ABSTRACT
Multiple sclerosis (MS) is a serious central nervous system (CNS) disease responsible for disability problems and deterioration of the quality of life. Several approaches have been applied to medications entering the market to treat this disease. However, no effective therapy currently exists, and the available drugs simply ameliorate the destructive disability effects of the disease. In this review article, we report on the efforts that have been conducted towards establishing the conformational properties of wild-type myelin basic protein (MBP), myelin proteolipid protein (PLP), myelin oligodendrocyte glycoprotein (MOG) epitopes or altered peptide ligands (ALPs). These efforts have led to the aim of discovering some non-peptide mimetics possessing considerable activity against the disease. These efforts have contributed also to unveiling the molecular basis of the molecular interactions implicated in the trimolecular complex, T-cell receptor (TCR)-peptide-major histocompatibility complex (MHC) or human leucocyte antigen (HLA).
ABSTRACT
It has been reported that beta amyloid induces production of radical oxygen species and oxidative stress in neuronal cells, which in turn upregulates ß-secretase (BACE-1) expression and beta amyloid levels, thereby propagating oxidative stress and increasing neuronal injury. A series of resveratrol derivatives, known to be inhibitors of oxidative stress-induced neuronal cell death (oxytosis) were biologically evaluated against BACE-1 using homogeneous time-resolved fluorescence (TRF) assay. Correlation between oxytosis inhibitory and BACE-1 inhibitory activity of resveratrol derivatives was statistically significant, supporting the notion that BACE-1 may act as pivotal mediator of neuronal cell oxytosis. Four of the biologically evaluated resveratrol analogs demonstrated considerably higher activity than resveratrol in either assay. The discovery of some "hits" led us to initiate detailed docking studies associated with Molecular Dynamics in order to provide a plausible explanation for the experimental results and understand their molecular basis of action.
Subject(s)
Alzheimer Disease/drug therapy , Amyloid Precursor Protein Secretases/antagonists & inhibitors , Aspartic Acid Endopeptidases/antagonists & inhibitors , Molecular Dynamics Simulation , Stilbenes/pharmacology , Alzheimer Disease/metabolism , Amyloid Precursor Protein Secretases/metabolism , Animals , Aspartic Acid Endopeptidases/metabolism , Cell Death/drug effects , Cell Line , Dose-Response Relationship, Drug , Mice , Molecular Structure , Neurons/cytology , Neurons/drug effects , Neurons/metabolism , Oxidative Stress/drug effects , Resveratrol , Stilbenes/chemistry , Stilbenes/therapeutic use , Structure-Activity RelationshipABSTRACT
Congeneric set of thirty-eight 4-aryl-4-oxo-2-(N-aryl/cycloalkyl)butanamides has been designed, synthesized and evaluated for acetyl- and butyrylcholinesterase inhibitory activity. Structural variations included cycloalkylamino group attached to C2 position of butanoyl moiety, and variation of amido moiety of molecules. Twelve compounds, mostly piperidino and imidazolo derivatives, inhibited AChE in low micromolar range, and were inactive toward BChE. Several N-methylpiperazino derivatives showed inhibition of BChE in low micromolar or submicromolar concentrations, and were inactive toward AChE. Therefore, the nature of the cycloalkylamino moiety governs the AChE/BChE selectivity profile of compounds. The most active AChE inhibitor showed mixed-type inhibition modality, indicating its binding to free enzyme and to enzyme-substrate complex. Thorough docking calculations of the seven most potent AChE inhibitors from the set, showed that the hydrogen bond can be formed between amide -NH- moiety of compounds and -OH group of Tyr 124. The 10 ns unconstrained molecular dynamic simulation of the AChE-compound 18 complex shows that this interaction is the most persistent. This is, probably, the major anchoring point for the binding.
