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Molecules, Volume 17, Issue 3 (March 2012), Pages 2271-3598

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Open AccessArticle Effects of a Natural Prolyl Oligopeptidase Inhibitor, Rosmarinic Acid, on Lipopolysaccharide-Induced Acute Lung Injury in Mice
Molecules 2012, 17(3), 3586-3598; https://doi.org/10.3390/molecules17033586
Received: 11 February 2012 / Revised: 6 March 2012 / Accepted: 9 March 2012 / Published: 22 March 2012
Cited by 42 | PDF Full-text (1746 KB)
Abstract
Rosmarinic acid (RA), a polyphenolic phytochemical, is a natural prolyl oligopeptidase inhibitor. In the present study, we found that RA exerted potent anti-inflammatory effects in in vivo models of acute lung injury (ALI) induced by lipopolysaccharide (LPS). Mice were pretreated with RA one
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Rosmarinic acid (RA), a polyphenolic phytochemical, is a natural prolyl oligopeptidase inhibitor. In the present study, we found that RA exerted potent anti-inflammatory effects in in vivo models of acute lung injury (ALI) induced by lipopolysaccharide (LPS). Mice were pretreated with RA one hour before challenge with a dose of 0.5 mg/kg LPS. Twenty-four hours after LPS was given, bronchoalveolar lavage fluid (BALF) was obtained to measure pro-inflammatory mediator and total cell counts. RA significantly decreased the production of LPS-induced TNF-a, IL-6, and IL-1β compare with the LPS group. When pretreated with RA (5, 10, or 20 mg/kg) the lung wet-to-dry weight (W/D) ratio of the lung tissue and the number of total cells, neutrophils and macrophages in the BALF were decreased significantly. Furthermore, RA may enhance oxidase dimutase (SOD) activity during the inflammatory response to LPS-induced ALI. And we further demonstrated that RA exerts anti-inflammation effect in vivo models of ALI through suppresses ERK/MAPK signaling in a dose dependent manner. These studies have important implications for RA administration as a potential treatment for ALI. Full article
Open AccessArticle Regulation of Inflammatory Cytokines in Lipopolysaccharide-Stimulated RAW 264.7 Murine Macrophage by 7-O-Methyl-naringenin
Molecules 2012, 17(3), 3574-3585; https://doi.org/10.3390/molecules17033574
Received: 4 January 2012 / Revised: 27 February 2012 / Accepted: 15 March 2012 / Published: 22 March 2012
Cited by 33 | PDF Full-text (458 KB)
Abstract
7-O-Methylnaringenin, extracted from Rhododendron speciferum, belongs to the flavanone class of polyphenols. In the present study, we investigated the anti-inflammatory effects of 7-O-methylnaringenin on cytokine production by lipopoly-saccharide (LPS)-stimulated RAW 264.7 macrophages in vitro. The results showed
[...] Read more.
7-O-Methylnaringenin, extracted from Rhododendron speciferum, belongs to the flavanone class of polyphenols. In the present study, we investigated the anti-inflammatory effects of 7-O-methylnaringenin on cytokine production by lipopoly-saccharide (LPS)-stimulated RAW 264.7 macrophages in vitro. The results showed that pretreatment with 10, 20 or 40 μg/mL of 7-O-methylnaringenin could downregulate tumour necrosis factor (TNF-α), interleukin (IL-6) and interleukin (IL-1β) in a dose-dependent manner. Furthermore, we investigated the signal transduction mechanisms to determine how 7-O-methylnaringenin affects RAW 264.7 macrophages. The activation of mitogen-activated protein kinases (MAPK) and IκBα were measured by Western blotting. The data showed that 7-O-methylnaringenin could downregulate LPS-induced levels of phosphorylation of ERK1/2, JNK and IκBα. These observations indicated that 7-O-methylnaringenin modulated inflammatory cytokine responses by blocking NF-қB, ERK1/2 and JNK/MAPKs activation. Full article
Open AccessArticle Synthesis of a New Group of Aliphatic Hydrazide Derivatives and the Correlations between Their Molecular Structure and Biological Activity
Molecules 2012, 17(3), 3560-3573; https://doi.org/10.3390/molecules17033560
Received: 25 January 2012 / Revised: 24 February 2012 / Accepted: 14 March 2012 / Published: 22 March 2012
Cited by 3 | PDF Full-text (250 KB)
Abstract
In view of the growing demand for new compounds showing biological activity against pathogenic microorganisms, such as pathogenic and phytopathogenic fungi, the objective of this study was to synthesize a new group of aliphatic and aromatic derivatives of hydrazide. In consequence of the
