| 1. |
- Areias, Filipe, et al.
(författare)
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2-Aryladenine Derivatives as a Potent Scaffold for Adenosine Receptor Antagonists : The 6-Morpholino Derivatives
- 2024
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Ingår i: Molecules. - : MDPI. - 1431-5157 .- 1420-3049. ; 29:11
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Tidskriftsartikel (refereegranskat)abstract
- A set of 2-aryl-9-H or methyl-6-morpholinopurine derivatives were synthesized and assayed through radioligand binding tests at human A1, A2A, A2B, and A3 adenosine receptor subtypes. Eleven purines showed potent antagonism at A1, A3, dual A1/A2A, A1/A2B, or A1/A3 adenosine receptors. Additionally, three compounds showed high affinity without selectivity for any specific adenosine receptor. The structure-activity relationships were made for this group of new compounds. The 9-methylpurine derivatives were generally less potent but more selective, and the 9H-purine derivatives were more potent but less selective. These compounds can be an important source of new biochemical tools and/or pharmacological drugs.
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| 2. |
- Brea, Oriana, et al.
(författare)
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Are beryllium-containing biphenyl derivatives efficient anion sponges?
- 2018
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Ingår i: Journal of Molecular Modeling. - : Springer Science and Business Media LLC. - 1610-2940 .- 0948-5023. ; 24:1
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Tidskriftsartikel (refereegranskat)abstract
- The structures and stabilities of 2,2'-diBeX-1,1'-biphenyl (X = H, F, Cl, CN) derivatives and their affinities for F-, Cl-, and CN- were theoretically investigated using a B3LYP/6-311 + G(3df, 2p)//B3LYP/6-31 + G(d,p) model. The results obtained show that the 2,2'-diBeX-1,1'-biphenyl derivatives (X = H, F, Cl, CN) exhibit very high F-, Cl-, and CN- affinities, albeit lower than those reported before for their 1,8-diBeX-naphthalene analogs, in spite of the fact that the biphenyl derivatives are more flexible than their naphthalene counterparts. Nevertheless, some of the biphenyl derivatives investigated are predicted to have anion affinities larger than those measured for SbF5, which is considered one of the strongest anion capturers. Therefore, although weaker than their naphthalene analogs, the 2,2'-diBeX-1,1'-biphenyl derivatives can still be considered powerful anion sponges. This study supports the idea that compounds containing -BeX groups in chelating positions behave as anion sponges due to the electron-deficient nature and consequently high intrinsic Lewis acidity of these groups.
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| 3. |
- Mallo-Abreu, Ana, et al.
(författare)
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Trifluorinated Pyrimidine-Based A(2B) Antagonists : Optimization and Evidence of Stereospecific Recognition
- 2019
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Ingår i: Journal of Medicinal Chemistry. - : AMER CHEMICAL SOC. - 0022-2623 .- 1520-4804. ; 62:20, s. 9315-9330
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Tidskriftsartikel (refereegranskat)abstract
- We report the identification of two subsets of fluorinated nonxanthine A(2B) adenosine receptor antagonists. The novel derivatives explore the effect of fluorination at different positions of two pyrimidine-based scaffolds. The most interesting ligands combine excellent hA(2B) affinity (K-i < 15 nM) and remarkable subtype selectivity. The results of functional cAMP experiments confirmed the antagonistic behavior of representative ligands. The compounds were designed on the basis of previous molecular models of the stereoselective binding of the parent scaffolds to the hA(2B) receptor, and we herein provide refinement of such models with the fluorinated compounds, which allows the explanation of the spurious effects of the fluorination at the different positions explored. These models are importantly confirmed by a synergistic study combining chiral HPLC, circular dichroism, diastereoselective synthesis, molecular modeling, and X-ray crystallography, providing experimental evidence toward the stereospecific interaction between optimized trifluorinated stereoisomers and the hA(2B) receptor.
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| 4. |
- Merced Montero-Campillo, M., et al.