Subject(s)
Acetylcholinesterase/metabolism , Amides/pharmacology , Butyrylcholinesterase/metabolism , Cholinesterase Inhibitors/pharmacology , Molecular Docking Simulation , Molecular Dynamics Simulation , Amides/chemical synthesis , Amides/chemistry , Cholinesterase Inhibitors/chemical synthesis , Cholinesterase Inhibitors/chemistry , Crystallography, X-Ray , Dose-Response Relationship, Drug , Ligands , Molecular Structure , Structure-Activity RelationshipABSTRACT
In the present work, a facile and efficient route for the synthesis of a series of N-substituted imidazole derivatives is described. Docking studies have revealed that N-substituted imidazole derivatives based on (E)-urocanic acid may be potential antihypertensive leads. Therefore, new AT1 receptor blockers bearing either the benzyl or the biphenylmethyl moiety at the N-1 or N-3 position, either the (E)-acrylate or the propanoate fragment and their related acids at the C-4 position as well as a halogen atom at the C-5 position of the imidazole ring, were synthesized. The newly synthesized analogues were evaluated for binding to human AT1 receptor. The biological results showed that this class of molecules possesses moderate or no activity, thus not always confirming high docking scores. Nonetheless, important conclusions can be derived for their molecular basis of their mode of action and help medicinal chemists to design and synthesize more potent ones. An aliphatic group as in losartan seems to be important for enhancing binding affinity and activity.
Subject(s)
Angiotensin II Type 1 Receptor Blockers/chemical synthesis , Angiotensin II Type 1 Receptor Blockers/pharmacology , Antihypertensive Agents/chemical synthesis , Antihypertensive Agents/pharmacology , Imidazoles/pharmacology , Angiotensin II Type 1 Receptor Blockers/chemistry , Antihypertensive Agents/chemistry , Drug Design , Humans , Imidazoles/chemical synthesis , Imidazoles/chemistry , Molecular Docking Simulation , Receptor, Angiotensin, Type 1/metabolism , Structure-Activity Relationship , Urocanic Acid/chemistry , Urocanic Acid/metabolismABSTRACT
A series of symmetrically bis-substituted imidazole analogs bearing at the N-1 and N-3 two biphenyl moieties ortho substituted either with tetrazole or carboxylate functional groups was designed based on docking studies and utilizing for the first time an extra hydrophobic binding cleft of AT1 receptor. The synthesized analogs were evaluated for their in vitro antagonistic activities (pA2 values) and binding affinities (-logIC50 values) to the Angiotensin II AT1 receptor. Among them, the potassium (-logIC50 = 9.04) and the sodium (-logIC50 = 8.54) salts of 4-butyl-N,N'-bis{[2'-(2H-tetrazol-5-yl)biphenyl-4-yl]methyl}imidazolium bromide (12a and 12b, respectively) as well as its free acid 11 (-logIC50 = 9.46) and the 4-butyl-2-hydroxymethyl-N,N'-bis{[2'-(2H-tetrazol-5-yl)biphenyl-4-yl]methyl}imidazolium bromide (14) (-logIC50 = 8.37, pA2 = 8.58) showed high binding affinity to the AT1 receptor and high antagonistic activity (potency). The potency was similar or even superior to that of Losartan (-logIC50 = 8.25, pA2 = 8.25). On the contrary, 2-butyl-N,N'-bis{[2'-[2H-tetrazol-5-yl)]biphenyl-4-yl]methyl}imidazolium bromide (27) (-logIC50 = 5.77) and 2-butyl-4-chloro-5-hydroxymethyl-N,N'-bis{[2'-[2H-tetrazol-5-yl)]biphenyl-4-yl]methyl}imidazolium bromide (30) (-logIC50 = 6.38) displayed very low binding affinity indicating that the orientation of the n-butyl group is of primary importance. Docking studies of the representative highly active 12b clearly showed that this molecule has an extra hydrophobic binding feature compared to prototype drug Losartan and it fits to the extra hydrophobic cavity. These results may contribute to the discovery and development of a new class of biologically active molecules through bis-alkylation of the imidazole ring by a convenient and cost effective synthetic strategy.
