- Bacterial Biosynthetic P450 Enzyme PikCD50N: A Potential Biocatalyst for the Preparation of Human Drug Metabolites
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Human drug metabolites (HDMs) are important chemicals widely used in drug-related studies. However, acquiring these enzyme-derived and regio-/stereo-selectively modified compounds through chemical approaches is complicated. PikC is a biosynthetic P450 enz
- Cheng, Fangyuan,Du, Lei,Durairaj, Pradeepraj,Guo, Jiawei,Li, Fengwei,Li, Shengying,Liu, Xiaohui,Long, Xiangtian,Ma, Li,Tang, Dandan,Zhang, Gang,Zhang, Wei,Zhang, Xingwang
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p. 14563 - 14571
(2021/11/12)
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- Investigation of metabolite-protein interactions by transient absorption spectroscopy and in silico methods
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Transient absorption spectroscopy in combination with in silico methods has been employed to study the interactions between human serum albumin (HSA) and the anti-psychotic agent chlorpromazine (CPZ) as well as its two demethylated metabolites (MCPZ and DCPZ). Thus, solutions containing CPZ, MCPZ or DCPZ and HSA (molar ligand:protein ratios between 1:0 and 1:3) were submitted to laser flash photolysis and the ΔAmax value at λ = 470 nm, corresponding to the triplet excited state, was monitored. In all cases, the protein-bound ligand exhibited higher ΔAmax values measured after the laser pulse and were also considerably longer-lived than the non-complexed forms. This is in agreement with an enhanced hydrophilicity of the metabolites, due to the replacement of methyl groups with H that led to a lower extent of protein binding. For the three compounds, laser flash photolysis displacement experiments using warfarin or ibuprofen indicated Sudlow site I as the main binding site. Docking and molecular dynamics simulation studies revealed that the binding mode of the two demethylated ligands with HSA would be remarkable different from CPZ, specially for DCPZ, which appears to come from the different ability of their terminal ammonium groups to stablish hydrogen bonding interactions with the negatively charged residues within the protein pocket (Glu153, Glu292) as well as to allocate the methyl groups in an apolar environment. DCPZ would be rotated 180° in relation to CPZ locating the aromatic ring away from the Sudlow site I of HSA.
- Limones-Herrero, Daniel,Palumbo, Fabrizio,Vendrell-Criado, Victoria,Andreu, Inmaculada,Lence, Emilio,González-Bello, Concepción,Miranda, Miguel A.,Jiménez, M. Consuelo
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- A Focused Library of Psychotropic Analogues with Neuroprotective and Neuroregenerative Potential
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Overcoming the lack of effective treatments and the continuous clinical trial failures in neurodegenerative drug discovery might require a shift from the prevailing paradigm targeting pathogenesis to the one targeting simultaneously neuroprotection and neuroregeneration. In the studies reported herein, we sought to identify small molecules that might exert neuroprotective and neuroregenerative potential as tools against neurodegenerative diseases. In doing so, we started from the reported neuroprotective/neuroregenerative mechanisms of psychotropic drugs featuring a tricyclic alkylamine scaffold. Thus, we designed a focused-chemical library of 36 entries aimed at exploring the structural requirements for efficient neuroprotective/neuroregenerative cellular activity, without the manifestation of toxicity. To this aim, we developed a synthetic protocol, which overcame the limited applicability of previously reported procedures. Next, we evaluated the synthesized compounds through a phenotypic screening pipeline, based on primary neuronal systems. Phenothiazine 2Bc showed improved neuroregenerative and neuroprotective properties with respect to reference drug desipramine (2Aa). Importantly, we have also shown that 2Bc outperformed currently available drugs in cell models of Alzheimer's and Parkinson's diseases and attenuates microglial activation by reducing iNOS expression.
