Reinvestigation of clopidogrel bioactivation unveils new cytochrome P450-catalyzed thioester cleavage mechanism.

The serendipitous prodrug clopidogrel (CPG, M0) is the mainstay antiplatelet drug in clinical use. The thiophene moiety of CPG undergoes ring opening to form the active metabolite (M13) through two steps of cytochrome P450 (CYP)-catalyzed oxidation. The stable intermediate resulting from the first oxidation, 2-oxo-CPG (M2), is proposed to be oxidized to form an S-oxide intermediate (M11), which proceeds with a hydrolytic pathway to yield a sulfenic acid (M12) and subsequently the bioreduced active metabolite (M13). To test the long-standing pathway of M2 to M13 via M11, we have chemically synthesized M11 but found it does not undergo the proposed hydrolytic activation in various conditions including in liver microsomal incubations. To seek an alternative mechanism, 18O tracing studies were performed with both H218O and 18O2, and LC-MS studies show that the carboxylate product moiety acquires its O-atom from oxygen instead of water, which rules out M11 as the bioactivation intermediate. To explain the 18O tracing results, a one-step Baeyer-Villiger-like mechanism is proposed for the CYP-dependent thioester cleavage, which features the incorporation of the two O-atoms of O2 into the two product moieties of carboxylate and sulfenic acid. The research presented herein provides a biochemical basis for delineating the clinical pharmacology of a mainstay treatment and expands our understanding of CYP catalysis.

Author Correction: Clopidogrel as a donor probe and thioenol derivatives as flexible promoieties for enabling H2S biomedicine.

The original version of this Article contained an error in the spelling of the author Bin Geng, which was incorrectly given as Bing Geng. This has been corrected in both the PDF and HTML versions of the Article.

Clopidogrel as a donor probe and thioenol derivatives as flexible promoieties for enabling H2S biomedicine.

Hydrogen sulfide has emerged as a critical endogenous signaling transmitter and a potentially versatile therapeutic agent. The key challenges in this field include the lack of approved hydrogen sulfide-releasing probes for in human exploration and the lack of controllable hydrogen sulfide promoieties that can be flexibly installed for therapeutics development. Here we report the identification of the widely used antithrombotic drug clopidogrel as a clinical hydrogen sulfide donor. Clopidogrel is metabolized in patients to form a circulating metabolite that contains a thioenol substructure, which is found to undergo spontaneous degradation to release hydrogen sulfide. Model studies demonstrate that thioenol derivatives are a class of controllable promoieties that can be conveniently installed on a minimal structure of ketone with an α-hydrogen. These results can provide chemical tools for advancing hydrogen sulfide biomedical research as well as developing hydrogen sulfide-releasing drugs.

Structural, spectroscopic, and theoretical analysis of a molecular system based on 2-((2-(4-chlorophenylhydrazone) methyl)quinolone / Análisis estructural, espectroscópico y teórico de un sistema molecular basado en la 2-((2-(4-clorofenilhidrazono) metil)quinolina / Análise estrutural, espectroscópico, e teórico de um sistema molecular com base na 2-((2-(4-Clorofenilhidrazona) metil)quinolina

Abstract A novel molecular system based on 2-((2-(4-chlorophenylhydrazone)methyl)quinoline (1-E ) was synthesized. Interconversion of 1-E to its configurational isomer 1-Z was achieved using UV radiation (250 W Hg lamp). Such isomerization was monitored by ¹H-NMR. The results suggest that the hydrazone derivative can act as a chemical brake in solution. This molecular system was structurally (Single Crystal X-Ray diffraction and DFT calculations) and spectroscopically (NMR, UV, and IR) characterized. Electrochemical measurements showed that configurational changes induce differential redox behavior. In this regard, the reported quinoline system exhibits different dynamic absorption and electrochemical properties that are modulated by UV-light. Therefore, 1-E can be regarded as a potential photo-electrochemical switch.

Resumen Se sintetizó un nuevo sistema molecular basado en 2-((2-(4-chlorofenilhidrazona)metil)quinolina. Del mismo modo, se evaluó la respuesta dinámica de este compuesto a radiación ultravioleta y formación de un enlace de hidrógeno intramolecular. Los resultados muestran que este derivado de hidrazona puede actuar como freno en solución. El sistema en mención es descrito estructural (Cristalografía de Rayos X y cálculos DFT) y espectroscópicamente (RMN, UV e IR). La interconversión de este sistema entre las configuraciones 1-E y 1-Z fue mediada por radiación UV y monitoreada a través de RMN-¹H. El estudio electroquímico mostró un comportamiento diferencial en función de su configuración, aspecto fundamental en el desarrollo de sistemas foto- y electroquímicamente modulados.

