Browse
Submit Data
Databases
API
Help

Dataset Information

8 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Potent CYP3A4 Inhibitors Derived from Dillapiol and Sesamol.

ABSTRACT: Synthesis of 50 analogues of the natural insecticide synergists, dillapiol and sesamol, is reported. These were evaluated as potential insecticide synergists based on their inhibition of human CYP3A4. The most potent inhibitors have a relatively large hydrophobic substituent at either position 5 or 6 of these molecules. For example, 5-(benzyloxy)-6-(3-phenylsulfonyl)propyl)benzo[d][1,3]dioxole (18) and the diphenyl acetate of (6,7-dimethoxybenzo[d][1,3]dioxol-5-yl)propan-1-ol (5n) show inhibitory concentrations for 50% activity IC50 values of 0.086 and 0.2 ?M, respectively. These compounds are 106 and 46 times more potent than dillapiol whose IC50 for the inhibition of CYP3A4 is 9.2 ?M. The ortho-chloro analogue (8f), whose activity is 86 times the activity of dillapiol, is the most potent of the fourteen 5-(benzyloxy-6-(2 propenyl)benzo[d][1,3]dioxoles prepared for this study.

SUBMITTER: Francis Carballo-Arce A

PROVIDER: S-EPMC6648837 | biostudies-literature | 2019 Jun

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Publications

Potent CYP3A4 Inhibitors Derived from Dillapiol and Sesamol.

Francis Carballo-Arce Ana A Raina Vikrant V Liu Suqi S Liu Rui R Jackiewicz Victoria V Carranza David D Arnason John Thor JT Durst Tony T

ACS omega 20190624 6

Synthesis of 50 analogues of the natural insecticide synergists, dillapiol and sesamol, is reported. These were evaluated as potential insecticide synergists based on their inhibition of human CYP3A4. The most potent inhibitors have a relatively large hydrophobic substituent at either position 5 or 6 of these molecules. For example, 5-(benzyloxy)-6-(3-phenylsulfonyl)propyl)benzo[d][1,3]dioxole (18) and the diphenyl acetate of (6,7-dimethoxybenzo[d][1,3]dioxol-5-yl)propan-1-o ...[more]

PMID: 31460189

Similar Datasets

Computationally Designed Sesamol Derivatives Proposed as Potent Antioxidants.

Project description:Oxidative stress has been recognized to play an important role in several diseases, such as Parkinson's and Alzheimer's disease, which justifies the beneficial effects of antioxidants in ameliorating the deleterious effects of these health disorders. Sesamol, in particular, has been investigated for the treatment of several conditions because of its antioxidant properties. This article reports a rational computational design of new sesamol derivatives. They were constructed by adding four functional groups (-OH, -NH2, -COOH, and -SH) in three different positions of the sesamol molecular framework. A total of 50 derivatives between mono-, di-, and trisubstituted compounds were obtained. All the derivatives were evaluated and compared with a reference set of commercial neuroprotective drugs. The estimated properties are absorption, distribution, metabolism, excretion, toxicity, and synthetic accessibility. Selection and elimination scores were used to choose a first set of promising candidates. Acid-based properties and reactivity indexes were then estimated using the density functional theory. Four sesamol derivatives were finally selected, which are hypothesized to be potent antioxidants, even better than sesamol and Trolox for that purpose.

| S-EPMC7191856 | biostudies-literature

Alflutinib (AST2818), primarily metabolized by CYP3A4, is a potent CYP3A4 inducer.

Project description:Alflutinib (AST2818) is a third-generation epidermal growth factor receptor (EGFR) inhibitor that inhibits both EGFR-sensitive mutations and T790M mutations. Previous study has shown that after multiple dosages, alflutinib exhibits nonlinear pharmacokinetics and displays a time- and dose-dependent increase in the apparent clearance, probably due to its self-induction of cytochrome P450 (CYP) enzyme. In this study, we investigated the CYP isozymes involved in the metabolism of alflutinib and evaluated the enzyme inhibition and induction potential of alflutinib and its metabolites. The data showed that alflutinib in human liver microsomes (HLMs) was metabolized mainly by CYP3A4, which could catalyze the formation of AST5902. Alflutinib did not inhibit CYP isozymes in HLMs but could induce CYP3A4 in human hepatocytes. Rifampin is a known strong CYP3A4 inducer and is recommended by the FDA as a positive control in the CYP3A4 induction assay. We found that the induction potential of alflutinib was comparable to that of rifampin. The Emax of CYP3A4 induction by alflutinib in three lots of human hepatocytes were 9.24-, 11.2-, and 10.4-fold, while the fold-induction of rifampin (10 μM) were 7.22-, 19.4- and 9.46-fold, respectively. The EC50 of alflutinib-induced CYP3A4 mRNA expression was 0.25 μM, which was similar to that of rifampin. In addition, AST5902 exhibited much weak CYP3A4 induction potential compared to alflutinib. Given the plasma exposure of alflutinib and AST5902, both are likely to affect the pharmacokinetics of CYP3A4 substrates. Considering that alflutinib is a CYP3A4 substrate and a potent CYP3A4 inducer, drug-drug interactions are expected during alflutinib treatment.

| S-EPMC7608132 | biostudies-literature

Potent enzyme inhibitors derived from dromedary heavy-chain antibodies.

