Showing papers in "Journal of Enzyme Inhibition and Medicinal Chemistry in 2014"
TL;DR: The state of the art in the field of antibacterials based on inhibitors of these three enzyme families is revue, when several X-ray crystal structures of such enzymes in complex with their inhibitors were reported.
Abstract: Recent advances in microbial genomics, synthetic organic chemistry and X-ray crystallography provided opportunities to identify novel antibacterial targets for the development of new classes of antibiotics and to design more potent antimicrobial compounds derived from existing antibiotics in clinical use for decades. The antimetabolites, sulfa drugs and trimethoprim (TMP)-like agents, are inhibitors of three families of enzymes. One family belongs to the carbonic anhydrases, which catalyze a simple but physiologically relevant reaction in all life kingdoms, carbon dioxide hydration to bicarbonate and protons. The other two enzyme families are involved in the synthesis of tetrahydrofolate (THF), i.e. dihydropteroate synthase (DHPS) and dihydrofolate reductase. The antibacterial agents belonging to the THF and DHPS inhibitors were developed decades ago and present significant bacterial resistance problems. However, the molecular mechanisms of drug resistance both to sulfa drugs and TMP-like inhibitors were understood in detail only recently, when several X-ray crystal structures of such enzymes in complex with their inhibitors were reported. Here, we revue the state of the art in the field of antibacterials based on inhibitors of these three enzyme families.
242 citations
TL;DR: The analysis of KI and KIS values proved that the two most promising compounds (3 and 5) had reversible mixed type I mechanisms, which confirmed that the key enzyme, PLpro, plays an important role in SARS virus replication.
Abstract: Severe acute respiratory syndrome coronavirus (SARS-CoV) papain-like protease (PLpro) is a key enzyme that plays an important role in SARS virus replication The ethanol extract of the seeds of Psoralea corylifolia showed high activity against the SARS-CoV PLpro with an IC50 of value of 15 µg/ml Due to its potency, subsequent bioactivity-guided fractionation of the ethanol extract led to six aromatic compounds (1-6), which were identified as bavachinin (1), neobavaisoflavone (2), isobavachalcone (3), 4'-O-methylbavachalcone (4), psoralidin (5) and corylifol A (6) All isolated flavonoids (1-6) inhibited PLpro in a dose-dependent manner with IC50 ranging between 42 and 384 µM Lineweaver-Burk and Dixon plots and their secondary replots indicated that inhibitors (1-6) were mixed inhibitors of PLpro The analysis of KI and KIS values proved that the two most promising compounds (3 and 5) had reversible mixed type I mechanisms
142 citations
TL;DR: A bioreactor containing the “PU-immobilized enzyme” (PU-SspCA) as shredded foam was used for experimental tests aimed to verify the CO2 capture capability in conditions close to those of a power plant application.
Abstract: The biomimetic approach represents an interesting strategy for carbon dioxide (CO2) capture, offering advantages over other methods, due to its specificity for CO2 and its eco-compatibility, as it ...
130 citations
TL;DR: Six sulfonamides derived from indanes and tetralines were synthesized and N-(5,6-dimethoxy-2,3-dihydro-1H-inden-2-yl)methane sulfonamide showed the most potent inhibitory effect against hCA I and hCA II.
Abstract: Six sulfonamides derived from indanes and tetralines were synthesized. The human carbonic anhydrase isozymes hCA I and hCA II inhibition effects of the synthesized sulfonamides were determined. From these compounds, while N-(5,6-dimethoxy-2,3-dihydro-1H-inden-2-yl)methane sulfonamide showed the most potent inhibitory effect against hCA I (Ki = 46 ± 5.4 µM, r2 = 0.978), N-(1,2,3,4-tetrahydronaphthalene-2-yl)methanesulfonamide was found to have the best inhibitory effect against hCA II (Ki = 94 ± 7.6 µM, r2 = 0.982).
104 citations
TL;DR: VchCA has a low esterase activity with 4-nitrophenyl acetate as substrate, and a high activity for the hydration of CO2 to bicarbonate, suggesting a pivotal role of this metalloenzymes in the microbial virulence.