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In view of the growing demand for new compounds showing biological activity against pathogenic microorganisms, such as pathogenic and phytopathogenic fungi, the objective of this study was to synthesize a new group of aliphatic and aromatic derivatives of hydrazide. In consequence of the reactions observed during synthesis, the resulting compounds retained their linear structure. Their structure and lipophilicity, measured by high-performance liquid chromatography (HPLC), were analyzed. Correlations were determined between the compounds’ molecular parameters and biological activity against Fusarium solani and Fusarium oxysporum fungi. The investigated compounds were also examined for their antifungal activity against Aspergillus fumigatus. The obtained results indicate that compounds with fluorine-containing substituents penetrate the cell structure more effectively and are characterized by higher antifungal potential than analogues with different substituents. Full article
(This article belongs to the Special Issue Advances in Medicinal Chemistry of Antifungals)
Open AccessArticle Acute Toxicity Evaluation, Antibacterial, Antioxidant and Immunomodulatory Effects of Melastoma malabathricum
Molecules 2012, 17(3), 3547-3559; https://doi.org/10.3390/molecules17033547
Received: 6 February 2012 / Revised: 12 March 2012 / Accepted: 14 March 2012 / Published: 20 March 2012
Cited by 12 | PDF Full-text (614 KB)
Abstract
Melastoma malabathricum (MM) is a well-known plant in Malaysian traditional medicine, locally known as senduduk. Its ethanol and aqueous extracts have been used in the present investigation to study the immunomodulatory role on human peripheral blood mononuclear cell (PBMC), and the DPPH, ABTS
[...] Read more.
Melastoma malabathricum (MM) is a well-known plant in Malaysian traditional medicine, locally known as senduduk. Its ethanol and aqueous extracts have been used in the present investigation to study the immunomodulatory role on human peripheral blood mononuclear cell (PBMC), and the DPPH, ABTS and FRAP free radical scavenging activities were also measured. Total flavonoids and total phenolic contents were assayed and the antibacterial effect was tested against four species of bacteria; two Gram-positive (Staphylococcus aureus and Streptococcus agalactiae) and two Gram-negative (Escherichia coli and Klebsilla pneumonia). The tests were carried out using the disc diffusion, minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) methods. Moreover, the acute toxicity was evaluated in vivo on the ethanol extract of MM to establish its safety when administered orally. In our results, both extracts of MM showed abilities to scavenge DPPH and ABTS free radicals, IC50 values: (11.599 ± 0.84, 10.573 ± 0.58 µmol/L) and (62.657 ± 0.78, 63.939 ± 0.48 µmol/L) for ethanol and aqueous extracts respectively. Indeed the ethanol extract evidenced high phenolic content (384.33 ± 0.005 mg/g), flavonoids contents (85.8 ± 0.009 mg/g) and ferric reducing antioxidant power (33,590 ± 0.038 mmol/g), with high activity against S. aureus and S. agalactiae (11 ± 0.3 and 12 ± 0.6 mm inhibition zones). Likewise, the percentage of peripheral blood mononuclear cells (PBMC) viability was increased in response to MM, IC50 values (1.781 ± 1.2 and 6.545 ± 0.93 µg/mL) for ethanol and aqueous extracts, respectively. In addition, our results showed that the MM extract is safe even at a high dose of 5,000 mg/kg and has no oral toxicity. These findings suggest the excellent medicinal bioactivity of MM and explain the popularity of this plant in the folk medicine as a remedy for different illnesses. Full article
Open AccessArticle A New Norisoprenoid and Other Compounds from Fuzhuan Brick Tea
Molecules 2012, 17(3), 3539-3546; https://doi.org/10.3390/molecules17033539
Received: 20 December 2011 / Revised: 8 March 2012 / Accepted: 14 March 2012 / Published: 19 March 2012
Cited by 18 | PDF Full-text (241 KB) | Supplementary Files
Abstract
Fuzhuan brick tea, a kind of dark tea consumed mainly in the border regions of Southwestern and Northwestern China since the 1860s, is produced from the leaves of Camellia sinensis var. sinensis by microbial fermentation. From this special fermented tea, a new norisoprenoid,
[...] Read more.
