scholarly journals Development of MTH1-Binding Nucleotide Analogs Based on 7,8-Dihalogenated 7-Deaza-dG Derivatives

2021 ◽  
Vol 22 (3) ◽  
pp. 1274
Author(s):  
Hui Shi ◽  
Ren Ishikawa ◽  
Choon Han Heh ◽  
Shigeki Sasaki ◽  
Yosuke Taniguchi
Keyword(s):  
Enzyme Activity ◽  
Active Site ◽  
Inhibitory Effects ◽  
Nucleotide Analogs ◽  
Computational Docking ◽  
Drug Candidates ◽  
Repair Enzymes ◽  
Nucleotide Pools ◽  
New Compounds ◽  
Inhibited Enzyme

MTH1 is an enzyme that hydrolyzes 8-oxo-dGTP, which is an oxidatively damaged nucleobase, into 8-oxo-dGMP in nucleotide pools to prevent its mis-incorporation into genomic DNA. Selective and potent MTH1-binding molecules have potential as biological tools and drug candidates. We recently developed 8-halogenated 7-deaza-dGTP as an 8-oxo-dGTP mimic and found that it was not hydrolyzed, but inhibited enzyme activity. To further increase MTH1 binding, we herein designed and synthesized 7,8-dihalogenated 7-deaza-dG derivatives. We successfully synthesized multiple derivatives, including substituted nucleosides and nucleotides, using 7-deaza-dG as a starting material. Evaluations of the inhibition of MTH1 activity revealed the strong inhibitory effects on enzyme activity of the 7,8-dihalogenated 7-deaza-dG derivatives, particularly 7,8-dibromo 7-daza-dGTP. Based on the results obtained on kinetic parameters and from computational docking simulating studies, these nucleotide analogs interacted with the active site of MTH1 and competitively inhibited the substrate 8-oxodGTP. Therefore, novel properties of repair enzymes in cells may be elucidated using new compounds.

scholarly journals Kinetics of the course of inactivation of aminoacylase by 1,10-phenanthroline

1992 ◽  
Vol 281 (1) ◽  
pp. 285-290 ◽  
Author(s):  
Z X Wang ◽  
H B Wu ◽  
X C Wang ◽  
H M Zhou ◽  
C L Tsou
Keyword(s):  
Enzyme Activity ◽  
Active Site ◽  
Inactivation Kinetics ◽  
Slow Inactivation ◽  
Phenanthroline Complex ◽  
Rapid Reaction ◽  
Kinetics Of ◽  
Active Site Conformation ◽  
Inhibited Enzyme ◽  
Substrate Competition

The kinetic theory of the substrate reaction during modification of enzyme activity previously described [Tsou (1988) Adv. Enzymol. Relat. Areas Mol. Biol. 61, 381-436] has been applied to a study on the kinetics of the course of inactivation of aminoacylase by 1,10-phenanthroline. Upon dilution of the enzyme that had been incubated with 1,10-phenanthroline into the reaction mixture, the activity of the inhibited enzyme gradually increased, indicating dissociation of a reversible enzyme–1,10-phenanthroline complex. The kinetics of the substrate reaction with different concentrations of the substrate chloroacetyl-L-alanine and the inactivator suggest a complexing mechanism for inactivation by, and substrate competition with, 1,10-phenanthroline at the active site. The inactivation kinetics are single phasic, showing that the initial formation of an enzyme-Zn(2+)-1,10-phenanthroline complex is a relatively rapid reaction, followed by a slow inactivation step that probably involves a conformational change of the enzyme. The presence of Zn2+ apparently stabilizes an active-site conformation required for enzyme activity.

Click Reactions in Chemistry of Triterpenes - Advances Towards Development of Potential Therapeutics

2018 ◽  
Vol 25 (5) ◽  
pp. 636-658 ◽  
Author(s):  
Jan Pokorny ◽  
Lucie Borkova ◽  
Milan Urban
Keyword(s):  
Biological Activities ◽  
Synthetic Approach ◽  
Clinical Use ◽  
New Approach ◽  
Click Reactions ◽  
Drug Candidates ◽  
The Past ◽  
Low Toxicity ◽  
New Compounds ◽  
Potential Therapeutics

Triterpenoids are natural compounds with a large variety of biological activities such as anticancer, antiviral, antibacterial, antifungal, antiparazitic, antiinflammatory and others. Despite their low toxicity and simple availability from the natural resources, their clinical use is still severely limited by their higher IC50 and worse pharmacological properties than in the currently used therapeutics. This fact encouraged a number of researchers to develop new terpenic derivatives more suitable for the potential clinical use. This review summarizes a new approach to improve both, the activity and ADME-Tox properties by connecting active terpenes to another modifying molecules using click reactions. Within the past few years, this synthetic approach was well explored yielding a lot of great improvements of the parent compounds along with some less successful attempts. A large quantity of the new compounds presented here are superior in both activity and ADME-Tox properties to their parents. This review should serve the researchers who need to promote their hit triterpenic structures towards their clinical use and it is intended as a guide for the chemical synthesis of better drug candidates.