Abstract: Vibrio cholerae, a Gram-negative bacterium, is the causative agent of cholera and colonizes the upper small intestine where sodium bicarbonate is present at a high concentration. Sodium bicarbonate is a potential inducer of virulence gene expression. Bacteria can increase cytosolic bicarbonate levels through the existence of transporter family proteins or through the action of metalloenzymes, called carbonic anhydrases (CAs, EC 4.2.1.1). Vibrio cholerae, lacking of transporter proteins in its genome, utilizes the CA system to accumulate bicarbonate into the cell suggesting a pivotal role of this metalloenzymes in the microbial virulence. Here, we report for the first time the characterization of the α-CA of V. cholerae (VchCA), which has been identified by translated genome inspection. The α-CA encoding gene was cloned and expressed in Escherichia coli and the recombinant protein purified to homogeneity. This investigation aimed to study the biochemical properties of VchCA and to provide preliminary insights in the field of this pathogen virulence. VchCA has a low esterase activity with 4-nitrophenyl acetate as substrate, and a high activity for the hydration of CO2 to bicarbonate.
93 citations
TL;DR: 4-Methyl-5,7-dihydroydroxycoumarin showed KIs >200 µM against CA I and II, being thus a selective, efficient inhibitor for the tumor-associated over cytosolic CA isoforms, and are interesting leads for designing isoform-selective enzyme inhibitors.
Abstract: A series of coumarins and benzocoumarins incorporating methyl and hydroxyl moieties in the heterocyclic ring were investigated for the inhibition of the zinc enzyme carbonic anhydrase (CA, EC 4.2.1.1). These coumarins were very weak or ineffective as inhibitors of the house-keeping, offtarget isoforms CA I and II, but showed effective, submicromolar inhibition of the transmembrane, tumor-associated isoforms CA IX and to a slightly less extent, CA XII. The nature and position of the groups substituting the coumarin ring influenced CA inhibitory properties. 4-Methyl-5,7-dihydroydroxycoumarin showed KIs >200 µM against CA I and II, of 0.19 µM against CA IX and of 6.4 µM against CA XII, being thus a selective, efficient inhibitor for the tumor-associated over cytosolic CA isoforms. These compounds are interesting leads for designing isoform-selective enzyme inhibitors.
79 citations
TL;DR: A concerted effort to retrace compounds covered from 2009-till date which owe diverse biological activities to the 2-pyrazoline scaffold and also condenses the retro-synthetic approaches employed for their synthesis.
Abstract: Pyrazoles, categorized as nitrogen-containing heterocycles, are well known for their interminable participation in the field of perpetual research and development of therapeutical active agents. As a consequence pyrazoles became an inevitable core of numerous drugs having diverse activities. The broad spectrum of activities portrayed by the pyrazoles instigated the researchers to modify the pyrazole ring as 4,5-dihydro-1H-pyrazoles commonly known as 2-pyrazolines. The present review is a concerted effort to retrace compounds covered from 2009-till date which owe diverse biological activities to the 2-pyrazoline scaffold and also condenses the retro-synthetic approaches employed for their synthesis. This endeavor culminated in revelation that inhibitory potential varied when the substituents in particular N-substituents of 2-pyrazolines were altered.
71 citations
TL;DR: Two carbonic anhydrase IX (CA IX) inhibitors were radiolabeled with 18F, and evaluated for imaging CA IX expression but due to minimal uptake in HT-29 tumors compared to other organs/tissues, these two tracers are not suitable for use for CA IX-targeted imaging.
Abstract: Two carbonic anhydrase IX (CA IX) inhibitors were radiolabeled with (18)F, and evaluated for imaging CA IX expression. Despite good affinity for CA IX and excellent plasma stability, uptake of both tracers in CA IX-expressing HT-29 tumor xenografts in mice was low. (18)F-FEC accumulated predominately in the liver and nasal cavity, whereas a significant amount of (18)F-U-104 was retained in blood. Due to minimal uptake in HT-29 tumors compared to other organs/tissues, these two tracers are not suitable for use for CA IX-targeted imaging.