Project description:Evidence is provided that dromedary heavy-chain antibodies, in vivo-matured in the absence of light chains, are a unique source of inhibitory antibodies. After immunization of a dromedary with bovine erythrocyte carbonic anhydrase and porcine pancreatic alpha-amylase, it was demonstrated that a considerable amount of heavy-chain antibodies, acting as true competitive inhibitors, circulate in the bloodstream. In contrast, the conventional antibodies apparently do not interact with the enzyme's active site. Next we illustrated that peripheral blood lymphocytes are suitable for one-step cloning of the variable domain fragments in a phage-display vector. By bio-panning, several antigen-specific single-domain fragments are readily isolated for both enzymes. In addition we show that among those isolated fragments active site binders are well represented. When produced as recombinant protein in Escherichia coli, these active site binders appear to be potent enzyme inhibitors when tested in chromogenic assays. The low complexity of the antigen-binding site of these single-domain antibodies composed of only three loops could be valuable for designing smaller synthetic inhibitors.

| S-EPMC1170688 | biostudies-other

Characterization of three naturally occurring lignans, sesamol, sesamolin, and sesamin, as potent inhibitors of human cytochrome P450 46A1: Implications for treating excitatory neurotoxicity.

Project description:CYP46A1 is a brain-specific enzyme responsible for cholesterol homeostasis. Inhibition of CYP46A1 activity serves as a therapeutic target for excitatory neurotoxicity. Sesame is a common medicine and food resource; its component lignans possess various pharmacological activities. In this study, the inhibitory effects of sesame lignans on CYP46A1 activity were investigated. Inhibition kinetics analyses revealed that sesamin and sesamolin produce mixed partial competitive inhibition of CYP46A1, while sesamol produces non-competitive inhibition. Notably, molecular simulations revealed that the sesame lignans have excellent orientations within the active cavity of CYP46A1. Importantly, the sesame lignans had high permeability coefficients and low efflux ratios. Furthermore, sesamin significantly reduced the levels of 24S-hydroxycholesterol in rat plasma and brain tissues, and down-regulated the protein expressions of CYP46A1, NMDAR2A, NMDAR2B, and HMGCR. Collectively, sesame lignans exhibit significant inhibitory effects on CYP46A1 activity, highlighting their potential therapeutic role in treating excitatory neurotoxicity.

| S-EPMC9722955 | biostudies-literature

Identification of diet-derived constituents as potent inhibitors of intestinal glucuronidation.

Project description:Drug-metabolizing enzymes within enterocytes constitute a key barrier to xenobiotic entry into the systemic circulation. Furanocoumarins in grapefruit juice are cornerstone examples of diet-derived xenobiotics that perpetrate interactions with drugs via mechanism-based inhibition of intestinal CYP3A4. Relative to intestinal CYP3A4-mediated inhibition, alternate mechanisms underlying dietary substance-drug interactions remain understudied. A working systematic framework was applied to a panel of structurally diverse diet-derived constituents/extracts (n = 15) as inhibitors of intestinal UDP-glucuronosyl transferases (UGTs) to identify and characterize additional perpetrators of dietary substance-drug interactions. Using a screening assay involving the nonspecific UGT probe substrate 4-methylumbelliferone, human intestinal microsomes, and human embryonic kidney cell lysates overexpressing gut-relevant UGT1A isoforms, 14 diet-derived constituents/extracts inhibited UGT activity by >50% in at least one enzyme source, prompting IC(50) determination. The IC(50) values of 13 constituents/extracts (≤10 μM with at least one enzyme source) were well below intestinal tissue concentrations or concentrations in relevant juices, suggesting that these diet-derived substances can inhibit intestinal UGTs at clinically achievable concentrations. Evaluation of the effect of inhibitor depletion on IC(50) determination demonstrated substantial impact (up to 2.8-fold shift) using silybin A and silybin B, two key flavonolignans from milk thistle (Silybum marianum) as exemplar inhibitors, highlighting an important consideration for interpretation of UGT inhibition in vitro. Results from this work will help refine a working systematic framework to identify dietary substance-drug interactions that warrant advanced modeling and simulation to inform clinical assessment.

| S-EPMC4164973 | biostudies-literature

Lactoferrin-derived Peptides Active towards Influenza: Identification of Three Potent Tetrapeptide Inhibitors.

Project description:Bovine lactoferrin is a biglobular multifunctional iron binding glycoprotein that plays an important role in innate immunity against infections. We have previously demonstrated that selected peptides from bovine lactoferrin C-lobe are able to prevent both Influenza virus hemagglutination and cell infection. To deeper investigate the ability of lactoferrin derived peptides to inhibit Influenza virus infection, in this study we identified new bovine lactoferrin C-lobe derived sequences and corresponding synthetic peptides were synthesized and assayed to check their ability to prevent viral hemagglutination and infection. We identified three tetrapeptides endowed with broad anti-Influenza activity and able to inhibit viral infection in a concentration range femto- to picomolar. Our data indicate that these peptides may constitute a non-toxic tool for potential applications as anti-Influenza therapeutics.

| S-EPMC5587682 | biostudies-literature

Dipeptide-Derived Alkynes as Potent and Selective Irreversible Inhibitors of Cysteine Cathepsins.