Design, Synthesis and Pharmacological Evaluation of Novel Antiinflammatory and Analgesic O-Benzyloxime Compounds Derived From Natural Eugenol

2019 ◽  
Vol 16 (10) ◽  
pp. 1157-1166
Author(s):  
Rodrigo César da Silva ◽  
Fabiano Veiga ◽  
Fabiana Cardoso Vilela ◽  
André Victor Pereira ◽  
Thayssa Tavares da Silva Cunha ◽  
...  
Keyword(s):  
Formalin Test ◽  
Docking Studies ◽  
Paw Edema ◽  
Inhibitory Effects ◽  
Structural Pattern ◽  
Design Synthesis ◽  
Drug Candidates ◽  
Anti Inflammatory ◽  
Analgesic Activities ◽  
Cox 1

Background: : A new series of O-benzyloximes derived from eugenol was synthesized and was evaluated for its antinociceptive and anti-inflammatory properties. Methods: : The target compounds were obtained in good global 25-28% yields over 6 steps, which led us to identify compounds (Z)-5,6-dimethoxy-2,2-dimethyl-2,3-dihydro-1H-inden-1-one-O-(4- (methylthio)benzyloxime (8b), (Z)-5,6-dimethoxy-2,2-dimethyl-2,3-dihydro-1H-inden-1-one-O-4- bromobenzyloxime (8d) and (Z)-5,6-dimethoxy-2,2-dimethyl-2,3-dihydro-1H-inden-1-one-O-4- (methylsulfonyl)benzyloxime (8f) as promising bioactive prototypes. Results:: These compounds have significant analgesic and anti-inflammatory effects, as evidenced by formalin-induced mice paw edema and carrageenan-induced mice paw edema tests. In the formalin test, compounds 8b and 8f evidenced both anti-inflammatory and direct analgesic activities and in the carrageenan-induced paw edema, with compounds 8c, 8d, and 8f showing the best inhibitory effects, exceeding the standard drugs indomethacin and celecoxib. Conclusion: : Molecular docking studies have provided additional evidence that the pharmacological profile of these compounds may be related to inhibition of COX enzymes, with slight preference for COX-1. These results led us to identify the new O-benzyloxime ethers 8b, 8d and 8f as orally bioactive prototypes, with a novel structural pattern capable of being explored in further studies aiming at their optimization and development as drug candidates.

Selection of oxypeucedanin as a potential antagonist from molecular docking analysis of HSP90

2020 ◽  
Vol 0 (0) ◽  
Author(s):  
Joshua Oluwasegun Bamidele ◽  
George Oche Ambrose ◽  
Oluwaseun Suleiman Alakanse
Keyword(s):  
Molecular Docking ◽  
Liver Toxicity ◽  
Docking Study ◽  
Docking Studies ◽  
Molecular Docking Study ◽  
Docking Analysis ◽  
Computational Docking ◽  
Drug Candidates ◽  
Expression Rate ◽  
Client Proteins

AbstractHSP90 is observed as one of the copious molecular chaperones that play a key role in mediating appropriate folding, maturation, and firmness of many client proteins in cells. The expression rate of HSP90 in cancer cells is at a level of 2- to 10-fold higher than the 1- to 2-fold of its unstressed and healthy ones. To combat this, several inhibitors to HSP90 protein have been studied (such as geldanamycin and its derivative 17-AAG and 17-DMAG) and have shown some primary side effects including plague, nausea, vomiting, and liver toxicity, hence the search for the best-in-class inhibitor for this protein through in silico. This study is aimed at analyzing the inhibitory potency of oxypeucedanin-a furocoumarin derivations, which have been reported to have antipoliferative activity in human prostrate carcinoma DN145 cells, and three other drug candidates retrieved from the literature via computational docking studies. The results showed oxypeucedanin as the compound with the highest binding energy of −9.2 kcal/mol. The molecular docking study was carried out using PyRx, Auto Dock Vina option, and the target was validated to confirm the proper target and the docking procedure employed for this study.

