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1.
Bioorg Chem ; 104: 104278, 2020 11.
Article in English | MEDLINE | ID: mdl-33010623

ABSTRACT

Extracellular ATP activates purinergic receptors such as P2X7, cationic channels for Ca2+, K+, and Na+. There is robust evidence of the involvement of these receptors in the immune response, so P2X7 receptors (P2X7R) are considered a potential therapeutic target for the development of anti-inflammatory drugs. Although there are many studies of the anti-inflammatory properties of naphthoquinones, these molecules have not yet been explored as P2X7 antagonists. In previous work, our group prepared 3-substituted (halogen or aryl) 2-hydroxy-1,4-naphthoquinones and studied their action on P2X7R. In this paper, eight 2-amino-3-aryl-1,4-naphthoquinones were evaluated to identify the inhibitory activity on P2X7R and the toxicological profile. Three analogues (AD-4CN, AD-4Me, and AD-4F) exhibited reduced toxicity for mammalian cells with CC50 values higher than 500 µM. These three 3-substituted 2-amino-1,4-naphthoquinones inhibited murine P2X7R (mP2X7R) in vitro. However, the analogues AD-4CN and AD-4Me showed low selectivity index values. AD-4F inhibited both mP2X7R and human P2X7R (hP2X7R) with IC50 values of 0.123 and 0.93 µM, respectively. Additionally, this analogue exhibited higher potency than BBG at inhibiting the ATP-induced release of IL-1ß in vitro. Carrageenan-induced paw edema in vivo was reversed for AD-4F with an ID50 value of 11.51 ng/kg. Although AD-4F was less potent than previous 3-substituted (halogen or aryl) 2-hydroxy-1,4-naphthoquinones such as AN-04in vitro, this 3-substituted 2-amino-1,4-naphthoquinone revealed higher potency in vivo to reduce the edematogenic response. In silico analysis suggests that the binding site of the novel 2-amino-3-aryl-1,4-naphthoquinone derivatives, including all the tautomeric forms, is located in the pore area of the hP2X7R model. Based on these results, we considered AD-4F to be a satisfactory P2X7R inhibitor. AD-4F might be used as a scaffold structure to design a novel series of inhibitors with potential inhibitory activity on murine (mP2X7R) and human (hP2X7R) P2X7 receptors.


Subject(s)
Naphthoquinones/pharmacology , Purinergic P2X Receptor Antagonists/pharmacology , Receptors, Purinergic P2X7/metabolism , Adenosine Triphosphate , Animals , Caco-2 Cells , Carrageenan , Dose-Response Relationship, Drug , Edema/chemically induced , Edema/drug therapy , HEK293 Cells , Humans , Male , Mice , Molecular Structure , Naphthoquinones/chemical synthesis , Naphthoquinones/chemistry , Purinergic P2X Receptor Antagonists/chemical synthesis , Purinergic P2X Receptor Antagonists/chemistry , Structure-Activity Relationship
2.
J Bioenerg Biomembr ; 51(4): 277-290, 2019 08.
Article in English | MEDLINE | ID: mdl-31256283

ABSTRACT

The P2X7 receptor (P2X7R) is an ion channel which is activated by interactions with the extracellular ATP molecules. The molecular complex P2X7R/ATP induces conformational changes in the protein subunits, opening a pore in the ion channel macromolecular structure. Currently, the P2X7R has been studied as a potential therapeutic target of anti-inflammatory drugs. Based on this, a series of eight boronic acids (NO) analogs were evaluated on the biologic effect of this pharmacophoric group on the human and murine P2X7R. The boronic acids derivatives NO-01 and NO-12 inhibited in vitro human and murine P2X7R function. These analogs compounds showed effect better than compound BBG and similar to inhibitor A740003 for inhibiting dye uptake, in vitro IL-1ß release and ATP-induced paw edema in vivo. In both, in vitro and in vivo assays the compound NO-01 showed to be the hit compound in the present series of the arylboronic acids analogs. The molecular docking suggests that the NO derivatives bind into the upper body domain of the P2X7 pore and that the main intermolecular interaction with the two most active NO derivatives occur with the residues Phe 95, 103 and 293 by hydrophobic interactions and with Leu97, Gln98 and Ser101 by hydrogen bonds.. These results indicate that the boronic acid derivative NO-01 shows the lead compound characteristics to be used as a scaffold structure to the development of new P2X7R inhibitors with anti-inflammatory action.


