scholarly journals Synthesis and Evaluation of Novel 2H-Benzo[e]-[1,2,4]thiadiazine 1,1-Dioxide Derivatives as PI3Kδ Inhibitors

Molecules ◽  
2019 ◽  
Vol 24 (23) ◽  
pp. 4299
Author(s):  
Gong ◽  
Tang ◽  
Liu ◽  
Liu
Keyword(s):  
Fluorine Atom ◽  
Indole Derivative ◽  
High Selectivity ◽  
Hydrophobic Pocket ◽  
Inhibitory Potency ◽  
Methyl Group ◽  
Arylboronic Acids ◽  
Lead Compounds ◽  
Ic50 Values ◽  
Quinazolinone Derivatives

In previous work, we applied the rotation-limiting strategy and introduced a substituent at the 3-position of the pyrazolo [3,4-d]pyrimidin-4-amine as the affinity element to interact with the deeper hydrophobic pocket, discovered a series of novel quinazolinones as potent PI3Kδ inhibitors. Among them, the indole derivative 3 is one of the most selective PI3Kδ inhibitors and the 3,4-dimethoxyphenyl derivative 4 is a potent and selective dual PI3Kδ/γ inhibitor. In this study, we replaced the carbonyl group in the quinazolinone core with a sulfonyl group, designed a series of novel 2H-benzo[e][1,2,4]thiadiazine 1,1-dioxide derivatives as PI3Kδ inhibitors. After the reduction of nitro group in N-(2,6-dimethylphenyl)-2-nitrobenzenesulfonamide 5 and N-(2,6-dimethylphenyl)-2-nitro-5-fluorobenzenesulfonamide 6, the resulting 2-aminobenzenesulfonamides were reacted with trimethyl orthoacetate to give the 3-methyl-2H-benzo[e][1,2,4]thiadiazine 1,1-dioxide derivatives. After bromination of the 3-methyl group, the nucleophilic substitution with the 3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amine provided the respective iodide derivatives, which were further reacted with a series of arylboronic acids via Suzuki coupling to furnish the 2H-benzo[e][1,2,4]thiadiazine 1,1-dioxide derivatives 15a–J and 16a–d. In agreement with the quinazolinone derivatives, the introduction of a 5-indolyl or 3,4-dimethoxyphenyl at the affinity pocket generated the most potent analogues 15a and 15b with the IC50 values of 217 to 266 nM, respectively. In comparison with the quinazolinone lead compounds 3 and 4, these 2H-benzo[e][1,2,4]thiadiazine 1,1-dioxide derivatives exhibited much decreased PI3Kδ inhibitory potency, but maintained the high selectivity over other PI3K isoforms. Unlike the quinazolinone lead compound 4 that was a dual PI3Kδ/γ inhibitor, the benzthiadiazine 1,1-dioxide 15b with the same 3,4-dimethoxyphenyl moiety was more than 21-fold selective over PI3Kγ. Moreover, the introducing of a fluorine atom at the 7-position of the 2H-benzo[e][1,2,4]thiadiazine 1,1-dioxide core, in general, was not favored for the PI3Kδ inhibitory activity. In agreement with their high PI3Kδ selectivity, 15a and 15b significantly inhibited the SU-DHL-6 cell proliferation.

scholarly journals Characterization of the Acetate Binding Pocket in the Methanosarcina thermophila Acetate Kinase

2005 ◽  
Vol 187 (7) ◽  
pp. 2386-2394 ◽  
Author(s):  
Cheryl Ingram-Smith ◽  
Andrea Gorrell ◽  
Sarah H. Lawrence ◽  
Prabha Iyer ◽  
Kerry Smith ◽  
...  
Keyword(s):  
Crystal Structure ◽  
Binding Site ◽  
Binding Pocket ◽  
Acetate Kinase ◽  
Phosphoryl Group ◽  
Acetyl Phosphate ◽  
Hydrophobic Pocket ◽  
Methanosarcina Thermophila ◽  
Methyl Group ◽  
Substrate Binding Sites

ABSTRACT Acetate kinase catalyzes the reversible magnesium-dependent synthesis of acetyl phosphate by transfer of the ATP γ-phosphoryl group to acetate. Inspection of the crystal structure of the Methanosarcina thermophila enzyme containing only ADP revealed a solvent-accessible hydrophobic pocket formed by residues Val93, Leu122, Phe179, and Pro232 in the active site cleft, which identified a potential acetate binding site. The hypothesis that this was a binding site was further supported by alignment of all acetate kinase sequences available from databases, which showed strict conservation of all four residues, and the recent crystal structure of the M. thermophila enzyme with acetate bound in this pocket. Replacement of each residue in the pocket produced variants with Km values for acetate that were 7- to 26-fold greater than that of the wild type, and perturbations of this binding pocket also altered the specificity for longer-chain carboxylic acids and acetyl phosphate. The kinetic analyses of variants combined with structural modeling indicated that the pocket has roles in binding the methyl group of acetate, influencing substrate specificity, and orienting the carboxyl group. The kinetic analyses also indicated that binding of acetyl phosphate is more dependent on interactions of the phosphate group with an unidentified residue than on interactions between the methyl group and the hydrophobic pocket. The analyses also indicated that Phe179 is essential for catalysis, possibly for domain closure. Alignments of acetate kinase, propionate kinase, and butyrate kinase sequences obtained from databases suggested that these enzymes have similar catalytic mechanisms and carboxylic acid substrate binding sites.