Subject(s)
Angiotensin II Type 1 Receptor Blockers/pharmacology , Drug Design , Imidazoles/pharmacology , Angiotensin II Type 1 Receptor Blockers/chemical synthesis , Angiotensin II Type 1 Receptor Blockers/chemistry , Dose-Response Relationship, Drug , Humans , Imidazoles/chemical synthesis , Imidazoles/chemistry , Models, Molecular , Molecular Structure , Quantum Theory , Structure-Activity RelationshipABSTRACT
Twenty-nine compounds were isolated from the aerial parts of the Greek plant C. zuccariniana DC. The structures of the isolated compounds were established by means of NMR- ((1) H,(1) H-COSY, (1) H,(13) C-HSQC, HMBC, NOESY, and ROESY) and mass-spectral analyses. These compounds comprise 13 sesquiterpene lactones, 14 flavonoids, two lignans, and one simple lactone. Among the isolated sesquiterpene lactones, three are new, namely one heliangolide, (1E,4Z)-15-hydroxy-8α-O-(4'-acetoxy-3'-hydroxy-2'-methylidenebutanoyl)-6ßH,7αH-germacra-1,4,11(13)-trien-6,12-olide; and two eudesmanolides, 8α-(4',5'-diacetoxyangeloyl)sonchucarpolide and one unusual eudesmanolide with an oxygenated bridge linking C(1) and C(4), named zuccarinin. The main sesquiterpene lactones were malacitenolide, cnicin, and 4'-O-acetylcnicin. These results are in agreement with those obtained from the previously studied Greek Centaurea sp. belonging to the section Acrolophus (Cass.) DC.; this finding could be of chemotaxonomic significance for the genus Centaurea. The in vitro antimicrobial activities of the isolated new sesquiterpene lactones were against eight bacteria and eight fungal species. A 96-well microbioassay procedure for fast and easy evaluation of antibacterial and antifungal activities was applied to compare these compounds with commercial antibiotic and fungicide standards, and with previously isolated analogous sesquiterpene lactones tested by the same bioassay. All of the compounds tested showed moderate antibacterial, but significant antifungal activities; the present results corroborate with previous data, indicating that these types of compounds exhibit low or moderate antibacterial, but potent antifungal activities. The unusual eudesmanolide zuccarinin proved to be the most potent among the present tested sesquiterpene lactones, as well as among all previously tested eudesmanolides isolated from Greek Centaurea sp.
Subject(s)
Anti-Infective Agents/chemistry , Centaurea/chemistry , Lactones/chemistry , Sesquiterpenes/chemistry , Anti-Infective Agents/isolation & purification , Anti-Infective Agents/pharmacology , Bacteria/drug effects , Fungi/drug effects , Lactones/isolation & purification , Lactones/pharmacology , Magnetic Resonance Spectroscopy , Microbial Sensitivity Tests , Molecular Conformation , Plant Components, Aerial/chemistryABSTRACT
The antibacterial and antifungal activities of an ample number of phenolic compounds isolated from Quercus ilex leaves, belonging to the classes of flavonoids, proanthocyanidins, and phenolic acids, are discussed. The isolation of A type proanthocyanidin, (+)-epigallocatechin-(2ßâOâ7, 4ßâ8)-(+)-catechin is reported for the first time. Its structure was established by means of highfield NMR (correlation spectroscopy, heteronuclear single quantum correlation, heteronuclear multiple bond correlation, and rotating frame Overhauser effect spectroscopy) and MS spectral analyses, while its absolute configuration was determined by circular dichroism measurements. The isolated compounds were tested for their antimicrobial effects against eight human bacterial species and 14 fungal species. In a second step, the most potent compounds were tested in combination with the conventional fungicides, bifonazole and ketoconazole, to evaluate possible synergistic effects. Results showed that proanthocyanidins 3 and 4 when combined with bifonazole and ketoconazole increase the activity of both of these conventional fungicides. Moreover, the pharmacokinetic profile of the isolated compounds was investigated using computational methods.