Subject(s)
Anti-Inflammatory Agents , Boronic Acids , Purinergic P2X Receptor Antagonists , Receptors, Purinergic P2X7/metabolism , Acetamides/chemistry , Acetamides/pharmacology , Animals , Anti-Inflammatory Agents/chemistry , Anti-Inflammatory Agents/pharmacology , Boronic Acids/chemistry , Boronic Acids/pharmacology , HEK293 Cells , Humans , Inflammation/drug therapy , Inflammation/genetics , Inflammation/metabolism , Inflammation/pathology , Male , Mice , Purinergic P2X Receptor Antagonists/chemistry , Purinergic P2X Receptor Antagonists/pharmacology , Quinolines/chemistry , Quinolines/pharmacology , Receptors, Purinergic P2X7/genetics
3.
ChemMedChem ; 13(14): 1395-1404, 2018 07 18.
Article in English | MEDLINE | ID: mdl-29856519

ABSTRACT

Molecules containing an (cyanovinyl)arene moiety are known as tyrphostins because of their ability to inhibit proteins from the tyrosine kinase family, an interesting target for the development of anticancer and trypanocidal drugs. In the present work, (E)-(cyanovinyl)benzeneboronic acids were synthesized by Knoevenagel condensations without the use of any catalysts in water through a simple protocol that completely avoided the use of organic solvents in the synthesis and workup process. The in vitro anticancer and trypanocidal activities of the synthesized boronic acids were also evaluated, and it was discovered that the introduction of the boronic acid functionality improved the activity of the boronic tyrphostins. In silico target fishing with the use of a chemogenomic approach suggested that tyrosine-phosphorylation-regulated kinase 1a (DYRK1A) was a potential target for some of the designed compounds.


Subject(s)
Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Boron Compounds/chemistry , Boron Compounds/pharmacology , Trypanocidal Agents/chemistry , Trypanocidal Agents/pharmacology , Tyrphostins/chemistry , Tyrphostins/pharmacology , Animals , Antineoplastic Agents/chemical synthesis , Boron Compounds/chemical synthesis , Cell Line , Cell Line, Tumor , Cells, Cultured , Chagas Disease/drug therapy , Drug Design , Humans , Mice , Models, Molecular , Neoplasms/drug therapy , Protein-Tyrosine Kinases/antagonists & inhibitors , Trypanocidal Agents/chemical synthesis , Trypanosoma cruzi/drug effects , Tyrphostins/chemical synthesis
4.
Arch Biochem Biophys ; 557: 55-64, 2014 Sep 01.
Article in English | MEDLINE | ID: mdl-24893147

ABSTRACT

Eumelanin is a heterogeneous polymer composed of 5,6-dihydroxyindole-2-carboxylic acid (DHICA) and 5,6-dihydroxyindole (DHI). Studies have shown that DHICA promotes single strand breaks in plasmid DNA exposed to ultraviolet B radiation (UVB, 313 nm) and in DNA from human keratinocytes exposed to ultraviolet A radiation (UVA, 340-400 nm). Singlet molecular oxygen ((1)O2) is the main reactive species formed by UVA radiation on the skin. In this context, we now report that DHICA can cause single strand breaks in plasmid DNA even in the absence of light radiation. Interestingly, when DHICA was pre-oxidized by (1)O2, it lost this harmful capacity. It was also found that DHICA could interact with DNA, disturbing Fpg activity and decreasing its recognition of lesions by ∼50%. Additionally, the free nucleoside deoxyguanosine (dGuo) was used to evaluate whether DHICA would interfere with the formation of 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodGuo) and spiroiminodihydantoin (dSp) by (1)O2 or with the formation of 8-oxodGuo by hydroxyl radical (OH). We observed that when dGuo was oxidized by (1)O2 in the presence of DHICA, 8-oxodGuo formation was increased. However, when dGuo was oxidized by OH in the presence of DHICA, 8-oxodGuo levels were lower than in the absence of the precursor. Overall, our data reveal an important role for this eumelanin precursor in both the promotion and the protection of DNA damage and imply that it can impair DNA repair.


Subject(s)
DNA Damage , DNA Repair , Indoles/chemistry , Reactive Oxygen Species/chemistry
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