68 citations
TL;DR: Diatom genome sequences clearly reveal the presence of different systems for HCO3− uptake, and phylogenetic analysis showed that δ-CAs are closer to the α- CAs than to the other classes of such enzymes.
Abstract: Diatom genome sequences clearly reveal the presence of different systems for HCO3(-) uptake. Carbon-concentrating mechanisms (CCM) based on HCO3(-) transport and a plastid-localized carbonic anhydrase (CA, EC 4.2.1.1) appear to be more probable than the others because CAs have been identified in the genome of many diatoms. CAs are key enzymes involved in the acquisition of inorganic carbon for photosynthesis in phytoplankton, as they catalyze efficiently the interconversion between carbon dioxide and bicarbonate. Five genetically distinct classes of CAs exist, α-, β-, γ-, δ- and ζ and all of them are metalloenzymes. Recently we investigated for the first time the catalytic activity and inhibition of the δ-class CA from the marine diatom Thalassiosira weissflogii, named TweCA. This enzyme is an efficient catalyst for the CO2 hydration and its inhibition profile with sulfonamide/sulfamate and anions have also been investigated. Here, we report the detailed biochemical characterization and chemico-physical properties of the δ-CA of T. weissflogii. The δ-CA encoding gene was cloned and expressed in Artic Express cells and the recombinant protein purified to homogeneity. Interesting to note that TweCA has no intrinsic esterase activity with 4-nitrophenyl acetate (pNpA) as substrate although the phylogenetic analysis showed that δ-CAs are closer to the α-CAs than to the other classes of such enzymes.
65 citations
TL;DR: Enzyme kinetic analysis showed that PgiCA is 62 times more effective as a catalyst compared to CAM, the only other γ-CA characterized in detail kinetically, which represents an interesting attractive for the drug design of inhibitors/activators of this new enzyme.
Abstract: Carbonic anhydrases (CAs, EC 4.2.1.1) catalyze a simple but physiologically relevant reaction in all life kingdoms, carbon dioxide hydration to bicarbonate and protons. CAs are present in many pathogenic species and are involved in the bicarbonate metabolism/biosynthetic reactions involving this ion. Ubiquity of these enzymes suggests a pivotal role in microbial virulence and pathogenicity. Porphyromonas gingivalis is an anaerobic bacterium, which colonizes the oral cavity, being involved in the pathogenesis of periodontitis, an inflammatory disease leading to tooth loss. Recently, we reported an anion inhibitory study on the γ-CA (denominated PgiCA) identified in the genome of this Gram-negative bacterium. In this paper we continue our research on PgiCA, and describe the biochemical characterization of the recombinant protein, its thermal stability, the oligomeric state and the enzyme kinetics. PgiCA is a polypeptide chain formed of 192 amino acids and displays an identity of 30–33% when compared...
63 citations
TL;DR: This study is a first to reveal the pancreatic lipase inhibitory activity by both D. opposita and its isolated compounds.
Abstract: Twenty-three phenolic compounds were isolated from Dioscorea opposita by bioactivity-guided method and their inhibitory effect against pancreatic lipase was evaluated. A total of 15 isolates reduced lipase activity at IC50 values of less than 50 µM and 3,3',5-trihydroxy-2'-methoxybibenzyl showed the highest inhibition with an IC50 value of 8.8 µM. This study is a first to reveal the pancreatic lipase inhibitory activity by both D. opposita and its isolated compounds.
TL;DR: Synthesis and carbonic anhydrase inhibitory properties of novel diarylmethylamines 22–25 and sulfonamide derivatives 26–28 were investigated and compound 28 was found to be the best inhibitor against both hCA I and II.
Abstract: Synthesis and carbonic anhydrase inhibitory properties of novel diarylmethylamines 22–25 and sulfonamide derivatives 26–28 were investigated. Acylation of methoxy-substituted benzenes with benzene carboxylic acids, reduction of ketones with NaBH4, conversion of alcohols to azides, Pd-C catalyzed hydrogenation of azides afforded title compounds 22–25. Compounds 22, 24 and 25 were converted to sulfonamide derivatives 26–28 with MeSO2Cl. The inhibitory effects of novel benzylamine derivatives 22–28 were tested on human carbonic anhydrase (hCA, EC 4.2.1.1) isozymes hCA I and II. The results demonstrated that compound 28 was found to be the best inhibitor against both hCA I (Ki: 3.68 µM) and hCA II (Ki: 9.23 µM).