scholarly journals Cytotoxic Minor Piericidin Derivatives from the Actinomycete Strain Streptomyces psammoticus SCSIO NS126

Marine Drugs ◽  
2021 ◽  
Vol 19 (8) ◽  
pp. 428
Author(s):  
Kunlong Li ◽  
Ziqi Su ◽  
Yongli Gao ◽  
Xiuping Lin ◽  
Xiaoyan Pang ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
Structural Diversity ◽  
Mangrove Sediment ◽  
Cytotoxic Activities ◽  
Spectroscopic Methods ◽  
Biosynthetic Pathways ◽  
Fermentation Conditions ◽  
Lead Compounds ◽  
Ic50 Values ◽  
Actinomycete Strain

The mangrove-sediment-derived actinomycete strain Streptomyces psammoticus SCSIO NS126 was found to have productive piericidin metabolites featuring anti-renal cell carcinoma activities. In this study, in order to explore more diverse piericidin derivatives, and therefore to discover superior anti-tumor lead compounds, the NS126 strain was further fermented at a 300-L scale under optimized fermentation conditions. As a result, eight new minor piericidin derivatives (piericidins L-R (1–7) and 11-demethyl-glucopiericidin A (8)) were obtained, along with glucopiericidin B (9). The new structures including absolute configurations were determined by spectroscopic methods coupled with experimental and calculated electronic circular dichroism. We also proposed plausible biosynthetic pathways for these unusual post-modified piericidins. Compounds 1 and 6 showed selective cytotoxic activities against OS-RC-2 cells, and 2–5 exhibited potent cytotoxicity against HL-60 cells, with IC50 values lower than 0.1 μM. The new piericidin glycoside 8 was cytotoxic against ACHN, HL-60 and K562, with IC50 values of 2.3, 1.3 and 5.5 μM, respectively. The ability to arrest the cell cycle and cell apoptosis effects induced by 1 and 6 in OS-RC-2 cells, 2 in HL-60 cells, and 8 in ACHN cells were then further investigated. This study enriched the structural diversity of piericidin derivatives and confirmed that piericidins deserve further investigations as promising anti-tumor agents.

scholarly journals Inhibition of Poly(ADP-Ribose) Polymerase by Nucleic Acid Metabolite 7-Methylguanine

Acta Naturae ◽  
2016 ◽  
Vol 8 (2) ◽  
pp. 108-115 ◽  
Author(s):  
D. K. Nilov ◽  
V. I. Tararov ◽  
A. V. Kulikov ◽  
A. L. Zakharenko ◽  
I. V. Gushchina ◽  
...  
Keyword(s):  
Nucleic Acid ◽  
Breast Cancer Cells ◽  
Inhibitory Concentration ◽  
Chemotherapeutic Agents ◽  
Purine Derivatives ◽  
Acid Metabolite ◽  
Methyl Group ◽  
Ic50 Values ◽  
Chemotherapeutic Treatment ◽  
Parp 1

The ability of 7-methylguanine, a nucleic acid metabolite, to inhibit poly (ADP-ribose) polymerase-1 (PARP-1) and poly(ADP-ribose)polymerase-2 (PARP-2) has been identified in silico and studied experimentally.The amino group at position 2 and the methyl group at position 7 were shown to be important substituents for the efficient binding of purine derivatives to PARPs. The activity of both tested enzymes, PARP-1 and PARP-2, was suppressed by 7-methylguanine with IC50 values of 150 and 50 M, respectively. At the PARP inhibitory concentration, 7-methylguanine itself was not cytotoxic, but it was able to accelerate apoptotic death of BRCA1-deficient breast cancer cells induced by cisplatin and doxorubicin, the widely used DNA-damaging chemotherapeutic agents. 7-Methylguanine possesses attractive predictable pharmacokinetics and an adverse-effect profile and may be considered as a new additive to chemotherapeutic treatment.

scholarly journals Molecular Modeling Studies of Benzimidazole Nucleus

2021 ◽  
Vol 12 (2) ◽  
pp. 1559-1563
Author(s):  
Vijey Aanandhi M ◽  
Anbhule Sachin J
Keyword(s):  
Three Dimensional ◽  
Quantitative Structure Activity Relationship ◽  
Biological Action ◽  
Dimensional Structure ◽  
Benzimidazole Derivatives ◽  
Training Set ◽  
Lead Compounds ◽  
Docking Tool ◽  
Ic50 Values ◽  
Molecular Modeling Studies