Subject(s)
Anti-Infective Agents/pharmacokinetics , Phenols/pharmacokinetics , Plant Extracts/pharmacokinetics , Proanthocyanidins/pharmacokinetics , Quercus/chemistry , Anti-Infective Agents/chemistry , Bacteria/drug effects , Dimerization , Drug Synergism , Fungi/drug effects , Molecular Structure , Phenols/chemistry , Plant Extracts/chemistry , Proanthocyanidins/chemistryABSTRACT
In previous studies it was shown that cannabinoids (CBs) bearing a phenolic hydroxyl group modify the thermal properties of lipid bilayers more significantly than methylated congeners. These distinct differential properties were attributed to the fact that phenolic hydroxyl groups constitute an anchoring group in the vicinity of the head-group, while the methylated analogs are embedded deeper towards the hydrophobic region of the lipid bilayers. In this work the thermal effects of synthetic polyphenolic stilbenoid analogs and their methylated congeners have been studied using differential scanning calorimetry (DSC). Molecular dynamics (MD) simulations have been performed to explain the DSC results. Thus, two of their phenolic hydroxyl groups orient in the lipid bilayers in such a way that they anchor in the region of the head-group. In contrast, their methoxy congeners cannot anchor effectively and are embedded deeper in the hydrophobic segment of the lipid bilayers. The MD results explain the fact that hydroxystilbenoid analogs exert more significant effects on the pretransition than their methoxy congeners, especially at low concentrations. To maximize the polar interactions, the two phenolic hydroxyl groups are localized in the vicinity of the head-group region, directing the remaining hydroxy group in the hydrophobic region. This topographical position of stilbenoid analogs forms a mismatch that explains the significant broadening of the width of the phase transition and lowering of the main phase-transition temperature in the lipid bilayers. At high concentrations, hydroxy and nonhydroxy analogs appear to form different domains. The correlation of thermal effects with antioxidant activity is discussed.
Subject(s)
Antioxidants/chemistry , Calorimetry, Differential Scanning/methods , Lipid Bilayers/chemistry , Molecular Dynamics Simulation , Stilbenes/chemistry , Temperature , 1,2-Dipalmitoylphosphatidylcholine/chemistry , Hydroxides/chemistry , Isomerism , Phenols/chemistry , Resveratrol , ThermodynamicsABSTRACT
Pyrrolyl-propionic and butyric-acid derivatives 1 and 2 were synthesized in order to study the effect of the variation of the methylene chain in comparison to the previously reported pyrrolyl-acetic acid compound I, which was found as potent aldose reductase inhibitor, while the pyrrolyl-tetrazole derivatives 3-5 were prepared as a non-classical bioisosteres of a carboxylic acid moiety. Also, pyrrolyl-tetrazole isomers 6 and 7 without an alkyl chain between the two aromatic rings were synthesized. The in vitro aldose reductase inhibitory activity of the prepared 1-7 compounds were estimated and compared with that of the initial compound (I). Overall, the data indicate that the presented chemotypes 6 and 7 are a promising lead compounds for the development of selective aldose reductase inhibitors, aiming to the long-term complications of diabetes mellitus.