TL;DR: Six compounds showing significantly excellent activity were compared with metolazone, prazosin and diazoxide as standards and exhibited most potent of the series, nitrobenzenesulfonamide.
Abstract: To explore the pharmacological and structure-activity relationship of a series of N-substituted-(4-oxo-2-substituted-phenylquinazolin-3-(4H)-yl), substituted benzene sulfonamide derivatives (1-25) were synthesized from substituted anthranilic acids derived amino quinazolines and substituted benzene sulphonamides. All the synthesized compounds were evaluated for their diuretic (by Lipschitz et al. method), antihypertensive activity by non-invasive blood pressure (NIBP) using the tail-cuff method and anti-diabetic potential in rats. Six compounds showing significantly excellent activity were compared with metolazone, prazosin and diazoxide as standards. Compound N-[7-chloro-2-(4-methoxyphenyl)-4-oxoquinazolin-3(4H)-yl]-4 nitrobenzenesulfonamide (20) exhibited most potent of the series.
TL;DR: The chemical profile of the methanolic extract was studied by high-performance liquid chromatography with diode array detection and abietanes showed potent antibacterial activity against Staphylococcus aureus and Enterococcus faecalis.
Abstract: Plectranthus madagascariensis is used as a traditional medicine in Southern Africa. In search of compounds and activities supporting the medicinal use, the chemical profile of the methanolic extract was studied by high-performance liquid chromatography with diode array detection (HPLC-DAD). Four major constituents were isolated and identified as rosmarinic acid (1), 7β,6β-dihydroxyroyleanone (2), 7β-acetoxy-6β-hydroxyroyleanone (3) and coleon U quinone (4). The two abietane diterpenoids (2 and 3) were isolated for the first time from this species. Antimicrobial, cholinesterase and α-glucosidase inhibitory activities of these compounds were studied. The compounds exhibited inhibitory activity on α-glucosidase with IC50 values from 33 to 275 μM. Abietanes showed potent antibacterial activity against Staphylococcus aureus and Enterococcus faecalis.
TL;DR: A series of phenols incorporating tertiary amine and trans-pyridylethenyl-carbonyl moieties were assayed as inhibitors of the β-carbonic anhydrase from Saccharomyces cerevisiae, ScCA and may be useful for detecting antifungals with a novel mechanism of action compared to the classical azole drugs to which significant drug resistance emerged.
Abstract: A series of phenols incorporating tertiary amine and trans-pyridylethenyl-carbonyl moieties were assayed as inhibitors of the β-carbonic anhydrase (CA, EC 4.2.1.1) from Saccharomyces cerevisiae, ScCA. One of these compounds was a low nanomolar ScCA inhibitor, whereas the remaining ones inhibited the enzyme with KIs in the range of 23.5–95.4 nM. The off-target human (h) isoforms hCA I and hCA II were much less inhibited by these phenols, with KIs in the range of 0.78–23.5 µM (hCA I) and 10.8–52.4 µM (hCA II). The model organism S. cerevisiae and this particular enzyme may be useful for detecting antifungals with a novel mechanism of action compared to the classical azole drugs to which significant drug resistance emerged.
TL;DR: The bioassay results indicate that four compounds namely 7d, 7n, 7r and 7s could be considered as possible potential agents against HIV-1 and HIV-2 viral strains.
Abstract: A series of novel hybrid quinazoline-triazine derivatives was designed and synthesized from cyanuric chloride and anthranilic acid through sequential reactions, which contain different pharmacophores like quinazoline and substituted diaryl triazine (DATA) linked with ethylene diamine. All the newly synthesized compounds were characterized by infrared, (1)H-NMR, (13)C-NMR, MS and elemental analysis. Further, we evaluated the in vitro anti-HIV activity of the newly synthesized compounds against HIV-1 (IIIB) and HIV-2 (ROD) viral strains and as well as in vitro antimicrobial activity against four bacteria (Staphylococcus aureus, Bacillus cereus, Pseudomonas aeruginosa, Klebsiella pneumoniae) and two fungi (Aspergillus clavatus, Candida albicans) using the paper agar streak dilution method. The bioassay results indicate that four compounds namely 7d, 7n, 7r and 7s could be considered as possible potential agents.