Fuzhuan brick tea, a kind of dark tea consumed mainly in the border regions of Southwestern and Northwestern China since the 1860s, is produced from the leaves of Camellia sinensis var. sinensis by microbial fermentation. From this special fermented tea, a new norisoprenoid, 3R,9R-oxido-5-megastigmene, was isolated, together with α-linolenic acid, strictin, isovitexin, astragalin, (+)-catechin, (−)-epicatechin, (−)-epicatechin gallate, (+)-gallocatechin, (−)-epigallocatechin, (−)-epigallocatechin gallate and gallic acid. The structures of the compounds were identified by spectroscopic means. The new compound didn’t show any inhibition activity against the tested enteric pathogenic microorganisms at a concentration of 800 μg/mL by the hole plate diffusion method. Full article
(This article belongs to the Section Natural Products Chemistry)
Open AccessReview Terpenoids as Potential Anti-Alzheimer’s Disease Therapeutics
Molecules 2012, 17(3), 3524-3538; https://doi.org/10.3390/molecules17033524
Received: 7 December 2011 / Revised: 12 March 2012 / Accepted: 16 March 2012 / Published: 19 March 2012
Cited by 46 | PDF Full-text (646 KB)
Abstract
Alzheimer’s disease (AD) is one of the most well-known neurodegenerative diseases and explains 50–60% of dementia in patients. The prevalence rate of AD is positively correlated with age and AD affects ≥ 40% of those over 85 years old. The major AD therapeutics
[...] Read more.
Alzheimer’s disease (AD) is one of the most well-known neurodegenerative diseases and explains 50–60% of dementia in patients. The prevalence rate of AD is positively correlated with age and AD affects ≥ 40% of those over 85 years old. The major AD therapeutics available on the market are acetylcholinesterase inhibitors, such as tacrine and donepezil. New therapeutic agents that can block the disease-inducing mechanisms are essential. Diverse efforts have been made to discover anti-AD agents from natural sources. In this review article, we describe some representative terpenoids such as ginsenosides, gingkolides, and canabinoids as potential anti-AD agents. These compounds exhibit promising in vitro and in vivo biological activities, but are still waiting clinical trials. Additionally, we also discuss some terpenoids including cornel iridoid glycoside, oleanolic acid, tenuifolin, cryptotanshinone, and ursolic acid, which are under investigation for their in vitro and in vivo animal studies. Full article
(This article belongs to the Special Issue Terpenoids)
Open AccessArticle Enrichment and Purification of Deoxyschizandrin and γ-Schizandrin from the Extract of Schisandra chinensis Fruit by Macroporous Resins
Molecules 2012, 17(3), 3510-3523; https://doi.org/10.3390/molecules17033510
Received: 6 February 2012 / Revised: 7 March 2012 / Accepted: 12 March 2012 / Published: 19 March 2012
Cited by 16 | PDF Full-text (488 KB)
Abstract
In present study, the performance and separation characteristics of 21 macroporous resins for the enrichment and purification of deoxyschizandrin and γ-schizandrin, the two major lignans from Schisandra chinensis extracts, were evaluated. According to our results, HPD5000, which adsorbs by the molecular tiers model,
[...] Read more.
In present study, the performance and separation characteristics of 21 macroporous resins for the enrichment and purification of deoxyschizandrin and γ-schizandrin, the two major lignans from Schisandra chinensis extracts, were evaluated. According to our results, HPD5000, which adsorbs by the molecular tiers model, was the best macroporous resin, offering higher adsorption and desorption capacities and higher adsorption speed for deoxyschizandrin and γ-schizandrin than other resins. Columns packed with HPD5000 resin were used to perform dynamic adsorption and desorption tests to optimize the technical parameters of the separation process. The results showed that the best adsorption time is 4 h, the rate of adsorption is 0.85 mL/min (4 BV/h) and the rate of desorption is 0.43 mL/min (2 BV/h). After elution with 90% ethanol, the purity of deoxy-schizandrin increased 12.62-fold from 0.37% to 4.67%, the purity of γ-schizandrin increased 15.8-fold from 0.65% to 10.27%, and the recovery rate was more than 80%. Full article
Open AccessArticle Synthesis and Structural Determination of Novel 5-Arylidene-3-N(2-alkyloxyaryl)-2-thioxothiazolidin-4-ones
Molecules 2012, 17(3), 3501-3509; https://doi.org/10.3390/molecules17033501
Received: 5 January 2012 / Revised: 26 February 2012 / Accepted: 1 March 2012 / Published: 19 March 2012
Cited by 9 | PDF Full-text (241 KB)
Abstract
As part of our project devoted to the synthesis of heterocycles including thiazole rings, some new 5-arylidene-2-thioxo-3-N-arylthiazolidin-4-ones were synthesized by Knoevenagel condensation. An interesting feature of these compounds is that their chirality is induced by that of their 3-N-(2-alkyloxyaryl)-2-thioxothiazolidin-4-one
[...] Read more.
