Structural Fusion of Natural and Synthetic Ligand Features Boosts RXR Agonist Potency.

The retinoid X receptors (RXRs) are ligand-activated transcription factors involved in, for example, differentiation and apoptosis regulation. Currently used reference RXR agonists suffer from insufficient specificity and poor physicochemical properties, and improved tools are needed to capture the unexplored therapeutic potential of RXR. Endogenous vitamin A-derived RXR ligands and the natural product RXR agonist valerenic acid comprise acrylic acid residues with varying substitution patterns to engage the critical ionic contact with the binding site arginine. To mimic and exploit this natural ligand motif, we probed its structural fusion with synthetic RXR modulator scaffolds, which had profound effects on agonist activity and remarkably boosted potency of an oxaprozin-derived RXR agonist chemotype. Bioisosteric replacement of the acrylic acid to overcome its pan-assay interference compounds (PAINS) character enabled the development of a highly optimized RXR agonist chemical probe.

De Novo Design of Nurr1 Agonists via Fragment-Augmented Generative Deep Learning in Low-Data Regime.

Generative neural networks trained on SMILES can design innovative bioactive molecules de novo. These so-called chemical language models (CLMs) have typically been trained on tens of template molecules for fine-tuning. However, it is challenging to apply CLM to orphan targets with few known ligands. We have fine-tuned a CLM with a single potent Nurr1 agonist as template in a fragment-augmented fashion and obtained novel Nurr1 agonists using sampling frequency for design prioritization. Nanomolar potency and binding affinity of the top-ranking design and its structural novelty compared to available Nurr1 ligands highlight its value as an early chemical tool and as a lead for Nurr1 agonist development, as well as the applicability of CLM in very low-data scenarios.

Biological Evaluation of New Thienopyridinium and Thienopyrimidinium Derivatives as Human Choline Kinase Inhibitors.

Due to its role in lipid biosynthesis, choline kinase α1 (CKα1) is an interesting target for the development of new antitumor agents. In this work, we present a series of 41 compounds designed based on the well-known and successful strategy of introducing thienopyridine and pyrimidine as bioisosteres of other heterocycles in active antitumor compounds. Notwithstanding the fact that some of these compounds do not show significant enzymatic inhibition, others, in contrast, feature substantially improved enzymatic and antiproliferative inhibition values. This is also confirmed by docking analysis, whereby compounds with longer linkers and thienopyrimidine cationic head have been identified as the most compelling. Among the best compounds is Ff-35, which inhibits the growth of different tumor cells at submicromolar concentrations. Moreover, Ff-35 is more potent in inhibiting CKα1 than other previous biscationic derivatives. Treatment of A549, Hela, and MDA-MB-231 cells with Ff-35 results in their arrest at the G1 phase of the cell cycle. Furthermore, the compound induces cellular apoptosis in a concentration-dependent manner. Altogether, these findings indicate that Ff-35 is a promising new chemotherapeutic agent with encouraging preclinical potential.

A straightforward synthesis of functionalized 6H-benzo[c]chromenes from 3-alkenyl chromenes by intermolecular Diels-Alder/aromatization sequence.

A new and metal-free approach to the synthesis of substituted 6H-benzo[c]chromenes has been developed. This three-step synthetic sequence starts from variously substituted salicylaldehydes and α,ß-unsaturated carbonyl compounds to form the chromene core. The de novo ring-forming key step is based on a highly regioselective intermolecular Diels-Alder cycloaddition between 3-vinyl-2H-chromenes and methyl propiolate, followed by oxidative aromatization of the cyclohexadiene cycloadduct intermediate to obtain the final products in good yields (up to 94% over two steps). A modular and divergent design was followed, including a multicomponent reaction, to maximize the scaffold diversity obtained from our approach. The mechanism, investigated by DFT calculations, was confirmed to be concerted through a slightly asynchronous transition state. Energetic analysis of the transition states which have been found confirmed the experimental results in terms of regioselectivity and reactivity tendencies.

Synthesis, biological evaluation, in silico modeling and crystallization of novel small monocationic molecules with potent antiproliferative activity by dual mechanism.

Seeking for new anticancer drugs with strong antiproliferative activity and simple molecular structure, we designed a novel series of compounds based on our previous reported pharmacophore model composed of five moieties. Antiproliferative assays on four tumoral cell lines and evaluation of Human Choline Kinase CKα1 enzymatic activity was performed for these compounds. Among tested molecules, those ones with biphenyl spacer showed betters enzymatic and antiproliferative activities (n-v). Docking and crystallization studies validate the hypothesis and confirm the results. The most active compound (t) induces a significant arrest of the cell cycle in G0/G1 phase that ultimately lead to apoptosis, following the mitochondrial pathway, as demonstrated for other choline kinase inhibitors. However additional assays reveal that the inhibition of choline uptake could also be involved in the antiproliferative outcome of this class of compounds.

