an important structural linker but it is likely not essential for the interaction with tubulin. Yet, it may be a potential site of metabolic degradation and interaction with biological nucleophiles. In this letter, we have replaced this olefinic portion of chalcones with two metabolically stable and chemically inert heterocyclic rings, namely triazole or tetrazole. Yet, our biologic data suggest that, unlike in other antitubulinic structures, the olephinic ring might not be merely a structural linker.

A novel α-isocyanoacetamide-based three-component reaction for the synthesis of dialkyl 2-acyl-5-aminofuran-3,4-dicarboxylates.

α-Isocyanoacetamides, acyl chlorides and dialkylacetylenedicarboxylates undergo a smooth multicomponent reaction to produce dialkyl 2-acyl-5-aminofuran-3,4-dicarboxylates in good yield. The scope and mechanism of this new multicomponent transformation are discussed.

Groebke multicomponent reaction and subsequent nucleophilic aromatic substitution for a convenient synthesis of 3,8-diaminoimidazo[1,2-a]pyrazines as potential kinase inhibitors.

In a program aimed at discovering novel protein kinase inhibitors, a convenient synthesis of 3,8-diaminoimidazo[1,2-a]pyrazines has been developed exploiting the isocyanide-based multicomponent Blackburn reaction, followed by a nucleophilic aromatic substitution with ammonia or primary and secondary amines. The potential of the reported scaffold is strengthened by the inhibition of STAT5-dependent transcription displayed by four of the synthesized compounds.

What's in a Name? Drug Nomenclature and Medicinal Chemistry Trends using INN Publications.

The World Health Organization assigns international nonproprietary names (INN), also known as common names, to compounds upon request from drug developers. Structures of INNs are publicly available and represent a source, albeit underused, to understand trends in drug research and development. Here, we explain how a common drug name is composed and analyze chemical entities from 2000 to 2021. In the analysis, we describe some changes that intertwine chemical structure, newer therapeutic targets (e.g., kinases), including a significant increase in the use of fluorine and of heterocycles, and some other evolutionary modifications, such as the progressive increase in molecular weight. Alongside these, small signs of change can be spotted, such as the rise in spirocyclic scaffolds and small rings and the emergence of unconventional structural moieties that might forecast the future to come.