As part of our project devoted to the synthesis of heterocycles including thiazole rings, some new 5-arylidene-2-thioxo-3-N-arylthiazolidin-4-ones were synthesized by Knoevenagel condensation. An interesting feature of these compounds is that their chirality is induced by that of their 3-N-(2-alkyloxyaryl)-2-thioxothiazolidin-4-one precursors, which in turn is due to the presence of a C2 axis of chirality. These new compounds were characterized by spectroscopic methods (IR, 1H-NMR, 13C-NMR). The structure of compound (Z)-(2g) was further determined by X-ray diffraction. Full article
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Open AccessArticle Synthesis and Preliminary Investigations of the siRNA Delivery Potential of Novel, Single-Chain Rigid Cationic Carotenoid Lipids
Molecules 2012, 17(3), 3484-3500; https://doi.org/10.3390/molecules17033484
Received: 29 February 2012 / Revised: 12 March 2012 / Accepted: 12 March 2012 / Published: 16 March 2012
Cited by 9 | PDF Full-text (359 KB)
Abstract
The success of nucleic acid delivery requires the development of safe and efficient delivery vectors that overcome cellular barriers for effective transport. Herein we describe the synthesis of a series of novel, single-chain rigid cationic carotenoid lipids and a study of their preliminary
[...] Read more.
The success of nucleic acid delivery requires the development of safe and efficient delivery vectors that overcome cellular barriers for effective transport. Herein we describe the synthesis of a series of novel, single-chain rigid cationic carotenoid lipids and a study of their preliminary in vitro siRNA delivery effectiveness and cellular toxicity. The efficiency of siRNA delivery by the single-chain lipid series was compared with that of known cationic lipid vectors, 3β-[N-(N',N'-dimethylaminoethane)carbamoyl]-cholesterol (DC-Chol) and 1,2-dimyristoyl-sn-glyceryl-3-phosphoethanolamine (EPC) as positive controls. All cationic lipids (controls and single-chain lipids) were co-formulated into liposomes with the neutral co-lipid, 1,2-dioleolyl-sn-glycerol-3-phosphoethanolamine (DOPE). Cationic lipid-siRNA complexes of varying (+/−) molar charge ratios were formulated for delivery into HR5-CL11 cells. Of the five single-chain carotenoid lipids investigated, lipids 1, 2, 3 and 5 displayed significant knockdown efficiency with HR5-CL11 cells. In addition, lipid 1 exhibited the lowest levels of cytotoxicity with cell viability greater than 80% at all (+/−) molar charge ratios studied. This novel, single-chain rigid carotenoid-based cationic lipid represents a new class of transfection vector with excellent cell tolerance, accompanied with encouraging siRNA delivery efficiency. Full article
Open AccessArticle Synthesis and Antimicrobial Activity of N′-Heteroarylidene-1-adamantylcarbohydrazides and (±)-2-(1-Adamantyl)-4-acetyl-5-[5-(4-substituted phenyl-3-isoxazolyl)]-1,3,4-oxadiazolines
Molecules 2012, 17(3), 3475-3483; https://doi.org/10.3390/molecules17033475
Received: 13 January 2012 / Revised: 16 February 2012 / Accepted: 6 March 2012 / Published: 16 March 2012
Cited by 11 | PDF Full-text (218 KB)
Abstract
The reaction of adamantane-1-carbohydrazide (1) with heterocyclic aldehydes, namely 5-(4-chlorophenyl)isoxazole-3-carboxaldehyde (2a), 5-(4-methylphenyl)isoxazole-3-carboxaldehyde (2b), 5-(4-methoxyphenyl)isoxazole-3-carboxaldehyde (2c), 1H-imidazole-2-carboxaldehyde and 2-butyl-4-chloro-1H-imidazole-5-carboxaldehyde, in ethanol, yielded the corresponding N′-heteroarylidene-1-adamantylcarbohydrazides 3a, 3b, 3c, 4 and 5, respectively, in good yields. The 4-acetyl-1,3,4-oxadiazoline analogues 6a‑c
[...] Read more.
