Methyl 2-diphenyl­phosphor­yloxy-2-aza­bicyclo­[2.2.1]hept-5-ene-3-exo-carboxyl­ate

In the title compound, C20H20NO4P, the dihedral angle between the phenyl rings is 68.52 (7)°. In the crystal structure, the mol­ecules are linked by a weak C—H⋯π(arene) inter­action along [010] involving the phenyl CH group and the phenyl rings. There are no further significant inter­molecular inter­actions

Experimental-Theoretic Approach to Drug-Lymphocyte Interactome Networks with Flow Cytometry and Spectral Moments Perturbation Theory

Modelos matematicos y citometria de flujoAbstract: We can combine experimental techniques like Flow Cytometry Analysis (FCA) with Chemoinformatics methods to predict the complex networks of interactions between organic compounds and targets in the immune system. In this work, we determined experimentally the values of EC50 = 17.82 μg/mL and Cytotoxicity = 20.6 % for the antimicrobial / anti-parasite drug Dermofural over Balb/C CD9 lymphocytes using flow cytometry. After that, we developed a new Perturbation-theory model for Drug-Cell Target Interactome in Lymphocytes based on dispersion-polarization moments of drug structure. The models correctly classifies 34591 out of 42715 (Accuracy = 80.9%) cases of perturbations in assay endpoints of 11492 drugs (including both train and validation series). Each endpoint correspond to one out of 2616 assays, 38 molecular and cellular targets, 77 standard type measures, in four possible (human and rodentsCONACY

(1RS,4RS,5RS)-Methyl 2-(3,5-dinitro­benzo­yl)-2-oxa-3-aza­bicyclo­[3.3.0]oct-7-ene-4-carboxyl­ate

The title compound, C15H13N3O8, comprises two crystallographically independent mol­ecules in the asymmetric unit. In the crystal, intermolecular C—H⋯O hydrogen bonds link the molecules and short C=O⋯π contacts are seen

Model for High-Throughput Screening of drug immunotoxicity - study of the antimicrobial G1 over peritoneal macrophages using flow cytometry

Modelos matematicos y citometriaQuantitative Structure-Activity (mt-QSAR) techniques may become an important tool for prediction of cytotoxicity and High-throughput Screening (HTS) of drugs to rationalize drug discovery process. In this work, we train and validate by the first time mt-QSAR model using TOPS-MODE approach to calculate drug molecular descriptors and Linear Discriminant Analysis (LDA) function. This model correctly classifies 8,258 out of 9,000 (Accuracy = 91.76%) multiplexing assay endpoints of 7903 drugs (including both train and validation series). Each endpoint correspond to one out of 1418 assays, 36 molecular and cellular targets, 46 standard type measures, in two possible organisms (human and mouse). After that, we determined experimentally, by the first time, the values of EC50 = 21.58 μg/mL and Cytotoxicity = 23.6 % for the anti-microbial / antiparasite drug G1 over Balb/C mouse peritoneal macrophages using flow cytometry. In addition, the model predicts for G1 only 7 positive endpoints out 1,251 cytotoxicity assays (0.56% of probability of cytotoxicity in multiple assays). The results obtained complement the toxicological studies of this important drug. This work adds a new tool to the existing pool of few methods useful for multi-target HTS of ChEMBL and other libraries of compounds towards drug discovery.Conacy

Exploring Non-orthosteric Interactions with a Series of Potent and Selective A(3) Antagonists

: A library of potent and highly A3AR selective pyrimidinebased compounds was designed to explore non-orthosteric interactions within this receptor. Starting from a prototypical orthosteric A3AR antagonist (ISVY130), the structure-based design explored functionalized residues at the exocyclic amide L1 region and aimed to provide additional interactions outside the A3AR orthosteric site. The novel ligands were assembled through an efficient and succinct synthetic approach, resulting in compounds that retain the A3AR potent and selective profile while improving the solubility of the original scaffold. The experimentally demonstrated tolerability of the L1 region to structural functionalization was further assessed by molecular dynamics simulations, giving hints of the non-orthosteric interactions explored by these series. The results pave the way to explore newly functionalized A3AR ligands, including covalent drugs and molecular probes for diagnostic and delivery purposes

Optimization of 2-Amino-4,6-diarylpyrimidine-5-carbonitriles as Potent and Selective A(1) Antagonists