Impact of Glomerular Filtration Rate on the Incidence and Prognosis of New-Onset Atrial Fibrillation in Acute Myocardial Infarction.

BACKGROUND: Atrial fibrillation (AF) is a frequent complication of acute myocardial infarction (AMI) and is associated with a worse prognosis. Patients with chronic kidney disease are more likely to develop AF. Whether the association between AF and glomerular filtration rate (GFR) is also true in AMI has never been investigated. METHODS: We prospectively enrolled 2445 AMI patients. New-onset AF was recorded during hospitalization. Estimated GFR was estimated at admission, and patients were grouped according to their GFR (group 1 (n = 1887): GFR >60; group 2 (n = 492): GFR 60-30; group 3 (n = 66): GFR <30 mL/min/1.73 m2). The primary endpoint was AF incidence. In-hospital and long-term (median 5 years) mortality were secondary endpoints. RESULTS: The AF incidence in the population was 10%, and it was 8%, 16%, 24% in groups 1, 2, 3, respectively (p < 0.0001). In the overall population, AF was associated with a higher in-hospital (5% vs. 1%; p < 0.0001) and long-term (34% vs. 13%; p < 0.0001) mortality. In each study group, in-hospital mortality was higher in AF patients (3.5% vs. 0.5%, 6.5% vs. 3.0%, 19% vs. 8%, respectively; p < 0.0001). A similar trend was observed for long-term mortality in three groups (20% vs. 9%, 51% vs. 24%, 81% vs. 50%; p < 0.0001). The higher risk of in-hospital and long-term mortality associated with AF in each group was confirmed after adjustment for major confounders. CONCLUSIONS: This study demonstrates that new-onset AF incidence during AMI, as well as the associated in-hospital and long-term mortality, increases in parallel with GFR reduction assessed at admission.

New Insights from Crystallographic Data: Diversity of Structural Motifs and Molecular Recognition Properties between Groups of IDO1 Structures.

A large number of crystallographic structures of IDO1 in different ligand-bound and -unbound states have been disclosed over the last decade. Yet, only a few of them have been exploited for structure-based drug design (SBDD) campaigns. In this study, we analyzed the structural motifs and molecular-recognition properties of three groups of IDO1 structures: 1) structures containing the heme group and inhibitors in the catalytic site; 2) heme-free structures of IDO1; 3) substrate-bound structures of IDO1. The results suggest that unrelated conformations of the enzyme have been solved with different ligand-induced changes of secondary motifs that localize even in regions remote from the catalytic site. Moreover, the study identified an uncharted region of molecular-recognition space covered by IDO1 binding sites that could guide the selection of diverse structures for additional SBDD studies aimed at the identification of novel lead compounds with differentiated chemical scaffolds.

Chemoselective and metal-free reduction of α,ß-unsaturated ketones by in situ produced benzeneselenol from O-(tert-butyl) Se-phenyl selenocarbonate.

The carbon-carbon double bond of arylidene acetones and chalcones can be selectively reduced with benzeneselenol generated in situ by reacting O-(tert-butyl) Se-phenyl selenocarbonate with hydrochloric acid in ethanol. This mild, metal-free and experimentally simple reduction procedure displays considerable functional-group compatibility, products are obtained in good to excellent yields, and the use of toxic Se/CO mixture and NaSeH, or the smelly and air-sensitive benzeneselenol, is avoided.

Targeting Aryl hydrocarbon receptor for next-generation immunotherapies: Selective modulators (SAhRMs) versus rapidly metabolized ligands (RMAhRLs).

Aryl Hydrocarbon Receptor (AhR) constitutes a major network hub of genomic and non-genomic signaling pathways, connecting host's immune cells to environmental factors. It shapes innate and adaptive immune processes to environmental stimuli with species-, cell- and tissue-type dependent specificity. Although an ever increasing number of studies has thrust AhR into the limelight as attractive target for the development of next-generation immunotherapies, concerns exist on potential safety issues associated with small molecule modulation of the receptor. Selective AhR modulators (SAhRMs) and rapidly metabolized AhR ligands (RMAhRLs) are two classes of receptor agonists that are emerging as interesting lead compounds to bypass AhR-related toxicity in favor of therapeutic effects. In this article, we discuss SAhRMs and RMAhRLs reported in literature, covering concepts underlying their definitions, specific binding modes, structure-activity relationships and AhR-mediated functions.