The reaction of adamantane-1-carbohydrazide (1) with heterocyclic aldehydes, namely 5-(4-chlorophenyl)isoxazole-3-carboxaldehyde (2a), 5-(4-methylphenyl)isoxazole-3-carboxaldehyde (2b), 5-(4-methoxyphenyl)isoxazole-3-carboxaldehyde (2c), 1H-imidazole-2-carboxaldehyde and 2-butyl-4-chloro-1H-imidazole-5-carboxaldehyde, in ethanol, yielded the corresponding N′-heteroarylidene-1-adamantylcarbohydrazides 3a, 3b, 3c, 4 and 5, respectively, in good yields. The 4-acetyl-1,3,4-oxadiazoline analogues 6a‑c were prepared in 48–55% yields by heating their corresponding N′-heteroarylidene-1-adamantylcarbohydrazides 3a–c with acetic anhydride for two hours. Compounds 3a–c, 4, 5 and 6a–c were tested for in vitro activities against a panel of Gram-positive and Gram-negative bacteria and the yeast-like pathogenic fungus Candida albicans. Compounds 4 and 5 displayed potent broad-spectrum antimicrobial activity, while compounds 3a–c showed good activity against the Gram-positive bacteria. Full article
(This article belongs to the Section Medicinal Chemistry)
Open AccessArticle Simultaneous Analysis of Irbesartan and Hydrochlorothiazide: An Improved HPLC Method with the Aid of a Chemometric Protocol
Molecules 2012, 17(3), 3461-3474; https://doi.org/10.3390/molecules17033461
Received: 23 February 2012 / Revised: 12 March 2012 / Accepted: 13 March 2012 / Published: 16 March 2012
Cited by 23 | PDF Full-text (819 KB)
Abstract
Experimental design method was used for HPLC determination of irbesartan and hydrochlorothiazide in combined dosage forms. The traditional approach for optimization of experiments is time-consuming, involves a large number of runs and does not allow establishing the multiple interacting parameters. The main advantages
[...] Read more.
Experimental design method was used for HPLC determination of irbesartan and hydrochlorothiazide in combined dosage forms. The traditional approach for optimization of experiments is time-consuming, involves a large number of runs and does not allow establishing the multiple interacting parameters. The main advantages of the experimental design method include the simultaneous screening of a larger number of factors affecting response and the estimation of possible interactions. On the basis of preliminary experiments, three factors-independent variables were selected as inputs (methanol content, pH of the mobile phase and temperature) and as dependent variables, five responses (resolution, symmetry of irbesartan peak, symmetry of hydrochlorothiazide peak, retention factor of irbesartan and retention factor of hydrochlorothiazide) were chosen. A full 23 factorial design, where factors were examined at two different levels (“low” and “high”) was used to determine which factors had an effect on the studied response. Afterwards, experimental design was used to optimize these influent parameters in the previously selected experimental domain. The novelty of our method lies in the optimization step accomplished by Derringer¢s desirability function. After optimizing the experimental conditions a separation was conducted on a Supelcosil C18 (150 mm × 4.6 mm, 5 mm particle size) column with a mobile phase consisting of methanol-tetrahydrofuran-acetate buffer 47:10:43 v/v/v, pH 6.5 and a column temperature of 25 °C. The developed method was successfully applied to the simultaneous separation of these drug-active compounds in their commercial pharmaceutical dosage forms. Full article
Open AccessArticle Modeling Chemical Interaction Profiles: II. Molecular Docking, Spectral Data-Activity Relationship, and Structure-Activity Relationship Models for Potent and Weak Inhibitors of Cytochrome P450 CYP3A4 Isozyme
Molecules 2012, 17(3), 3407-3460; https://doi.org/10.3390/molecules17033407
Received: 20 January 2012 / Revised: 27 February 2012 / Accepted: 28 February 2012 / Published: 15 March 2012
Cited by 14 | PDF Full-text (1209 KB) | Supplementary Files
Abstract
Polypharmacy increasingly has become a topic of public health concern, particularly as the U.S. population ages. Drug labels often contain insufficient information to enable the clinician to safely use multiple drugs. Because many of the drugs are bio-transformed by cytochrome P450 (CYP) enzymes,
[...] Read more.