Project description:The potential of designing irreversible alkyne-based inhibitors of cysteine cathepsins by isoelectronic replacement in reversibly acting potent peptide nitriles was explored. The synthesis of the dipeptide alkynes was developed with special emphasis on stereochemically homogeneous products obtained in the Gilbert-Seyferth homologation for C≡C bond formation. Twenty-three dipeptide alkynes and 12 analogous nitriles were synthesized and investigated for their inhibition of cathepsins B, L, S, and K. Numerous combinations of residues at positions P1 and P2 as well as terminal acyl groups allowed for the derivation of extensive structure-activity relationships, which were rationalized by computational covalent docking for selected examples. The determined inactivation constants of the alkynes at the target enzymes span a range of >3 orders of magnitude (3-10 133 M-1 s-1). Notably, the selectivity profiles of alkynes do not necessarily reflect those of the nitriles. Inhibitory activity at the cellular level was demonstrated for selected compounds.

| S-EPMC10041539 | biostudies-literature

Synthesis of Spin-Labelled Bergamottin: A Potent CYP3A4 Inhibitor with Antiproliferative Activity.

Project description:Bergamottin (BM, 1), a component of grapefruit juice, acts as an inhibitor of some isoforms of the cytochrome P450 (CYP) enzyme, particularly CYP3A4. Herein, a new bergamottin containing a nitroxide moiety (SL-bergamottin, SL-BM, 10) was synthesized; chemically characterized, evaluated as a potential inhibitor of the CYP2C19, CYP3A4, and CYP2C9 enzymes; and compared to BM and known inhibitors such as ketoconazole (KET) (3A4), warfarin (WAR) (2C9), and ticlopidine (TIC) (2C19). The antitumor activity of the new SL-bergamottin was also investigated. Among the compounds studied, BM showed the strongest inhibition of the CYP2C9 and 2C19 enzymes. SL-BM is a more potent inhibitor of CYP3A4 than the parent compound; this finding was also supported by docking studies, suggesting that the binding positions of BM and SL-BM to the active site of CYP3A4 are very similar, but that SL-BM had a better ?Gbind value than that of BM. The nitroxide moiety markedly increased the antitumor activity of BM toward HeLa cells and marginally increased its toxicity toward a normal cell line. In conclusion, modification of the geranyl sidechain of BM can result in new CYP3A4 enzyme inhibitors with strong antitumor effects.

| S-EPMC7013880 | biostudies-literature

Potent inhibitors of pro-inflammatory cytokine production produced by a marine-derived bacterium.

Project description:Cytokines produced through the antigen presenting cell (APC)-T-cell interaction play a key role in the activation of the allergic asthmatic response. Evaluating small molecules that inhibit the production of these pro-inflammatory proteins is therefore important for the discovery of novel chemical structures with potential antiasthma activity. We adapted a mouse splenocyte cytokine assay to screen a library of 2,500 marine microbial extracts for their ability to inhibit T(H)2 cytokine release and identified potent activity in a marine-derived strain CNQ431, identified as a Streptomyces species. Bioactivity guided fractionation of the organic extract of this strain led to the isolation of ten new 9-membered bis-lactones, splenocins A-J (1-10). The new compounds display potent biological activities, comparable to that of the corticosteroid dexamethasone, with IC(50) values from 2 to 50 nM in the splenocyte cytokine assay. This study provides the foundation for the optimization of these potent anti-inflammatory compounds for development in the treatment of asthma.

| S-EPMC2735501 | biostudies-literature

Discovery of Natural Product Derived Labdane Appended Triazoles as Potent Pancreatic Lipase Inhibitors.

Project description:Obesity contributes to the genesis of many metabolic disorders including dyslipidemia, coronary heart disease (CHD), nonalcoholic fatty liver, type 2 diabetes, etc. Pancreatic lipase plays a vital role in food fat digestion and absorption. Therefore, to control obesity, inhibition of pancreatic lipase is the active therapy. Thus, novel natural product derived labdane appended triazoles with pancreatic lipase inhibition potential were designed and synthesized. Among these hybrids, 6b and 6f exhibited excellent inhibitory activity (IC50 0.75 ± 0.02 ?M and 0.77 ± 0.01 ?M), slightly better than that of the positive control Orlistat (IC50 0.8 ± 0.03 ?M). Compounds 6c, 6e, and 6g-j inhibited the PL comparable to that of positive control. Interestingly none of the compounds showed cytotoxicity (Hep G2) in the concentration range from 0.5 to 100 ?M. Overall results reveal the potential of labdane appended triazoles as antiobesity agents.

| S-EPMC6047173 | biostudies-literature

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data