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Crystal structure of a mixed-ligand silver(I) complex of the non-steroidal anti-inflammatory drug diclofenac and pyrimidine.

ABSTRACT: In the title mixed-ligand silver(I) coordination polymeric complex with the non-steroidal anti-inflammatory drug diclofenac (C₁₄H₁₁Cl₂NO₂) (diclH) and pyrimidine (pym), namely poly[{μ₂-2-[2-(2,6-di-chloro-anilino)phen-yl]acetato-κ²O:O'}(μ₂-pyrimidine-κ²N¹:N³)silver(I)], [Ag(C₁₄H₁₀Cl₂NO₂)(C₄H₄N₂)] _n or [Ag(μ-dicl)(μ-pym)] _n , the very distorted tetra-hedral AgN₂O₂ coordination centres comprise two N-atom donors from bridging pym ligands [Ag-N = 2.381 (3) and 2.412 (3) Å] and two carboxyl-ate O-atom donors from dicl ligands [Ag-O = 2.279 (2) and 2.280 (2) Å], which bridge Ag atoms, giving a centrosymmetric dinuclear units with a short Ag⋯Ag separation [2.8931 (5) Å]. Within the units are short intra-ligand C-Cl⋯π(pym) inter-actions [3.6409 (15) Å]. The units are linked through the bridging N atoms of the pym ligand into a two-dimensional sheet-polymer structure lying parallel to (100) and stabilized by inter-ring π-π inter-actions between the pym ligands [Cg⋯Cg = 3.4199 (17) Å]. Additional inter-unit C-H⋯O and C-H⋯Cg hydrogen-bonding inter-actions between the sheets give an overall three-dimensional structure.

SUBMITTER: Hamamci Alisir S

PROVIDER: S-EPMC5050780 | biostudies-literature | 2016 Oct

REPOSITORIES: biostudies-literature

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Crystal structure of a mixed-ligand silver(I) complex of the non-steroidal anti-inflammatory drug diclofenac and pyrimidine.

Hamamci Alisir Sevim S Dege Necmi N

Acta crystallographica. Section E, Crystallographic communications 20160927 Pt 10

In the title mixed-ligand silver(I) coordination polymeric complex with the non-steroidal anti-inflammatory drug diclofenac (C14H11Cl2NO2) (diclH) and pyrimidine (pym), namely poly[{μ2-2-[2-(2,6-di-chloro-anilino)phen-yl]acetato-κ2O:O'}(μ2-pyrimidine-κ2N1:N3)silver(I)], [Ag(C14H10Cl2NO2)(C4H4N<s ...[more]

PMID: 27746945

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Project description:Aldo-keto reductase 1C3 (AKR1C3) catalyses the NADPH dependent reduction of carbonyl groups in a number of important steroid and prostanoid molecules. The enzyme is also over-expressed in prostate and breast cancer and its expression is correlated with the aggressiveness of the disease. The steroid products of AKR1C3 catalysis are important in proliferative signalling of hormone-responsive cells, while the prostanoid products promote prostaglandin-dependent proliferative pathways. In these ways, AKR1C3 contributes to tumour development and maintenance, and suggest that inhibition of AKR1C3 activity is an attractive target for the development of new anti-cancer therapies. Non-steroidal anti-inflammatory drugs (NSAIDs) are one well-known class of compounds that inhibits AKR1C3, yet crystal structures have only been determined for this enzyme with flufenamic acid, indomethacin, and closely related analogues bound. While the flufenamic acid and indomethacin structures have been used to design novel inhibitors, they provide only limited coverage of the NSAIDs that inhibit AKR1C3 and that may be used for the development of new AKR1C3 targeted drugs. To understand how other NSAIDs bind to AKR1C3, we have determined ten crystal structures of AKR1C3 complexes that cover three different classes of NSAID, N-phenylanthranilic acids (meclofenamic acid, mefenamic acid), arylpropionic acids (flurbiprofen, ibuprofen, naproxen), and indomethacin analogues (indomethacin, sulindac, zomepirac). The N-phenylanthranilic and arylpropionic acids bind to common sites including the enzyme catalytic centre and a constitutive active site pocket, with the arylpropionic acids probing the constitutive pocket more effectively. By contrast, indomethacin and the indomethacin analogues sulindac and zomepirac, display three distinctly different binding modes that explain their relative inhibition of the AKR1C family members. This new data from ten crystal structures greatly broadens the base of structures available for future structure-guided drug discovery efforts.

Project description:Introduction: The P2X3 receptor (P2X3R), an ATP-gated non-selective cation channel of the P2X receptor family, is expressed in sensory neurons and involved in nociception. P2X3R inhibition was shown to reduce chronic and neuropathic pain. In a previous screening of 2000 approved drugs, natural products, and bioactive substances, various non-steroidal anti-inflammatory drugs (NSAIDs) were found to inhibit P2X3R-mediated currents. Methods: To investigate whether the inhibition of P2X receptors contributes to the analgesic effect of NSAIDs, we characterized the potency and selectivity of various NSAIDs at P2X3R and other P2XR subtypes using two-electrode voltage clamp electrophysiology. Results: We identified diclofenac as a hP2X3R and hP2X2/3R antagonist with micromolar potency (with IC50 values of 138.2 and 76.7 µM, respectively). A weaker inhibition of hP2X1R, hP2X4R, and hP2X7R by diclofenac was determined. Flufenamic acid (FFA) inhibited hP2X3R, rP2X3R, and hP2X7R (IC50 values of 221 µM, 264.1 µM, and ∼900 µM, respectively), calling into question its use as a non-selective ion channel blocker, when P2XR-mediated currents are under study. Inhibition of hP2X3R or hP2X2/3R by diclofenac could be overcome by prolonged ATP application or increasing concentrations of the agonist α,β-meATP, respectively, indicating competition of diclofenac and the agonists. Molecular dynamics simulation showed that diclofenac largely overlaps with ATP bound to the open state of the hP2X3R. Our results suggest a competitive antagonism through which diclofenac, by interacting with residues of the ATP-binding site, left flipper, and dorsal fin domains, inhibits the gating of P2X3R by conformational fixation of the left flipper and dorsal fin domains. In summary, we demonstrate the inhibition of the human P2X3 receptor by various NSAIDs. Diclofenac proved to be the most effective antagonist with a strong inhibition of hP2X3R and hP2X2/3R and a weaker inhibition of hP2X1R, hP2X4R, and hP2X7R. Discussion: Considering their involvement in nociception, inhibition of hP2X3R and hP2X2/3R by micromolar concentrations of diclofenac, which are rarely reached in the therapeutic range, may play a minor role in analgesia compared to the high-potency cyclooxygenase inhibition but may explain the known side effect of taste disturbances caused by diclofenac.

Dataset Information

Crystal structure of a mixed-ligand silver(I) complex of the non-steroidal anti-inflammatory drug diclofenac and pyrimidine.

Publications

Crystal structure of a mixed-ligand silver(I) complex of the non-steroidal anti-inflammatory drug diclofenac and pyrimidine.

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