Inhibitory Effects of Vitamin A on TCDD-induced Cytochrome P-450 1A1 Enzyme Activity and Expression

2005 ◽  
Vol 85 (1) ◽  
pp. 727-734 ◽  
Author(s):  
Yan-Mei Yang ◽  
Dong-Yang Huang ◽  
Ge-Fei Liu ◽  
Jiu-Chang Zhong ◽  
Kun Du ◽  
...  
Keyword(s):  
Enzyme Activity ◽  
Vitamin A ◽  
Inhibitory Effects ◽  
Cytochrome P 450

Phosphatase systems in Fasciolopsis buski Lankester, 1857 and Gastrodiscus aegyptiacus Cobbold, 1876

Parasitology ◽  
1973 ◽  
Vol 67 (2) ◽  
pp. 197-204 ◽  
Author(s):  
Madan M. Goil
Keyword(s):  
Enzyme Activity ◽  
Tartaric Acid ◽  
Maximum Activity ◽  
Nitrophenyl Phosphate ◽  
Biochemical Studies ◽  
Phosphate Hydrolysis ◽  
Fasciolopsis Buski ◽  
Enzyme I ◽  
Inhibited Enzyme ◽  
Acid Phosphomonoesterase

Biochemical studies on the non-specific phosphomonoesterases have demonstrated the presence of acid phosphomonoesterase with maximum activity at pH 4·0 in Gastrodiscus aegyptiacus (enzyme I) and at pH 4·5 in the case of Fasdolopsis buski (enzyme II). The Km for ρ-nitrophenyl phosphate hydrolysis was 0·66 mM for enzyme I and 1·1 mM for enzyme II. Different concentrations of fluoride, arsenate, tartrate, tartaric acid, cysteine and copper brought about inhibition of both enzymes and magnesium, iodoaeetate, iodoacetamide and EDTA had no influence on either enzyme activity. Cobalt activated both enzymes while zinc inhibited enzyme I and strongly stimulated enzyme II.

Exploration of Umbelliferone Based Derivatives as Potent MAO Inhibitors: Dry vs. Wet Lab Evaluation

2019 ◽  
Vol 18 (21) ◽  
pp. 1857-1871 ◽  
Author(s):  
Priyanka Dhiman ◽  
Neelam Malik ◽  
Anurag Khatkar
Keyword(s):  
Active Site ◽  
Docking Simulation ◽  
Selectivity Index ◽  
Drug Candidates ◽  
Ic50 Value ◽  
Spectrophotometric Titrations ◽  
Wet Lab ◽  
Inhibitory Potential ◽  
Anxiety Depression ◽  
The Impact

Background: Monoamine oxidase inhibitors are potential drug candidates within therapeutics of different neuropsychological and neurodegenerative disorders including anxiety, depression and Parkinson’s disease. Objective: We investigated the MAO inhibitory effects of the umbelliferone based derivatives for the treatment of neurological disorders. The potential antioxidant effects of the derivatives were evaluated by DPPH and H2O2 scavenging methods. Method: A series of different umbelliferone derivatives was designed and synthesized, and the derivatives were screened for hMAO-A and hMAO-B inhibition. Moreover, the mechanistic insight for enzyme- compound infractions was achieved by docking simulation. The antioxidant potential was dually assessed by two spectrophotometric titrations methods. Results: Compound 5 with bromo 5-bromo-isatin exhibited a remarkable hMAO-A inhibitory potential (7.473±0.035 µM and the selectivity index of 0.14) revealing the impact of hybrid coumarin and 5- bromo-2-oxoindolin-3-yl ring with hydrazine linker on the hMAO-A active site. Compound 13 exhibited significant hMAO-B inhibition with an IC50 value of 10.32±0.044µM with an exceptional selectivity index of 8.55. Incorporation of 2-hydroxy-2-phenylacetate moiety on 2-oxo-2H-chromen ring led the important binding infractions within the hMAO active site. Conclusion: Our findings revealed a good correlation between experimental MAO inhibition and docking score by computational studies. Notably, the compounds with remarkable MAO inhibitory potential were also observed as potential antioxidants.

scholarly journals Natalenamides A–C, Cyclic Tripeptides from the Termite-Associated Actinomadura sp. RB99

Molecules ◽  
2018 ◽  
Vol 23 (11) ◽  
pp. 3003 ◽  
Author(s):  
Seoung Rak Lee ◽  
Dahae Lee ◽  
Jae Sik Yu ◽  
René Benndorf ◽  
Sullim Lee ◽  
...  
Keyword(s):  
Mass Spectrometry ◽  
Cyclic Peptides ◽  
Culture Broth ◽  
Resonance Spectroscopy ◽  
Ionization Mass ◽  
Inhibitory Effects ◽  
Associated Bacteria ◽  
Chemical Structures ◽  
New Compounds ◽  
Powerful Strategy