Polypharmacy increasingly has become a topic of public health concern, particularly as the U.S. population ages. Drug labels often contain insufficient information to enable the clinician to safely use multiple drugs. Because many of the drugs are bio-transformed by cytochrome P450 (CYP) enzymes, inhibition of CYP activity has long been associated with potentially adverse health effects. In an attempt to reduce the uncertainty pertaining to CYP-mediated drug-drug/chemical interactions, an interagency collaborative group developed a consensus approach to prioritizing information concerning CYP inhibition. The consensus involved computational molecular docking, spectral data-activity relationship (SDAR), and structure-activity relationship (SAR) models that addressed the clinical potency of CYP inhibition. The models were built upon chemicals that were categorized as either potent or weak inhibitors of the CYP3A4 isozyme. The categorization was carried out using information from clinical trials because currently available in vitro high-throughput screening data were not fully representative of the in vivo potency of inhibition. During categorization it was found that compounds, which break the Lipinski rule of five by molecular weight, were about twice more likely to be inhibitors of CYP3A4 compared to those, which obey the rule. Similarly, among inhibitors that break the rule, potent inhibitors were 2–3 times more frequent. The molecular docking classification relied on logistic regression, by which the docking scores from different docking algorithms, CYP3A4 three-dimensional structures, and binding sites on them were combined in a unified probabilistic model. The SDAR models employed a multiple linear regression approach applied to binned 1D 13C-NMR and 1D 15N-NMR spectral descriptors. Structure-based and physical-chemical descriptors were used as the basis for developing SAR models by the decision forest method. Thirty-three potent inhibitors and 88 weak inhibitors of CYP3A4 were used to train the models. Using these models, a synthetic majority rules consensus classifier was implemented, while the confidence of estimation was assigned following the percent agreement strategy. The classifier was applied to a testing set of 120 inhibitors not included in the development of the models. Five compounds of the test set, including known strong inhibitors dalfopristin and tioconazole, were classified as probable potent inhibitors of CYP3A4. Other known strong inhibitors, such as lopinavir, oltipraz, quercetin, raloxifene, and troglitazone, were among 18 compounds classified as plausible potent inhibitors of CYP3A4. The consensus estimation of inhibition potency is expected to aid in the nomination of pharmaceuticals, dietary supplements, environmental pollutants, and occupational and other chemicals for in-depth evaluation of the CYP3A4 inhibitory activity. It may serve also as an estimate of chemical interactions via CYP3A4 metabolic pharmacokinetic pathways occurring through polypharmacy and nutritional and environmental exposures to chemical mixtures. Full article
(This article belongs to the Special Issue QSAR and Its Applications)
Open AccessArticle Modeling Chemical Interaction Profiles: I. Spectral Data-Activity Relationship and Structure-Activity Relationship Models for Inhibitors and Non-inhibitors of Cytochrome P450 CYP3A4 and CYP2D6 Isozymes
Molecules 2012, 17(3), 3383-3406; https://doi.org/10.3390/molecules17033383
Received: 20 January 2012 / Revised: 27 February 2012 / Accepted: 28 February 2012 / Published: 15 March 2012
Cited by 11 | PDF Full-text (251 KB) | Supplementary Files
Abstract
An interagency collaboration was established to model chemical interactions that may cause adverse health effects when an exposure to a mixture of chemicals occurs. Many of these chemicals—drugs, pesticides, and environmental pollutants—interact at the level of metabolic biotransformations mediated by cytochrome P450 (CYP)
[...] Read more.