(författare)
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Gas-phase reactivity tuned through the interaction with alkaline-earth derivatives
- 2019
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Ingår i: Theoretical Chemistry accounts. - : Springer Science and Business Media LLC. - 1432-881X .- 1432-2234. ; 138:5
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Tidskriftsartikel (refereegranskat)abstract
- The cooperativity between MX2:XH alkaline-earth bonds and XH:NH3 hydrogen bonds (M=Mg, Ca; X=F, Cl) was investigated at the G4 level of theory. The cooperativity between these two non-covalent linkages is extremely large, to the point that the increase in their bond dissociation enthalpies may be as large as 240%. More importantly, the weaker the interaction, the larger the increase, so in some cases the linkage that stabilizes the most is the alkaline-earth bond, whereas in others is the hydrogen bond. In all cases, the formation of the MX2:XH:NH3 ternary complex is followed by a spontaneous proton transfer, very much as previously found for the Be-containing analogues. Similarly, MX2:FCl:NH3 complexes evolve from a chlorine-shared ternary complex (MX2FClNH3) or from an ion pair (MX2F-NH3Cl+) if M=Ca. Although F is the only halogen without sigma-hole, MgCl2 derivatives induce the appearance of a sigma-hole on it, though less deep than those induced by BeCl2. We have also studied whether Mg and Ca bond-containing complexes MR2:FY (R=H, F, Cl; Y=NH2, OH, F, Cl) may react to form radicals, as it has been found for the Be-containing analogues. These interactions provoke a drastic decrease in the F-Y bond dissociation enthalpy, very much as the one reported for the corresponding Be-analogues, to the point that in some cases the formation of the corresponding MR2F center dot+Y radicals becomes exothermic. Hence, the general conclusion of this study is that Mg or Ca derivatives give place to similar or even larger perturbations on the electron density than those induced by Be, a result not easily predictable.
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| 5. |
- Merced Montero-Campillo, M., et al.
(författare)
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Modulating the intrinsic reactivity of molecules through non-covalent interactions
- 2019
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Ingår i: Physical Chemistry, Chemical Physics - PCCP. - : Royal Society of Chemistry (RSC). - 1463-9076 .- 1463-9084. ; 21:5, s. 2222-2233
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Tidskriftsartikel (refereegranskat)abstract
- Non-covalent interactions unavoidably involve a certain disturbance of the electronic density of the interacting systems. Such perturbations are particularly strong when dealing with electron deficient systems such as boron, beryllium, magnesium (pre-p elements) or calcium (a pre-d element) derivatives. Indeed, these compounds have been shown to modify the intrinsic reactivity of the systems interacting with them. In the first part of this paper, we present an overview on (i) how electron deficient systems, acting as Lewis acids, modulate the intrinsic acidity of Lewis bases, explaining for instance why a typical base, such as aniline, can be converted by association with borane into an acid as strong as phosphoric acid; (ii) how other weak non-covalent interactions, such as halogen bonds, permit one to modulate the intrinsic basicity of typical oxyacids changing them into strong BrOnsted bases; (iii) how cooperativity between different non-covalent interactions may lead to the spontaneous formation of ion-pairs in the gas phase; (iv) how non-covalent interactions generate sigma-holes in systems where this feature is not present; and (v) how these interactions can induce exergonic and spontaneous formation of neutral radicals. In the second part of the paper, we show, by using G4 high-level ab initio calculations, that the acidity enhancement phenomenon is a general mechanism whenever a given base interacts with non-protic and protic acids. In the non-protic acid case, the underlying mechanism behind the enhancement is similar to the one reported for electron-deficient compounds, whereas the protic acid case appears in complexes stabilized through conventional hydrogen bonds. We also show that the former could be classified as an a priori mechanism, whereas the latter would be an a posteriori mechanism. This same a posteriori mechanism is behind the significant basicity enhancement of water and ammonia when interacting with conventional N-bases. Finally, we present a detailed analysis of the role that deformation can play in the intensity and nature of these enhancements.
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| 6. |
- Miranda-Pastoriza, Dario, et al.
(författare)
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Exploring Non-orthosteric Interactions with a Series of Potent and Selective A(3) Antagonists
- 2022
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Ingår i: ACS Medicinal Chemistry Letters. - : American Chemical Society (ACS). - 1948-5875. ; 13:2, s. 243-249
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Tidskriftsartikel (refereegranskat)abstract
- : 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.
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| 7. |
- Prieto-Diaz, Ruben, et al.