- Uliassi, Elisa,Pena-Altamira, Luis Emiliano,Morales, Aixa V.,Massenzio, Francesca,Petralla, Sabrina,Rossi, Michele,Roberti, Marinella,Martinez Gonzalez, Loreto,Martinez, Ana,Monti, Barbara,Bolognesi, Maria Laura
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p. 279 - 294
(2018/10/20)
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- Butyl methacrylate-co-ethylene glycol dimethacrylate monolith for online in-tube SPME-UHPLC-MS/MS to determine chlopromazine, clozapine, quetiapine, olanzapine, and their metabolites in plasma samples
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This manuscript describes a sensitive, selective, and online in-tube solid-phase microextraction coupled with an ultrahigh performance liquid chromatography-tandem mass spectrometry (in-tube SPME-UHPLC-MS/MS) method to determine chlopromazine, clozapine, quetiapine, olanzapine, and their metabolites in plasma samples from schizophrenic patients. Organic poly(butyl methacrylate-co-ethylene glycol dimethacrylate) monolith was synthesized on the internal surface of a fused silica capillary (covalent bonds) for in-tube SPME. Analyte extraction and analysis was conducted by connecting the monolithic capillary to an UHPLC-MS/MS system. The monolith was characterized by scanning electron microscopy (SEM) and Fourier transform infrared spectrometry (FTIR). The developed method presented adequate linearity for all the target antipsychotics: R2 was higher than 0.9975, lack-of-fit ranged from 0.115 to 0.955, precision had variation coefficients lower than 14.2%, and accuracy had relative standard error values ranging from ?13.5% to 14.6%, with the exception of the lower limit of quantification (LLOQ). The LLOQ values in plasma samples were 10 ng mL?1 for all analytes. The developed method was successfully applied to determine antipsychotics and their metabolites in plasma samples from schizophrenic patients.
- Beloti, Luiz G.M.,Miranda, Luis F.C.,Queiroz, Maria Eugênia C.
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- NB 06: From a simple lysosomotropic aSMase inhibitor to tools for elucidating the role of lysosomes in signaling apoptosis and LPS-induced inflammation
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Ceramide generation is involved in signal transduction of cellular stress response, in particular during stress-induced apoptosis in response to stimuli such as minimally modified Low-density lipoproteins, TNFalpha and exogenous C6-ceramide. In this paper we describe 48 diverse synthetic products and evaluate their lysosomotropic and acid sphingomyelinase inhibiting activities in macrophages. A stimuli-induced increase of C16-ceramide in macrophages can be almost completely suppressed by representative compound NB 06 providing an effective protection of macrophages against apoptosis. Compounds like NB 06 thus offer highly interesting fields of application besides prevention of apoptosis of macrophages in atherosclerotic plaques in vessel walls. Most importantly, they can be used for blocking pH-dependent lysosomal processes and enzymes in general as well as for analyzing lysosomal dependent cellular signaling. Modulation of gene expression of several prominent inflammatory messengers IL1B, IL6, IL23A, CCL4 and CCL20 further indicate potentially beneficial effects in the field of (systemic) infections involving bacterial endotoxins like LPS or infections with influenza A virus.
- Blaess, Markus,Bibak, Nelly,Claus, Ralf A.,Kohl, Matthias,Bonaterra, Gabriel A.,Kinscherf, Ralf,Laufer, Stefan,Deigner, Hans-Peter
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supporting information
p. 73 - 104
(2017/10/17)
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- Chemical synthetic platform for chlorpromazine oligomers that were reported as photo-degradation products of chlorpromazine
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A synthetic platform for chlorpromazine (CPZ) oligomers, which could be generated via photo-reaction of CPZ, is essential to promote their biological and structural studies. In this paper, the first synthetic platform for CPZ oligomers is described. A photo-irradiation experiment of CPZ to confirm whether the structure of the CPZ dimer generated by the photo-irradiation was identical to that prepared by our synthetic method is also reported.