Subject(s)
Aldehyde Reductase/antagonists & inhibitors , Carboxylic Acids/chemistry , Drug Design , Enzyme Inhibitors/pharmacology , Pyrroles/pharmacology , Tetrazoles/chemistry , Animals , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/chemistry , Female , Male , Molecular Structure , Pyrroles/chemical synthesis , Pyrroles/chemistry , Rats , Rats, Inbred F344 , Stereoisomerism , Structure-Activity RelationshipABSTRACT
Nine sesquiterpene lactones, anthemin A (1), 1alpha-hydroxydeacetylirinol-4alpha,5beta-epoxide (2), anthemin C (3), tatridin A (4), 1-epi-tatridin B (5), anthemin B (6), 6-deacetyl-beta-cyclopyrethrosin (7), elegalactone A (8), and 1beta,4alpha,6alpha-trihydroxyeudesm-11-en-8alpha-12-olide (9), were isolated from the aerial parts of A. melanolepis in addition to eight known flavonoids and three phenolic acids. Compounds 1, 3, and 6 are new natural products. The structures of the compounds were deduced by spectroscopic methods. The in vitro antimicrobial potential of the isolated sesquiterpene lactones against four Gram-positive and five Gram-negative bacteria and one fungus was evaluated using the microdilution method, and their in vitro cytotoxic activity was determined against a panel of human tumor cell lines. Furthermore, the pharmacokinetic profile of the sesquiterpene lactones was investigated using computational methods.
Subject(s)
Anthemis/chemistry , Anti-Bacterial Agents/isolation & purification , Anti-Bacterial Agents/pharmacology , Antineoplastic Agents, Phytogenic/isolation & purification , Antineoplastic Agents, Phytogenic/pharmacology , Lactones/isolation & purification , Lactones/pharmacology , Plants, Medicinal/chemistry , Sesquiterpenes/isolation & purification , Sesquiterpenes/pharmacology , Anti-Bacterial Agents/chemistry , Antineoplastic Agents, Phytogenic/chemistry , Drug Screening Assays, Antitumor , Gram-Negative Bacteria/drug effects , Gram-Positive Bacteria/drug effects , Greece , Humans , Lactones/chemistry , Microbial Sensitivity Tests , Molecular Structure , Nuclear Magnetic Resonance, Biomolecular , Sesquiterpenes/chemistryABSTRACT
Aldose reductase (ALR2) of the polyol metabolic pathway is a target enzyme for the treatment of diabetic complications. A variety of synthetic and natural compounds have been observed to inhibit aldose reductase. Among them, rosmarinic acid has been shown to be in vitro an aldose reductase inhibitor in a micromolar range. In this study, two nitro derivatives of rosmarinic acid synthesized previously, 6'-nitro and 6',6''-dinitrorosmarinic acids, are proposed as aldose reductase inhibitors. Docking studies of the nitro derivatives have been carried out in the active site of aldose reductase. The theoretical results have shown a higher estimated binding energy of both compounds in comparison to that of rosmarinic acid suggesting a higher ALR2 inhibitory activity. The in vitro biological assays confirmed that these compounds were more potent than the parent rosmarinic acid.
Subject(s)
Aldehyde Reductase/antagonists & inhibitors , Cinnamates/pharmacology , Depsides/pharmacology , Enzyme Inhibitors/pharmacology , Binding Sites , Cinnamates/chemistry , Depsides/chemistry , Drug Evaluation, Preclinical , Enzyme Inhibitors/chemistry , Models, Molecular , Rosmarinic AcidABSTRACT
When X-ray structure of a ligand-bound receptor is not available, homology models of the protein of interest can be used to obtain the ligand-binding cavities. The steroelectronic properties of these cavities are directly related to the performed molecular model coordinates. Thus, the use of different template structures for homology may result in variation of ligand-binding modes. We have recently reported the MD simulations of a potent CB ligand at bovine rhodopsin-based CB1 and CB2 receptors (Durdagi et al., Bioorg Med Chem 16:7377-7387, 2008). In this present study, a homology modeling study based on the beta2-adrenergic receptor for both CB1 and CB2 receptors was performed, and the results were compared with rhodopsin-based models. In addition, the role of membrane bilayers to the adopted conformations of potent AMG3 CB ligand has been analyzed for receptor-free and membrane-associated receptor systems. The performed MD trajectory analysis results have shown that gauche conformations at the terminal segment of the alkyl side chain of AMG3 are not favored in solution. Different adopting dihedral angles defined between aromatic and dithiolane rings at the active sites of the CB1 and CB2 receptors, which are adapted lead to different alkyl side chain orientations and thus, may give clues to the medicinal chemists to synthesize more selective CB ligands. The binding sites of receptors derived by rhodopsin-based models have been regenerated using the beta2-adrenergic based template receptors. The re-obtained models confirmed the ligand-binding pockets that were derived based on rhodopsin.