In recent years, investigations into the biochemistry of insect-associated bacteria have increased. When combined with analytical dereplication processes, these studies provide a powerful strategy to identify structurally and/or biologically novel compounds. Non-ribosomally synthesized cyclic peptides have a broad bioactivity spectrum with high medicinal potential. Here, we report the discovery of three new cyclic tripeptides: natalenamides A–C (compounds 1–3). These compounds were identified from the culture broth of the fungus-growing termite-associated Actinomadura sp. RB99 using a liquid chromatography (LC)/ultraviolet (UV)/mass spectrometry (MS)-based dereplication method. Chemical structures of the new compounds (1–3) were established by analysis of comprehensive spectroscopic methods, including one-dimensional (1H and 13C) and two-dimensional (1H-1H-COSY, HSQC, HMBC) nuclear magnetic resonance spectroscopy (NMR), together with high-resolution electrospray ionization mass spectrometry (HR-ESIMS) data. The absolute configurations of the new compounds were elucidated using Marfey’s analysis. Through several bioactivity tests for the tripeptides, we found that compound 3 exhibited significant inhibitory effects on 3-isobutyl-1-methylxanthine (IBMX)-induced melanin production. The effect of compound 3 was similar to that of kojic acid, a compound extensively used as a cosmetic material with a skin-whitening effect.

Coenzyme A metabolism

1985 ◽  
Vol 248 (1) ◽  
pp. E1-E9 ◽  
Author(s):  
J. D. Robishaw ◽  
J. R. Neely
Keyword(s):  
Enzyme Activity ◽  
Cardiac Muscle ◽  
Heart Muscle ◽  
Coenzyme A ◽  
Free Carnitine ◽  
Pantothenate Kinase ◽  
Acetyl Coenzyme A ◽  
Synthetic Pathway ◽  
And Control ◽  
Inhibited Enzyme

The metabolism of coenzyme A and control of its synthesis are reviewed. Pantothenate kinase is an important rate-controlling enzyme in the synthetic pathway of all tissues studied and appears to catalyze the flux-generating reaction of the pathway in cardiac muscle. This enzyme is strongly inhibited by coenzyme A and all of its acyl esters. The cytosolic concentrations of coenzyme A and acetyl coenzyme A in both liver and heart are high enough to totally inhibit pantothenate kinase under all conditions. Free carnitine, but not acetyl carnitine, deinhibits the coenzyme A-inhibited enzyme. Carnitine alone does not increase enzyme activity. Thus changes in the acetyl carnitine-to-carnitine ratio that occur with nutritional states provides a mechanism for regulation of coenzyme A synthetic rates. Changes in the rate of coenzyme A synthesis in liver and heart occurs with fasting, refeeding, and diabetes and in heart muscle with hypertrophy. The pathway and regulation of coenzyme A degradation are not understood.

Combined blockade of thrombin anion binding exosite-1 and PAR4 produces synergistic antiplatelet effect in human platelets

2011 ◽  
Vol 105 (01) ◽  
pp. 88-95 ◽  
Author(s):  
Wei-Ya Wang ◽  
Chien-Kei Wei ◽  
Che-Ming Teng ◽  
Chin-Chung Wu
Keyword(s):  
Platelet Aggregation ◽  
Active Site ◽  
Antithrombotic Therapy ◽  
Specific Binding ◽  
Anticoagulant Activity ◽  
Human Platelets ◽  
Anion Binding ◽  
Inhibitory Effects ◽  
Clotting Time ◽  
Potential Strategy

SummaryThrombin exosite-1 mediates the specific binding of thrombin with fibrinogen and protease-activated receptor (PAR) 1. Exosite-1 inhibitors have been shown to effectively decrease the clotting activity of thrombin, while their antiplatelet effects are relatively weak. In the present study, the inhibitory effects of two exosite-1 inhibitors, hirugen and HD1, but not the exosite-2 inhibitor HD22, on thrombin-induced platelet aggregation and P-selectin expression were dramatically enhanced by a PAR4 antagonist, YD-3. In contrast, the PAR1 antagonist SCH-79797 did not affect the antiplatelet effects of exosite-1 inhibitors. The exosite-1 inhibitors and YD-3 prevented the Ca2+ spike and the prolonged Ca2+ response in thrombin-stimulated platelets, respectively; and combination of these two classes of agents led to abolishment of Ca2+ signal. Unlike exosite-1 inhibitors, the antiplatelet effects of the active site inhibitor PPACK and the bivalent inhibitor bivalirudin were not significantly enhanced by YD-3. In addition, the platelet-stimulating activity of γ-thrombin, an autolytic product of α-thrombin which lacks exosite-1, was inhibited by YD-3. These results suggest that the synergistic antiplatelet effects of exosite-1 inhibitor and PAR4 antagonist are resulted from combined blockade of PAR1 and PAR4 in platelets. In fibrinogen or plasma clotting assay, YD-3 neither prolonged the clotting time on its own nor enhanced the anticoagulant activity of exosite-1 inhibitors. Therefore, the combined blockade of exosite-1 and PAR4 may offer a potential strategy for improving the balance of benefits and risks of antithrombotic therapy.

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