TL;DR: Results show that bee products possess a sedative effect and may be effective in protecting humans against depression and similar diseases, related to samples’ TPCs and antioxidant capacities.
Abstract: Monoamine oxidase (MAO) inhibitors are generally used in the treatment of depressive disorders and some neurodegenerative illnesses, such as Parkinson's disease and Alzheimer's disease. The aim of this preliminary study was to investigate the MAO [MAO (E.C.1.4.3.4)] inhibiting effect of various apitherapeutic products, such as chestnut honey, pollen and propolis. Extracts' MAO inhibition was measured using peroxidase-linked spectrophotometric assay in enzyme isolated from rat liver microsomes, and the values are expressed as the inhibition concentration (IC50) causing 50% inhibition of MAO. The antioxidant activity of the bee products was also determined in terms of total phenolic content (TPC) and ferric reducing/antioxidant power in aquatic extracts. All samples exhibited substantial inhibition of MAO, propolis having the highest. Inhibition was related to samples' TPCs and antioxidant capacities. These results show that bee products possess a sedative effect and may be effective in protecting humans against depression and similar diseases.
TL;DR: Results indicate that the steric and electrostatic factors play a significant role in mtCA 2 inhibition for the investigated compounds and proposed nine new not yet synthesizedmtCA 2 inhibitors, all of them probably with significantly improved anti-Rv3588c inhibitory activity.
Abstract: The human pathogen Mycobacterium tuberculosis contains three β-carbonic anhydrases (CAs, EC 4.2.1.1) in its genome. Inhibition of some of these CAs was shown to modulate the growth of M. tuberculosis. 3D-QSAR Comparative molecular field analyses (CoMFA) were carried out on inhibitors of the enzyme Rv3588c (also denominated mtCA 2). A series of sulfonamides known to inhibit mtCA 2, including some diazenylbenzenesulfonamides, was considered in our study. The predictive ability of the model was assessed using a test set of seven compounds. The best model has demonstrated a good fit having predictive r2 value of 0.93 and cross-validated coefficient q2 value as 0.88 in tripos CoMFA region. Our results indicate that the steric and electrostatic factors play a significant role in mtCA 2 inhibition for the investigated compounds. We proposed nine new not yet synthesized mtCA 2 inhibitors, all of them probably with significantly improved anti-Rv3588c inhibitory activity.
TL;DR: Collagenase treatment increased the concentration of tripeptides in the collagen hydrolysates by 13–15% (w/w), and of the three peptides, Gly-Pro-Hyp was a true peptidic inhibitor of diPEptidylpeptidase-IV (DPP-IV), because DPP-IV could not hydrolyze the bond between Pro-Hyp.
Abstract: The collagen tripeptide fragments Gly-Ala-Hyp, Gly-Pro-Ala and Gly-Pro-Hyp were generated by hydrolyzing collagen from pig-skin, cattle-skin, fish-scales and chicken-feet, respectively, with Streptomyces collagenase. Collagenase treatment increased the concentration of tripeptides in the hydrolysates by 13-15% (w/w). Of the three peptides, Gly-Pro-Hyp was a true peptidic inhibitor of dipeptidylpeptidase-IV (DPP-IV), because DPP-IV could not hydrolyze the bond between Pro-Hyp. This tripeptide was a moderately competitive inhibitor (Ki=4.5 mM) of DPP-IV, and its level in the collagen hydrolysates could be greatly increased (4-9% [w/w]) using Streptomyces collagenase.
TL;DR: As some of these enzymes are crucial for the life cycle of this bacterium, the class of β-CA inhibitors reported in this study may lead to antimycobacterial agents with a different mechanism of action compared to the clinically used drugs for which the pathogen developed extensive drug resistance.