Subject(s)
Cannabinoids/chemistry , Molecular Dynamics Simulation , Receptors, Cannabinoid/chemistry , 1,2-Dipalmitoylphosphatidylcholine/chemistry , Animals , Binding Sites , Cannabinoids/metabolism , Catalytic Domain , Cattle , Cluster Analysis , Computational Biology , Dimethyl Sulfoxide/chemistry , Drug Design , Ligands , Lipid Bilayers/chemistry , Monte Carlo Method , Receptors, Adrenergic, beta-2/chemistry , Receptors, Adrenergic, beta-2/metabolism , Receptors, Cannabinoid/metabolism , Reproducibility of Results , Rhodopsin/chemistry , Structural Homology, Protein , ThermodynamicsABSTRACT
Diterpen labd-13(E)-ene-8a,15-diol (1) is a natural product found to possess potential cytotoxic and cytostatic effects against human cancer cell lines. Adenylyl cyclases (ACs) are promising pharmacological targets for treating heart failure, cancer, and psychosis. It has been demonstrated that forskolin is a potent adenylyl cyclase activator. Labdane 1 belongs to same family as forskolin. Its conformational properties are explored using a combination of 1D, 2D NMR spectroscopy, and molecular modeling techniques. The derived low energy conformers are subjected to docking calculations aiming to reveal similarities and differences in the binding mode between 1 and forskolin. Additionally, docking calculations performed on the 1alpha,9alpha-OH and 1alpha-OH derivatives of 1 suggest major contribution of 1alpha position in increasing binding affinity. This information may be of paramount importance to medicinal chemists who are interested in the synthesis of proposed analogs and test the docking results through in vitro experiments.
Subject(s)
Adenylyl Cyclases/chemistry , Colforsin/chemistry , Computer Simulation , Diterpenes/chemistry , Diterpenes/pharmacology , Models, Chemical , Adenylyl Cyclase Inhibitors , Binding Sites/drug effects , Colforsin/pharmacology , Crystallography, X-Ray , Ligands , Magnetic Resonance Spectroscopy/methods , Magnetic Resonance Spectroscopy/standards , Models, Molecular , Molecular Conformation , Reference Standards , Stereoisomerism , Structure-Activity RelationshipABSTRACT
A novel elemanolide with an alpha-methyl-gamma-lactone moiety, 8alpha-O-(4-hydroxy-2-methylenebutanoyloxy)melitensine, in addition to four known sesquiterpene lactones also bearing the same lactone ring, melitensin, 11beta,13 dihydrosalonitenolide, 8alpha-hydroxy-11beta,13-dihydro-4-epi-sonchucarpolide, and 8alpha-hydroxy-11beta,13-dihydro-onopordaldehyde have been isolated from the aerial parts of Centaurea pullata. The in vitro antibacterial and antifungal activities of the isolated sesquiterpene lactones were tested against six bacteria and eight fungal species, using a microdilution method. All compounds tested showed greater antibacterial and antifungal activities than the positive controls used. Moreover, the pharmacokinetic profile of these compounds was investigated using computational methods.