Resumo Neste trabalho é apresentado um novo sistema molecular baseado na 2-((2-(4-clorofenilhidrazona)metil)quinolina, capaz de responder dinamicamente à radiação ultravioleta formando uma ligação de hidrogénio intramolecular que atua como um freio na solução. Este sistema é descrito estruturalmente (cristalografia de raios-X e DFT) e por diferentes técnicas espectroscópicas (RMN, de UV e de IV). Radiação UV foi usada para fazer a interconversão da hidrazona 1-E no seu isômero configuracional 1-Z . Este processo foi monitorado pelo RMN. As medidas eletroquímicas mostraram que as mudanças configuracionais entre os isômeros induzem a comportamentos redox diferentes, o que é uma caraterística chave no desenvolvimento de interruptores fotoelectroquímicos.

Single crystal structures and theoretical calculations of uranium endohedral metallofullerenes (U@C2n , 2n = 74, 82) show cage isomer dependent oxidation states for U.

Charge transfer is a general phenomenon observed for all endohedral mono-metallofullerenes. Since the detection of the first endohedral metallofullerene (EMF), La@C82, in 1991, it has always been observed that the oxidation state of a given encapsulated metal is always the same, regardless of the cage size. No crystallographic data exist for any early actinide endohedrals and little is known about the oxidation states for the few compounds that have been reported. Here we report the X-ray structures of three uranium metallofullerenes, U@D3h-C74, U@C2(5)-C82 and U@C2v(9)-C82, and provide theoretical evidence for cage isomer dependent charge transfer states for U. Results from DFT calculations show that U@D3h-C74 and U@C2(5)-C82 have tetravalent electronic configurations corresponding to U4+@D3h-C744- and U4+@C2(5)-C824-. Surprisingly, the isomeric U@C2v(9)-C82 has a trivalent electronic configuration corresponding to U3+@C2v(9)-C823-. These are the first X-ray crystallographic structures of uranium EMFs and this is first observation of metal oxidation state dependence on carbon cage isomerism for mono-EMFs.

(E)-5-[1-Hy-droxy-3-(3,4,5-tri-meth-oxy-phen-yl)allyl-idene]-1,3-di-methyl-pyrimidine-2,4,6-trione: crystal structure and Hirshfeld surface analysis.

In the title compound, C18H20N2O7, the dihedral angle between the aromatic rings is 7.28 (7)° and the almost planar conformation of the mol-ecule is supported by an intra-molecular O-H⋯O hydrogen bond, which closes an S(6) ring. In the crystal, weak C-H⋯O hydrogen bonds and aromatic π-π stacking link the mol-ecules into a three-dimensional network. A Hirshfeld surface analysis showed that the major contribution to the inter-molecular inter-actions are van der Waals inter-actions (H⋯H contacts), accounting for 48.4% of the surface.

Cove-Edge Nanoribbon Materials for Efficient Inverted Halide Perovskite Solar Cells.

Two cove-edge graphene nanoribbons hPDI2-Pyr-hPDI2 (1) and hPDI3-Pyr-hPDI3 (2) are used as efficient electron-transporting materials (ETMs) in inverted planar perovskite solar cells (PSCs). Devices based on the new graphene nanoribbons exhibit maximum power-conversion efficiencies (PCEs) of 15.6 % and 16.5 % for 1 and 2, respectively, while a maximum PCE of 14.9 % is achieved with devices based on [6,6]-phenyl-C61 -butyric acid methyl ester (PC61 BM). The interfacial effects induced by these new materials are studied using photoluminescence (PL), and we find that 1 and 2 act as efficient electron-extraction materials. Additionally, compared with PC61 BM, these new materials are more hydrophobic and have slightly higher LUMO energy levels, thus providing better device performance and higher device stability.

6-Bromo-pyridine-2-carbaldehyde phenyl-hydrazone.

The title compound, C(12)H(10)BrN(3), is essentially planar (r.m.s. deviation of all non-H atoms = 0.0174 Å), with a dihedral angle of 0.5 (2)° between the two aromatic rings. In the crystal, mol-ecules are linked by weak N-H⋯N inter-actions, forming a zigzag chain running parallel to [001].