An interagency collaboration was established to model chemical interactions that may cause adverse health effects when an exposure to a mixture of chemicals occurs. Many of these chemicals—drugs, pesticides, and environmental pollutants—interact at the level of metabolic biotransformations mediated by cytochrome P450 (CYP) enzymes. In the present work, spectral data-activity relationship (SDAR) and structure-activity relationship (SAR) approaches were used to develop machine-learning classifiers of inhibitors and non-inhibitors of the CYP3A4 and CYP2D6 isozymes. The models were built upon 602 reference pharmaceutical compounds whose interactions have been deduced from clinical data, and 100 additional chemicals that were used to evaluate model performance in an external validation (EV) test. SDAR is an innovative modeling approach that relies on discriminant analysis applied to binned nuclear magnetic resonance (NMR) spectral descriptors. In the present work, both 1D 13C and 1D 15N-NMR spectra were used together in a novel implementation of the SDAR technique. It was found that increasing the binning size of 1D 13C-NMR and 15N-NMR spectra caused an increase in the tenfold cross-validation (CV) performance in terms of both the rate of correct classification and sensitivity. The results of SDAR modeling were verified using SAR. For SAR modeling, a decision forest approach involving from 6 to 17 Mold2 descriptors in a tree was used. Average rates of correct classification of SDAR and SAR models in a hundred CV tests were 60% and 61% for CYP3A4, and 62% and 70% for CYP2D6, respectively. The rates of correct classification of SDAR and SAR models in the EV test were 73% and 86% for CYP3A4, and 76% and 90% for CYP2D6, respectively. Thus, both SDAR and SAR methods demonstrated a comparable performance in modeling a large set of structurally diverse data. Based on unique NMR structural descriptors, the new SDAR modeling method complements the existing SAR techniques, providing an independent estimator that can increase confidence in a structure-activity assessment. When modeling was applied to hazardous environmental chemicals, it was found that up to 20% of them may be substrates and up to 10% of them may be inhibitors of the CYP3A4 and CYP2D6 isoforms. The developed models provide a rare opportunity for the environmental health branch of the public health service to extrapolate to hazardous chemicals directly from human clinical data. Therefore, the pharmacological and environmental health branches are both expected to benefit from these reported models. Full article
(This article belongs to the Special Issue QSAR and Its Applications)
Open AccessArticle Oxime Esters of 2,6-Diazaanthracene-9,10-dione and 4,5-Diazafluoren-9-one as Photo-induced DNA-Cleaving Agents
Molecules 2012, 17(3), 3370-3382; https://doi.org/10.3390/molecules17033370
Received: 29 January 2012 / Revised: 10 March 2012 / Accepted: 12 March 2012 / Published: 15 March 2012
Cited by 10 | PDF Full-text (357 KB)
Abstract
Two series of oxime esters containing the 2,6-diazaanthracene-9,10-dione bis-(O-benzoyloxime) and 4,5-diazafluoren-9-one O-9-benzoyloxime moieties have been synthesized and tested as photo-induced DNA cleaving agents. All these compounds were found to cleave DNA upon irradiation with 312 nm UV light. The structure-activity
[...] Read more.
Two series of oxime esters containing the 2,6-diazaanthracene-9,10-dione bis-(O-benzoyloxime) and 4,5-diazafluoren-9-one O-9-benzoyloxime moieties have been synthesized and tested as photo-induced DNA cleaving agents. All these compounds were found to cleave DNA upon irradiation with 312 nm UV light. The structure-activity relationship of these molecules for DNA cleavage was established. A plausible reaction mechanism is also proposed. Full article
(This article belongs to the Section Organic Chemistry)
Open AccessArticle Synthesis of Azanucleosides through Regioselective Ring-Opening of Epoxides Catalyzed by Sulphated Zirconia under Microwave and Solvent-Free Conditions
Molecules 2012, 17(3), 3359-3369; https://doi.org/10.3390/molecules17033359
Received: 10 February 2012 / Revised: 7 March 2012 / Accepted: 9 March 2012 / Published: 15 March 2012
Cited by 7 | PDF Full-text (272 KB)
Abstract
New azanucleosides were obtained using sulphated zirconia (ZS) as catalyst in the nucleophilic oxirane ring opening reaction of 1-allyl-3-(oxiran-2-ylmethyl) pyrimidine-2,4(1H,3H)-dione and 1-allyl-5-methyl-3-(oxiran-2-ylmethyl)-pyrimidine-2,4(1H,3H)-dione, with (S)-prolinol. The new templates were obtained with good yields following
[...] Read more.
New azanucleosides were obtained using sulphated zirconia (ZS) as catalyst in the nucleophilic oxirane ring opening reaction of 1-allyl-3-(oxiran-2-ylmethyl) pyrimidine-2,4(1H,3H)-dione and 1-allyl-5-methyl-3-(oxiran-2-ylmethyl)-pyrimidine-2,4(1H,3H)-dione, with (S)-prolinol. The new templates were obtained with good yields following a route which exploits the reactivity of epoxides in the presence of sulphated zirconia as catalyst. The key step was carried out using microwave and solvent-free conditions and proceeds with high selectivity. Full article
(This article belongs to the Section Organic Chemistry)
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