Subject(s)
Anti-Bacterial Agents/chemistry , Anti-Bacterial Agents/pharmacology , Centaurea/chemistry , Lactones/chemistry , Lactones/pharmacology , Sesquiterpenes/chemistry , Anti-Bacterial Agents/isolation & purification , Lactones/isolation & purification , Magnetic Resonance Spectroscopy , Microbial Viability/drug effects , Molecular Structure , Structure-Activity RelationshipABSTRACT
In this study, five secondary metabolites (caffeic acid, rosmarinic acid, lithospermic acid B, 12-hydroxyjasmonic acid 12-O-beta-glucoside and p-menth-3-ene-1,2-diol 1-O-beta-glucopyranoside) isolated from the polar extracts of the plant Origanum vulgare L. ssp. hirtum, were tested in vitro for their ability to inhibit soybean lipoxygenase. Among the examined compounds, lithospermic acid B demonstrated the best inhibitory activity on soybean lipoxygenase with IC50 = 0.1 mM. Docking studies have been undertaken as an attempt for better understanding the interactions of these compounds within the active site of soybean lipoxygenase. The predicted binding energy values correlated well with the observed biological data.
Subject(s)
Glycine max/enzymology , Lipoxygenase Inhibitors/pharmacology , Lipoxygenase/metabolism , Origanum/chemistry , Plant Extracts/pharmacology , Lipoxygenase Inhibitors/chemistry , Lipoxygenase Inhibitors/metabolism , Models, Molecular , Plant Extracts/chemistry , Plant Extracts/metabolismABSTRACT
From the polar extracts of Origanum vulgare L. ssp. hirtum 19 compounds have been isolated. The structures and relative stereochemistry have been elucidated by spectroscopic analysis and determined as apigenin, luteolin, chrysoeriol, diosmetin, quercetin, eriodictyol, cosmoside, vicenin-2, caffeic acid, p-menth-3-ene-1,2-diol 1-O-beta-glucopyranoside, thymoquinol 2-O-beta-glucopyranoside, thymoquinol 5-O-beta-glucopyranoside, thymoquinol 2,5-O-beta-diglucopyranoside, 12-hydroxyjasmonic acid, 12-hydroxyjasmonic acid 12-O-beta-glucopyranoside, lithospermic acid B, rosmarinic acid, 10-epi-lithospermic acid, and epi-lithospermic acid B. The three latter products display unusual stereochemistry of the 3,4-hydroxyphenyllactic acid unit(s), which to the authors' best knowledge has never been reported before in similar compounds. Moreover, lithospermic acid B (and its stereoisomers), p-menth-3-ene-1,2-diol 1-O-beta-glucopyranoside, 12-hydroxyjasmonic acid, and 12-hydroxyjasmonic acid 12-O-beta-glucopyranoside were isolated for the first time from Origanum species.
Subject(s)
Origanum/chemistry , Plant Extracts/chemistry , Circular Dichroism , Flavonoids/analysis , Glucosides/analysis , Greece , Magnetic Resonance Spectroscopy , Phenols/analysis , Plant Leaves/chemistry , Terpenes/analysisABSTRACT
The effect of methanol and aqueous methanol extract of Origanum vulgare L. ssp. hirtum on aldose reductase and soybean lipoxygenase was investigated. The results revealed a promising potential of oregano for preventing diabetes complications in the long term and an antiinflammatory efficacy by inhibiting soybean lipoxygenase.
Subject(s)
Aldehyde Reductase/antagonists & inhibitors , Glycine max/enzymology , Lipoxygenase Inhibitors/pharmacology , Lipoxygenase/metabolism , Origanum/chemistry , Aldehyde Reductase/metabolism , Methanol/chemistry , Plant Extracts/chemistry , Plant Extracts/pharmacology , Plant Proteins/chemistry , Plant Proteins/pharmacologyABSTRACT
Five polar constituents of Origanum vulgare L. ssp. hirtum were investigated for their ability to inhibit aldose reductase (ALR2), the first enzyme of the polyol pathway implicated in the secondary complications of diabetes. The most active compound was found to be lithospermic acid B. Caffeic acid was inactive as it showed no inhibitory activity against the enzyme. The order of the inhibitory activity of the remaining compounds was: rosmarinic acid >12-hydroxyjasmonic acid 12-O-beta-glucopyranoside > p-menth-3-ene-1,2-diol 1-O-beta-glucopyranoside. Docking studies have been undertaken to gain insight into the binding mode of the investigated compounds at the active site of ALR2. The predicted hydrogen bonding and hydrophobic interactions may explain the observed inhibitory activity.