Abstract: A new series of fluorine containing 1,3,5-triazinyl sulfonamide derivatives obtained from cyanuric fluoride, sulfanilamide/4-aminoethylbenzenesulfonamide followed and incorporating also amin0, amino alcohol and amino acid moieties have been investigated as inhibitors of three β-carbonic anhydrases (CAs, EC 4.2.1.1) from the bacterial pathogen Mycobacterium tuberculosis, mtCA1 (Rv1284), mtCA 2 (Rv3588c) and mtCA 3 (Rv3273). All three enzymes were efficiently inhibited by these sulfonamides with KI values in the nanomolar or submicromolar range, depending on the substitution of one or both fluorine atoms at the 1,3,5-triazine ring. As some of these enzymes are crucial for the life cycle of this bacterium, the class of β-CA inhibitors reported in this study may lead to antimycobacterial agents with a different mechanism of action compared to the clinically used such drugs for which the pathogen developed extensive drug resistance.
TL;DR: Synthesis of total eighteen 2-amino-substituted 4-coumarinylthiazoles including sixteen new compounds (3a–o and 5b) bearing the benzenesulfonamide moiety is described in the present report.
Abstract: Synthesis of total eighteen 2-amino-substituted 4-coumarinylthiazoles including sixteen new compounds (3a-o and 5b) bearing the benzenesulfonamide moiety is described in the present report. All the synthesized target compounds were examined for their in vivo anti-inflammatory (AI) activity and in vitro antimicrobial activity. Results revealed that six compounds (3 d, 3 f, 3 g, 3 h, 3 j and 3 n) exhibited pronounced anti-inflammatory activity comparable to the standard drug indomethacin. AI results were further confirmed by the docking studies of the most active (3n) and the least active compound (3a) with COX-1 and COX-2 active sites. In addition, most of the compounds exhibited moderate antimicrobial activity against Gram-positive bacteria as well as fungal yeast, S. cervisiae. Comparison between 3 and 5 indicated that incorporation of additional substituted pyrazole nucleus into the scaffold significantly enhanced AI activity.
TL;DR: Both naproxen and cromolyn have significant anti-cancer properties and were found to significantly reduce the viability and have potent dose-dependent reduction of cellular proliferation.
Abstract: We previously reported the inhibitory profiles of naproxen and cromolyn against glycogen synthase kinase-3β, which partly explain the molecular mechanisms of their anti-cancer properties. In this study, we performed a detailed biochemical evaluation of the two drugs against colorectal adenocarcinoma (Caco2), hepatocellular carcinoma (HepG2), mammary gland carcinoma (MCF7), epitheloid cervix carcinoma (Hela), lung carcinoma (A5W9) and epidermoid larynx carcinoma (Hep2) cell lines. Additionally, we performed cellular viability tests using trypan blue, proliferation MTT assay, apoptosis, p53 and real-time polymerase chain reaction for gene expression of survivin and caspase-3. Not only the two drugs were found to significantly reduce the viability of different cell lines, but they also were shown to have potent dose-dependent reduction of cellular proliferation. They exhibited cytotoxicity IC50 values of 3.69 and 4.16 μM for naproxen and cromolyn, respectively. Viability and proliferation results clearly correlated with apoptosis and p53 experiments in showing that both drugs significantly raised apoptotic percentages. Furthermore, we observed a significant reduction in survivin and elevation of caspase-3 gene expression upon exposure to the two drugs. It can be concluded that both naproxen and cromolyn have significant anti-cancer properties.
TL;DR: After the synthesis of benzimidazoles, ester and hydrazide derivatives under microwave irradiation with good yields were synthesized and showed lipase inhibition at various concentrations.
Abstract: A practical protocol has been used for the synthesis of benzimidazoles. The reaction of iminoester hydrochlorides of phenylacetic with 4,5-dichloro-1,2-phenylenediamine under microwave irradiation leads to the benzimidazole derivatives with good yields and in short reaction times. After the synthesis of benzimidazoles, we synthesized ester and hydrazide derivatives under microwave irradiation with good yields. All compounds were evaluated with regard to pancreatic lipase activity and 3b, 3c, 5a and 6a showed lipase inhibition at various concentrations.