- Kohiki, Taiki,Nishikawa, Yusuke,Inokuma, Tsubasa,Shigenaga, Akira,Otaka, Akira
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p. 1161 - 1166
(2017/12/26)
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- Chemical synthetic platform for chlorpromazine oligomers that were reported as photo-degradation products of chlorpromazine
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A synthetic platform for chlorpromazine (CPZ) oligomers, which could be generated via photo-reaction of CPZ, is essential to promote their biological and structural studies. In this paper, the first synthetic platform for CPZ oligomers is described. A photo-irradiation experiment of CPZ to confirm whether the structure of the CPZ dimer generated by the photo-irradiation was identical to that prepared by our synthetic method is also reported.
- Kohiki, Taiki,Nishikawa, Yusuke,Inokuma, Tsubasa,Shigenaga, Akira,Otaka, Akira
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p. 1161 - 1166
(2018/05/02)
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- Synthesis and synergistic antimycobacterial screening of chlorpromazine and its metabolites
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The antimycobacterial activities of chlorpromazine and its metabolites were evaluated alone and in combination with antitubercular drugs. Although associated with limited antimycobacterial activity when tested individually, chlorpromazine and its metabolites exhibited clear synergy when tested in combination with a number of aminoglycosides as well as the active metabolite of rifampicin, 25-desaceteylrifampicin. The combination of chlorpromazine and spectinomycin was associated with the greatest synergy, yielding a fractional inhibitory concentration index (FICI) of 0.31. Synergistic interactions were also observed for combinations of 7-hydroxychlorpromazine or nor-chlorpromazine with kanamycin, streptomycin, spectinomycin and 25-desacetylrifampicin (FICI 0.19-0.5).
- Kigondu, Elizabeth M.,Njoroge, Mathew,Singh, Kawaljit,Njuguna, Nicholas,Warner, Digby F.,Chibale, Kelly
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supporting information
p. 502 - 506
(2014/04/17)
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- Potential utility of histamine H3 receptor antagonist pharmacophore in antipsychotics
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Histamine H3 receptor (H3R) antagonists have some antipsychotic properties although the clear molecular mechanism is still unknown. As actually the most effective and less side effective antipsychotics are drugs with multiple targets
- von Coburg,Kottke,Weizel,Ligneau,Stark
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scheme or table
p. 538 - 542
(2011/02/28)
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- The singlet oxygen oxidation of chlorpromazine and some phenothiazine derivatives. Products and reaction mechanisms
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(Chemical Equation Presented) A kinetic and product study of the reactions of chlorpromazine 1, N-methylphenothiazine 2, and N-ethylphenothiazine 3 with singlet oxygen was carried out in MeOH and MeCN. 1 undergoes exclusive side-chain cleavage, whereas the reactions of 2 and 3, in MeOH, afforded only the corresponding sulfoxides. A mechanism for the reaction of 1 is proposed where the first step involves an interaction between singlet oxygen and the side-chain dimethylamino nitrogen. This explains why no side-chain cleavage is observed for 2 and 3.
- Baciocchi, Enrico,Del Giacco, Tiziana,Lanzalunga, Osvaldo,Lapi, Andrea,Raponi, Daniele
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p. 5912 - 5915
(2008/02/10)
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- Catalytic N-Dealkylation of Tertiary Amines--A Biomimetic Oxygenation Reaction
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A heterogeneous catalyst system is described for N-dealkylation of tertiary amines.A large number of tertiary amines including some important synthetic drugs were N-dealkylated to give the corresponding secondary amines in 50-65percent yields.The reaction was carried out at room temperature by stirring a solution of a tertiary amine in methanol containing 10percent palladium-on-charcoal catalyst.The reaction had absolute requirement for molecular oxygen like the enzymatic dealkylation reaction.It also needed methanol to act as the reductant of molecular oxygen like the NADPH in the enzymatic reaction.A catalytic cycle similar to cytochrome P-450-catalysed oxygenation cycle is proposed for activation and transfer of oxygen to the α-carbon of tertiary amines to give unstable carbinolamines which on dissociation yield secondary amines.
- Chaudhuri, Naba K.,Servando, Ofelia,Markus, Bohdan,Galynker, Igor,Sung, Ming-Sang
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p. 899 - 903
(2007/10/02)
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