Subject(s)
Aldehyde Reductase/antagonists & inhibitors , Aldehyde Reductase/metabolism , Enzyme Inhibitors/pharmacology , Origanum/chemistry , Aldehyde Reductase/chemistry , Animals , Binding Sites , Cinnamates/pharmacology , Computer Simulation , Crystallography, X-Ray , Databases, Factual , Depsides , Diabetes Mellitus/metabolism , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/isolation & purification , Glucosides/pharmacology , Humans , Hydrogen Bonding , Models, Molecular , NADP/metabolism , Static Electricity , Structure-Activity Relationship , Rosmarinic AcidABSTRACT
The sensitivity of breast neoplasms to hormonal control provides the basis of novel investigational treatments with steroidal alkylators. An androsterone D-lactam steroidal ester, the 3beta-hydroxy-13alpha-amino-13,17-seco- 5alpha-androstan-17-oic-13,17-lactam, p-bis(2-chloroethyl)amino phenyl acetate (lactandrate) was synthesized and tested for antitumor activity against six human breast cancer cell lines in vitro and against two murine and one xenograft mammary tumors in vivo. A docking study on the binding interactions of lactandrate with the ligand-binding domain (LBD) of estrogen receptor-alpha (ERalpha) was inquired. In vitro testing of lactandrate cytostatic and cytotoxic activity was performed on T47D, MCF7, MDA-MB-231, BT-549, Hs578T, MDA-MB-435 breast adenocarcinoma human cell lines. In vivo testing was performed on two murine mammary tumors, the MXT tumor and CD8F1 adenocarcinoma, as well as on human mammary carcinoma MX-1 xenograft. Molecular modeling techniques were adopted to predict a possible location and interaction mode of the molecule into LBD. Lactandrate induced significantly high antitumor effect against all tested in vitro and in vivo models. The cell lines with positive ER expression found to be significantly more sensitive to lactandrate. Moreover, lactandrate found to be positioned inside the binding cavity with its steroidal moiety, whilst the alkylating moiety protrudes out of receptor's pocket. Lactandrate produced important anticancer activity on breast cancer in vitro and in vivo. Some correlation between ER and lactandrate effect was demonstrated. Docking studies provide the basis for the structure-based design of improved steroidal alkylating esters for the treatment of estrogen-related cancers.
Subject(s)
Alkylating Agents/therapeutic use , Antineoplastic Agents/therapeutic use , Azasteroids/therapeutic use , Homosteroids/therapeutic use , Mammary Neoplasms, Experimental/drug therapy , Secosteroids/therapeutic use , Adenocarcinoma/drug therapy , Androsterone/therapeutic use , Animals , Cell Proliferation/drug effects , Estrogen Receptor alpha/metabolism , Female , Humans , Male , Mice , Mice, Inbred C57BL , Mice, Inbred DBA , Molecular Structure , Tumor Cells, Cultured/drug effectsABSTRACT
Sesquiterpene lactones are terpenoid compounds characteristic of the Asteraceae (Compositae) possessing a variety of biological activities, such as cytotoxic, antitumor, antibacterial, and antifungal. The prediction of the pharmacokinetic profile of several antifungal sesquiterpene lactones, isolated from Greek taxa of Centaurea sp., was undertaken in this study using the VolSurf procedure. The molecules were projected on the following pre-calculated ADME models: Caco-2 cell permeability, plasma protein affinity, blood-brain barrier permeation and thermodynamic solubility. The in silico projection revealed a non optimal pharmacokinetic profile for the studied compounds. ADME in silico screening of a semi-synthetic derivatives virtual library has been performed in order to optimize the pharmacokinetic properties. A number of derivatives were proposed as it was predicted to have higher Caco-2 cell permeability, while the pharmacokinetic behaviour regarding BBB penetration, protein binding and solubility was mainly preserved.