TL;DR: The interesting inhibition profile of Grayanotoxin III, coupled with various possibilities of interacting with the enzyme active site make this family of natural compounds attractive leads for designing novel chemotypes acting as CAIs.
Abstract: Grayanotoxin III (GTX3) was investigated for inhibition of all catalytically active mammalian carbonic anhydrase (CA, EC 4.2.1.1) isoforms, i.e. CA I to CA XIV. It showed micromolar inhibition (KIs of 8.01 and 6.13 µM) for cytosolic isoforms CA I and II, respectively. GTX3 showed a submicromolar inhibition (KIs in the range of 0.51-2.15 µM) for the remaining cytosolic (CA III, VII and XIII), membrane-associated/transmembrane (CA IV, IX, XII and XIV), mitochondrial (CA VA and CA VB) and secreted (CA VI) isoforms. This inhibition profile is very different from that of the sulfonamide CA inhibitors (CAIs), which possess different clinical applications. A molecular docking study for GTX3 within the active sites of CA I and II assisted to the understanding of molecular mechanism of the ligand. The interesting inhibition profile, coupled with various possibilities of interacting with the enzyme active site make this family of natural compounds attractive leads for designing novel chemotypes acting as CAIs.
TL;DR: In this article, the antioxidant and polyphenol oxidase (PPO) properties of Yomra apple were investigated by reverse phase high-performance liquid chromatography (RP-HPLC).
Abstract: In this study, firstly, antioxidant and polyphenol oxidase (PPO) properties of Yomra apple were investigated. Seventeen phenolic constituents were measured by reverse phase-high-performance liquid chromatography (RP-HPLC). Total phenolic compounds (TPCs), ferric reducing antioxidant power (FRAP) and 2, 2-diphenyl-1-picrylhydrazyl radical (DPPH) scavenging activities were performed to measure antioxidant capacity. Some kinetic parameters (Km, Vmax), and inhibition behaviors against five different substrates were measured in the crude extract. Catechin and chlorogenic acid were found as the major components in the methanolic extract, while ferulic acid, caffeic acid, p-hydroxybenzoic acid, quercetin and p-coumaric acid were small quantities. Km values ranged from 0.70 to 10.10 mM in the substrates, and also 3-(4-hydroxyphenyl) propanoic acid (HPPA) and L-DOPA showed the highest affinity. The inhibition constant of Ki were ranged from 0.05 to 14.90 mM against sodium metabisulphite, ascorbic acid, sod...
TL;DR: RLA may be more effective than LA in improving chronic wound healing in patients undergoing HBO therapy, and is associated with increased EGF and VEGF and reduced plasma TNF-α and IL-6.
Abstract: Context: Lipoic acid (LA) and hyperbaric oxygenation therapy (HBOT) improve chronic wound healing.Objective: We compared the effects of LA or its enantiomer R-(+)-lipoic acid (RLA) on wound healing.Materials and methods: Groups LA + HBOT (L), RLA + HBOT (R) and placebo + HBOT (P). Lesion areas measured before treatment and on 20th and 40th day. The biopsies and plasma were harvested before treatment and on 7th and 14th (measurements of VEGF, vascular endothelial growth factor; EGF, epidermal growth factor, TNF-α and IL-6).Results: Ulcers improved more on RLA. In both L and R groups, EGF and VEFG increased in time. RLA decreased IL-6 on T7 and T14, which did not happen with LA. TNF-α levels decreased on T14 in both LA and RLA.Discussion: The improved wound healing is associated with increased EGF and VEGF and reduced plasma TNF-α and IL-6.Conclusion: RLA may be more effective than LA in improving chronic wound healing in patients undergoing HBO therapy.
TL;DR: A series of 5-substitutedphenyl-1,3,4-thiadiazole-based hydroxamic acids as analogues of SAHA were designed and synthesized and found to possess potent anticancer cytotoxicity and HDAC inhibition effects.