(författare)
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Exploring Biginelli-based scaffolds as A2B adenosine receptor antagonists : Unveiling novel structure-activity relationship trends, lead compounds, and potent colorectal anticancer agents
- 2024
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Ingår i: Biomedicine and Pharmacotherapy. - : Elsevier. - 0753-3322 .- 1950-6007. ; 173
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Tidskriftsartikel (refereegranskat)abstract
- Antagonists of the A2B adenosine receptor have recently emerged as targeted anticancer agents and immune checkpoint inhibitors within the realm of cancer immunotherapy. This study presents a comprehensive evaluation of novel Biginelli-assembled pyrimidine chemotypes, including mono-, bi-, and tricyclic derivatives, as A2BAR antagonists. We conducted a comprehensive examination of the adenosinergic profile (both binding and functional) of a large compound library consisting of 168 compounds. This approach unveiled original lead compounds and enabled the identification of novel structure-activity relationship (SAR) trends, which were supported by extensive computational studies, including quantum mechanical calculations and free energy perturbation (FEP) analysis. In total, 25 molecules showed attractive affinity (Ki < 100 nM) and outstanding selectivity for A2BAR. From these, five molecules corresponding to the new benzothiazole scaffold were below the Ki < 10 nM threshold, in addition to a novel dual A2A/A2B antagonist. The most potent compounds, and the dual antagonist, showed enantiospecific recognition in the A2BAR. Two A2BAR selective antagonists and the dual A2AAR/A2BAR antagonist reported in this study were assessed for their impact on colorectal cancer cell lines. The results revealed a significant and dose-dependent reduction in cell proliferation. Notably, the A2BAR antagonists exhibited remarkable specificity, as they did not impede the proliferation of non-tumoral cell lines. These findings support the efficacy and potential that A2BAR antagonists as valuable candidates for cancer therapy, but also that they can effectively complement strategies involving A2AAR antagonism in the context of immune checkpoint inhibition.
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| 8. |
- Prieto-Díaz, Rubén, et al.
(författare)
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Exploring the Effect of Halogenation in a Series of Potent and Selective A2B Adenosine Receptor Antagonists
- 2023
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Ingår i: Journal of Medicinal Chemistry. - : American Chemical Society (ACS). - 0022-2623 .- 1520-4804. ; 66:1, s. 890-912
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Tidskriftsartikel (refereegranskat)abstract
- 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.
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| 9. |
- Rodriguez, Anna, et al.
(författare)
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New selective A(2A) agonists and A(3) antagonists for human adenosine receptors : synthesis, biological activity and molecular docking studies
- 2015
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Ingår i: MedChemComm. - : Royal Society of Chemistry (RSC). - 2040-2503 .- 2040-2511. ; 6:6, s. 1178-1185
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Tidskriftsartikel (refereegranskat)abstract
- We report the synthesis and pharmacological characterization of a new series of adenosine derivatives on the four adenosine receptors (ARs). In radioligand binding assays, some of the compounds (1, 4, 6 and (R)-6) display a potent affinity for the A(2A)AR (K-i values < 10 nM) with high A(1)/A(2A) and A(2B)/A(2A) selectivity, moderate for the A(3)AR and low for the A(1)AR. The affinity of the epimeric mixture 6 was similar to that of the corresponding (R)-6 stereoisomer and 10-fold higher than that of the (S)-6 stereoisomer. The phenylethylamino group appears to play a key role on the activity, but introduction of groups of different sizes and electronegativity does not induce a substantial change in affinity for the A(2A)AR. In functional assays, most of the compounds produced similar amounts of cAMP compared to NECA, thus behaving as full A(2A)AR agonists. In addition, compounds 1, 2, 3, 5, (S)-6 and 9 resulted to be good antagonists for A(3)AR with K-B in the 6-14 nM range. Docking studies on the A(2A)AR showed a conserved binding mode consistent with previous A(2A)AR agonist-bound crystal structures, allowing for a rational interpretation of the SAR of this compound series.
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| 10. |
- Tay, Apple Hui Min, et al.
(författare)
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A(2B) adenosine receptor antagonists rescue lymphocyte activity in adenosine-producing patient-derived cancer models
- 2022
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Ingår i: Journal for ImmunoTherapy of Cancer. - : BMJ. - 2051-1426. ; 10:5, s. e004592-
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Tidskriftsartikel (refereegranskat)abstract
- 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.
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