Medicinal Chemistry Research最新文献

The biosynthetic schemes for the production of halogenated peptidic natural products offer avenues for the discovery of peptide halogenases, and opportunities for development of biocatalysts for derivatization of peptides and proteins. Here, a short review of recent discoveries regarding biocatalytic protein and peptide halogenation is provided. Halogenation in two major classes of peptidic natural products is discussed, those that are produced as ribosomal peptides and post translationally modified, and those that are produced by assembly line-like non ribosomal peptide synthetases. Mechanistic considerations and biocatalytic applications of peptide halogenases are briefly discussed.

Kava, the root of Piper methysticum – plants dominantly cultivated in the South Pacific Islands, is traditionally consumed in the form of an aqueous suspension for its stress-reducing benefits. Beyond its traditional use, kava has demonstrated anticancer, anti-inflammatory, anxiolytic and other potentials. These effects are largely attributed to its major components, termed kavalactones. However, clinical findings of purported hepatotoxic risk have raised its safety concerns with a few causes hypothesized, including the potential of drug-herb interactions due to kavalactone perturbation of cytochrome P450 enzymes. In order to rigorously evaluate kava in the preclinical and clinical settings for its potential benefits and risks in future studies, a critical assessment of the possible contributing factors and mechanisms behind its purported hepatotoxic risk is essential. This review examines the current data on kava and kavalactones to modulate cytochrome P450 enzymes, including biochemical, cell-based, animal, and clinical data, and assess their potential contribution to kava’s hepatotoxic risk due to drug-herb interactions.

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Glutathionylation is an important Phase II biotransformation pathway that utilizes glutathione transferases (GSTs) to conjugate glutathione with reactive electrophiles represented by a great diversity in chemical structures. After further processing, the resulting metabolite is highly polar and rapidly eliminated. This pathway thus represents an important route of xenobiotic detoxification. Cats and dogs possess a combined repertoire of at least 27 cytosolic glutathione transferases belonging to the GST-A, -M, -P, -T, -Z and -O classes, with the greatest genetic diversity observed for the GSTA, GSTM, GSTP, and GSTT classes. GST transcript and protein expression have been demonstrated for most tissues in dogs, but less so in cats. In contrast to humans, these two species have fewer actively expressing GSTM genes, but a larger number of active GSTT genes. Dogs and cats also express distinct GSTP1-like and GSTT1-like enzymes. These differences in GST type and multiplicity, as well as residue changes that impact the secondary and tertiary structure of the cat and dog GST proteins, affect substrate selectivity and catalytic efficiency. Further research is required, especially in cats, to understand how species differences in glutathionylation modulate the risk of toxicity following exposure to certain drugs and environmental contaminants.

Cholinergic neuron damage and oxidative stress are prominent hypotheses explaining the pathogenesis of Alzheimer’s disease (AD). In this study, dual-acting compounds combining carbamate and diazepine structures were designed to function as both butyrylcholinesterase (BChE) inhibitors and antioxidants. Selective inhibition of BChE, particularly during the late stages of AD when its activity increases, was targeted. Introducing different diazepine derivatives (14, 15 and 16) provided insights into inhibitor basicity and enzyme-binding affinity. Among the synthesized compounds, heptyl carbamate (6b) demonstrated an IC₅₀ value of 32 ± 25 nM for BChE, with 96.5% purity confirmed by HPLC. Post-carbamoylation, the released compounds 15 and 16 exhibited antioxidant activities (70.2–85.3%) at 0.0136–0.1088 mM, comparable to ascorbic acid and α-tocopherol. The prepared carbamates demonstrated selectivity for BChE over acetylcholinesterase (AChE). Docking studies corroborated biological data, revealing compound 6b as the most potent. These findings highlight the therapeutic potential of these dual-acting compounds in addressing the multifaceted pathology of AD.

Antimicrobial resistance (AMR) has become a massive concern because it causes the loss of human life and an economic burden in many parts of the world. Antimicrobial peptides (AMPs) can be investigated as an alternative solution to combat AMR because their mechanism has the potential to reduce microbe resistance. In this study, the native P01 peptide from Chondrus crispus macroalgae was modified to P01.1, P01.2, and P01.3 peptides via residue mutations and capping of the N- and C-termini to systematically improve their α-helical content, bacterial membrane interaction, and antibacterial activity. C-terminus amidation and mutations to remove helix breaker residues in P01 to give P01.1 peptide enhanced its α-helical stability. Acetylation of the N-terminus P01.1 to give P01.2 peptide further enhanced the α-helical content of the peptide. Mutations of low-to-high helical former residues in P01.2 to give P01.3 peptide further improve its α-helical stability. The binding activity of peptides to a model of Gram-positive membrane is in the following order P01.3 > P01.2 > P01.1 > P01; this is correlated with their antibacterial activity against Gram-positive S. aureus with MICs in the following order P01.3 = 15.63 μg/mL > P01.2 = 125 μg/mL > P01.1 and P01 larger than 250 μg/mL. In a model of Gram-negative membrane, the peptide-membrane binding is in the following order P01.3 = P01.2 > P01.1 > P01; however, P01.3, P01.2, and P01.1 have the same antibacterial activity against Gram-negative E.coli (MIC = 3.91 μg/mL) while P01 has no activity. In conclusion, the α-helical stability and amphipathicity of the peptide have correlation with the membrane binding and antibacterial activity of the peptide.

Graphical Abstract

The estrogen sulfotransferase (EST), also called sulfotransferase 1E1 (SULT1E1), plays an important role in estrogen homeostasis by sulfonating and deactivating estrogens. The identification and characterization of EST inhibitors has been an active field of research. The EST inhibitors can not only be used as tool compounds to characterize the biochemical and pathophysiological functions of EST, but also have therapeutic potential due to the implications of EST and its regulation in hormone-dependent and independent pathological conditions. This review article is intended to provide a historical perspective and summary of the recent progress in the development and characterization of EST inhibitors.