We herein document a large collection of 108 2-amino-4,6-disubstituted-pyrimidine derivatives as potent, structurally simple, and highly selective A(1)AR ligands. The most attractive ligands were confirmed as antagonists of the canonical cyclic adenosine monophosphate pathway, and some pharmacokinetic parameters were preliminarily evaluated. The library, built through a reliable and efficient three-component reaction, comprehensively explored the chemical space allowing the identification of the most prominent features of the structure-activity and structure-selectivity relationships around this scaffold. These included the influence on the selectivity profile of the aromatic residues at positions R-4 and R-6 of the pyrimidine core but most importantly the prominent role to the unprecedented A(1)AR selectivity profile exerted by the methyl group introduced at the exocyclic amino group. The structure-activity relationship trends on both A(1) and A(2A)ARs were conveniently interpreted with rigorous free energy perturbation simulations, which started from the receptor-driven docking model that guided the design of these series

A2B adenosine receptor antagonists rescue lymphocyte activity in adenosine-producing patient-derived cancer models

Background Adenosine is a metabolite that suppresses antitumor immune response of T and NK cells via extracellular binding to the two subtypes of adenosine-2 receptors, A(2)ARs. While blockade of the A(2A)ARs subtype effectively rescues lymphocyte activity, with four A(2A)AR antagonists currently in anticancer clinical trials, less is known for the therapeutic potential of the other A(2B)AR blockade within cancer immunotherapy. Recent studies suggest the formation of A(2A)AR/A(2B)AR dimers in tissues that coexpress the two receptor subtypes, where the A(2B)AR plays a dominant role, suggesting it as a promising target for cancer immunotherapy. Methods We report the synthesis and functional evaluation of five potent A(2B)AR antagonists and a dual A(2A)AR/A(2B)AR antagonist. The compounds were designed using previous pharmacological data assisted by modeling studies. Synthesis was developed using multicomponent approaches. Flow cytometry was used to evaluate the phenotype of T and NK cells on A(2B)AR antagonist treatment. Functional activity of T and NK cells was tested in patient-derived tumor spheroid models. Results We provide data for six novel small molecules: five A(2B)AR selective antagonists and a dual A(2A)AR/A(2B)AR antagonist. The growth of patient-derived breast cancer spheroids is prevented when treated with A(2B)AR antagonists. To elucidate if this depends on increased lymphocyte activity, immune cells proliferation, and cytokine production, lymphocyte infiltration was evaluated and compared with the potent A(2A)AR antagonist AZD-4635. We find that A(2B)AR antagonists rescue T and NK cell proliferation, IFN gamma and perforin production, and increase tumor infiltrating lymphocytes infiltration into tumor spheroids without altering the expression of adhesion molecules. Conclusions Our results demonstrate that A(2B)AR is a promising target in immunotherapy, identifying ISAM-R56A as the most potent candidate for A(2B)AR blockade. Inhibition of A(2B)AR signaling restores T cell function and proliferation. Furthermore, A(2B)AR and dual A(2A)AR/A(2B)AR antagonists showed similar or better results than A(2A)AR antagonist AZD-4635 reinforcing the idea of dominant role of the A(2B)AR in the regulation of the immune system

Exploring the Effect of Halogenation in a Series of Potent and Selective A2B Adenosine Receptor Antagonists

The modulation of the A2B adenosine receptor is a promising strategy in cancer (immuno) therapy, with A2BAR antagonists emerging as immune checkpoint inhibitors. Herein, we report a systematic assessment of the impact of (di- and mono-)halogenation at positions 7 and/or 8 on both A2BAR affinity and pharmacokinetic properties of a collection of A2BAR antagonists and its study with structure-based free energy perturbation simulations. Monohalogenation at position 8 produced potent A2BAR ligands irrespective of the nature of the halogen. In contrast, halogenation at position 7 and dihalogenation produced a halogen-size-dependent decay in affinity. Eight novel A2BAR ligands exhibited remarkable affinity (Ki < 10 nM), exquisite subtype selectivity, and enantioselective recognition, with some eutomers eliciting sub-nanomolar affinity. The pharmacokinetic profile of representative derivatives showed enhanced solubility and microsomal stability. Finally, two compounds showed the capacity of reversing the antiproliferative effect of adenosine in activated primary human peripheral blood mononuclear cells