Abstract: Since the first histone deacetylase (HDAC) inhibitor (Zolinza®, widely known as suberoylanilide hydroxamic acid; SAHA) was approved by the Food and Drug Administration for the treatment of T-cell lymphoma in 2006, the search for newer HDAC inhibitors has attracted a great deal of interest of medicinal chemists worldwide. As a continuity of our ongoing research in this area, we designed and synthesized a series of 5-substitutedphenyl-1,3,4-thiadiazole-based hydroxamic acids as analogues of SAHA and evaluated their biological activities. A number of compounds in this series, for example, N(1)-hydroxy-N(8)-(5-(2-chlorophenyl)-1,3,4-thiadiazol-2-yl)octandiamide (5b), N(1)-hydroxy-N(8)-(5-(3-chlorophenyl-1,3,4-thiadiazol-2-yl)octandiamide (5c) and N(1)-hydroxy-N(8)-(5-(4-chlorophenyl)-1,3,4-thiadiazol-2-yl)octandiamide (5d), were found to possess potent anticancer cytotoxicity and HDAC inhibition effects. Compounds 5b-d were generally two- to five-fold more potent in terms of cytotoxicity compared to SAHA against five cancer cell lines tested. Docking studies revealed that these hydroxamic acid displayed higher affinities than SAHA toward HDAC8.
TL;DR: The research presented is the evaluation of Cucs, as B-RAF and MEK1 kinase inhibitors, as potential candidate for inhibiting cell growth and shows potential inhibition for the total and phosphorylated ERK using ELISA kits.
Abstract: Cucurbitacins (Cucs) have been classified as signal transducer and activator of transcription 3 inhibitors. Kinase inhibition has been a validated drug target in multiple types of malignancies. B-RAF mutations are highly expressed in the melanoma. Our hypothesis is the Cucs can be a potential candidate to inhibit the signaling kinase pathway. The research presented is the evaluation of Cucs, as B-RAF and MEK1 kinase inhibitors. Virtual screening methods were employed to identify lead compounds. The hypothesis was tested on mutant B-RAF cell lines, A-375 and Sk-Mel-28 cell lines to determine the activity toward melanoma. A series of natural Cucs show an improved activity toward Sk-Mel-28 and A-375 cell lines. Cucs show potential inhibition for the total and phosphorylated ERK using ELISA kits. Cucs could be potential candidate for inhibiting cell growth.
TL;DR: The aryl 2-imino-1,2-dihydropyridine derivatives 5d and 5e displayed the most potent inhibitory activity on EGFR, and the anti-proliferative activity of these most active compounds on MDA-MB-231 breast cancer cell lines showed an IC50 range of 2.4 and 2.5 μM, respectively.
Abstract: Herein, we designed and synthesized certain anilinoquinazoline derivatives bearing bulky arylpyridinyl, arylpropenoyl and arylpyrazolyl moieties at the 4' position of the anilinoquinazoline, as potential dual HER2/EGFR kinase inhibitors. A detailed molecular modeling study was performed by docking the synthesized compounds in the active site of the epidermal growth factor receptor (EGFR). The synthesized compounds were further tested for their inhibitory activity on EGFR and HER2 tyrosine kinases. The aryl 2-imino-1,2-dihydropyridine derivatives 5d and 5e displayed the most potent inhibitory activity on EGFR with IC50 equal to 2.09 and 1.94 μM, respectively, and with IC50 equal to 3.98 and 1.04 μM on HER2, respectively. Furthermore, the anti-proliferative activity of these most active compounds on MDA-MB-231 breast cancer cell lines, known to overexpress EGFR, showed an IC50 range of 2.4 and 2.5 μM, respectively.
TL;DR: A group of compounds containing a benzimidazole substituent in the para position of the benzenesulfonamide ring was found to exhibit higher binding potency toward tested CAs than meta-substituted benzeneulfonamides.
Abstract: A series of benzenesulfonamide derivatives, bearing benzimidazole moieties, were designed and synthesized as inhibitors of carbonic anhydrases (CAs). Their binding affinities to recombinant human CA isozymes I, II, VII, XII and XIII were determined by the thermal shift assay. A group of compounds containing a benzimidazole substituent in the para position of the benzenesulfonamide ring was found to exhibit higher binding potency toward tested CAs than meta-substituted benzenesulfonamides. Some of these compounds exhibited nanomolar affinities and selectivity toward the CA isozymes tested.