Platycodin D (PD), a unique oleane-type triterpene saponin found in the roots of Platycodon grandiflorum (Jacq.) A. DC. (PG), has been included in the pharmacopoeia of many countries as a core indicator for quality control of PG. Modern studies have shown that PD has a wide range of pharmacological activities, including antitumor, anti-inflammatory, antioxidant, antifibrotic, antiviral, and multiorgan protective effects, and acts on the nervous system, digestive system, and internal organs of the human body through multiple pathways. In terms of extraction and purification, the traditional solvent method combined with green technologies such as ultrasound and microwave has significantly improved the extraction efficiency, while enzyme-catalyzed conversion of precursor substances and HPLC technology can achieve efficient purification of PD. Pharmacokinetic studies have shown that the oral bioavailability of PD is relatively low. However, the extract of PG can enhance its absorption through component synergy. Meanwhile, enteric-coated and gut microbiota regulation strategies provide new ideas for improving its efficacy. The content determination is mainly carried out by HPLC-ELSD, which is significantly affected by origin, processing methods, and environmental factors. This article systematically reviews the research progress in the extraction and purification, pharmacological activity, pharmacokinetics, and content determination of PD. Meanwhile, it advocates sustainable production and clinical transformation to fully utilize its therapeutic potential.

Attention-deficit/hyperactivity disorder (ADHD) is a neurodevelopmental disorder, with methylphenidate used as a first-line treatment. Methylphenidate is primarily hydrolyzed by carboxylesterase 1 (CES1) to inactive ritalinic acid, with minor oxidative metabolism producing active p-OH-methylphenidate and 6-oxo-methylphenidate lactam. The functional single-nucleotide polymorphism (SNP) in CES1, resulting in a glycine (G) to glutamic acid (E) substitution at 143 (G143E), is reported to significantly impair CES1 activity. However, limited clinical research has explored the pharmacokinetics of methylphenidate and its oxidation metabolites in ADHD therapeutics in G143E carriers. Three G143E ADHD subjects were genotyped for the G143E variant, and four non-carriers were identified and enrolled in the pharmacokinetic study. Participants received a single oral dose of methylphenidate, and plasma concentrations of methylphenidate, 6-oxo-methylphenidate, and p-OH-methylphenidate were extracted and quantified. Pharmacokinetic data were analyzed, and in vitro incubation of 6-oxo-methylphenidate with G143E S9 has been conducted. No significant differences were observed in the pharmacokinetics of methylphenidate. CES1 G143E carriers exhibited significantly elevated plasma concentrations of 6-oxo-methylphenidate, with a higher peak plasma concentration (C_max), area under the curve from time zero to infinity (AUC_0→∞), and longer half-life (T_1/2). Reduced function in in vitro studies suggested the impaired CES-mediated biotransformation of 6-oxo-methyphnidate to 6-oxo-ritalinic acid. These results provide pilot data on the substrate-dependent impact of the CES1 G143E variant. Whether or not the elevated concentrations of 6-oxo-methyphenidate contribute to the clinical activity of methylphenidate treatment remains a matter of speculation. Registry: ClinicalTrials.gov, TRN: NCT03781752, Registration date: 4-March-2018.

African trypanosomiasis is a major health threat to humans and animals in 36 countries within sub-Saharan Africa. We previously identified quinolone hydrazides exhibiting sub-micromolar anti-trypanosomal activity. However, the most potent compounds had poor aqueous solubility of <5 µM, hindering advancement to efficacy studies in animals. Accordingly, we generated a series of nine quinolone hydrazide analogues and evaluated in vitro anti-trypanosomal activity, cell toxicity and selected physicochemical properties. Compounds 4 and 5, exhibited potent anti-trypanosomal activity of 0.362 ± 0060 µM and 1.251 ± 0.295 µM, respectively and showed no toxicity (CC₅₀ > 20 µM) against HEK 293 cells. The two compounds showed slightly improved aqueous solubility of 5 µM when compared to the previously identified lead compounds and good LogD values (2–3).

Polychlorinated biphenyls (PCBs) are globally distributed pollutants that continue to pose health risks for humans and wildlife. Many effects of PCBs differ between the non-ortho-substituted, dioxin-like (DL), and the ortho-substituted non-dioxin-like (NDL) congeners. Metabolism of PCB congeners by cytochrome P450 enzymes can strongly affect their toxicity. Here we report on metabolism of a NDL PCB congener, 2,2′,5,5′-tetrachlorobiphenyl (PCB52), by a P450 purified from the marine fish Stenotomus chrysops (scup). (Without sequence information this protein is necessarily referred to by its original name, scup P450B.) PCB52 was metabolized at rates from 0.2–2 pmol/min/mg of liver microsomal protein, correlated with immunodetected amounts of P450B, and antibodies to P450B inhibited PCB52 metabolism. We conclude that PCB52 is metabolized by scup P450B. The P450B N-terminal amino acid sequence shares identity with mammalian CYP2Bs. However, PCB52 is metabolized in mammals by CYP2As. Thus, scup P450B has properties of both mammalian CYP2A and CYP2B proteins. Comparative sequence analyses point to scup P450B being a fish CYP2Y. Notably zebrafish CYP2Y3 shares synteny with a cluster of CYP2 genes in mammals. Thus, catalytic function, sequence searching, and zebrafish synteny data lead us to conclude that scup P450B is a CYP2Y and a co-ortholog to genes in the mammalian CYP2ABFGST cluster.