For the identification of the lead compounds, a molecular docking tool is used. The little structure, namely Ligand, generally holds together the protein places. It describes a similar approach that utilizes to place over another three-dimensional structure of a probable drug on its prospective object sites. Given that, it was worthwhile to build a virtual library of benzimidazole derivatives to find lead structures to test against C. Albicans. The two-dimensional structure of all planned compounds was drawn by using the current version software and pass on to the software window. The energy of all three-dimensional structures was reduced by Molecular Orbital Package up to Root mean square gradient 0.001 and put aside in MDL Molfile (.Mol) format. To assess the likely potential of the Quantitative Structure-Activity Relationship models, the dataset was split into a training set comprising of 32 molecules and a test set of 8 molecules in such a way that the structural variety and an extensive range of biological action in the specific set were added. The IC50 values were transformed to pIC50 to give numerically larger data values.

scholarly journals Synthesis, Biological Evaluation and Docking Studies of 13-Epimeric 10-fluoro- and 10-Chloroestra-1,4-dien-3-ones as Potential Aromatase Inhibitors

Molecules ◽  
2019 ◽  
Vol 24 (9) ◽  
pp. 1783 ◽  
Author(s):  
Rebeka Jójárt ◽  
Péter Traj ◽  
Édua Kovács ◽  
Ágnes Horváth ◽  
Gyula Schneider ◽  
...  
Keyword(s):  
Biological Activity ◽  
Inhibitory Action ◽  
Molecular Level ◽  
Docking Studies ◽  
Biological Evaluation ◽  
Computational Simulations ◽  
Simultaneous Application ◽  
Methyl Group ◽  
Ic50 Values

Fluorination of 13-epimeric estrones and their 17-deoxy counterparts was performed with Selectfluor as the reagent. In acetonitrile or trifluoroacetic acid (TFA), 10β-fluoroestra-1,4-dien-3-ones were formed exclusively. Mechanistic investigations suggest that fluorinations occurred via SET in acetonitrile, but another mechanism was operative in TFA. Simultaneous application of N-chlorosuccinimide (NCS) and Selectfluor in TFA led to a 1.3:1 mixture of 10β-fluoroestra-1,4-dien-3-one and 10β-chloroestra-1,4-dien-3-one as the main products. The potential inhibitory action of the 10-fluoro- or 10-chloroestra-1,4-dien-3-one products on human aromatase was investigated via in vitro radiosubstrate incubation. The classical estrane conformation with trans ring anellations and a 13β-methyl group seems to be crucial for the inhibition of the enzyme, while test compounds bearing the 13β-methyl group exclusively displayed potent inhibitory action with submicromolar or micromolar IC50 values. Concerning molecular level explanation of biological activity or inactivity, computational simulations were performed. Docking studies reinforced that besides the well-known Met374 H-bond connection, the stereocenter in the 13 position has an important role in the binding affinity. The configuration inversion at C-13 results in weaker binding of 13α-estrone derivatives to the aromatase enzyme.

Combining properties of different classes of PI3Kα inhibitors to understand the molecular features that confer selectivity

2017 ◽  
Vol 474 (13) ◽  
pp. 2261-2276 ◽  
Author(s):  
Grace Q. Gong ◽  
Jackie D. Kendall ◽  
James M.J. Dickson ◽  
Gordon W. Rewcastle ◽  
Christina M. Buchanan ◽  
...  
Keyword(s):  
First Generation ◽  
High Selectivity ◽  
Cell Signalling ◽  
Class I ◽  
Cellular Functions ◽  
Lipid Kinase ◽  
Molecular Features ◽  
Ic50 Values ◽  
Major Target ◽  
Mcf 7

Phosphoinositide 3-kinases (PI3Ks) are major regulators of many cellular functions, and hyperactivation of PI3K cell signalling pathways is a major target for anticancer drug discovery. PI3Kα is the isoform most implicated in cancer, and our aim is to selectively inhibit this isoform, which may be more beneficial than concurrent inhibition of all Class I PI3Ks. We have used structure-guided design to merge high-selectivity and high-affinity characteristics found in existing compounds. Molecular docking, including the prediction of water-mediated interactions, was used to model interactions between the ligands and the PI3Kα affinity pocket. Inhibition was tested using lipid kinase assays, and active compounds were tested for effects on PI3K cell signalling. The first-generation compounds synthesized had IC50 (half maximal inhibitory concentration) values >4 μM for PI3Kα yet were selective for PI3Kα over the other Class I isoforms (β, δ and γ). The second-generation compounds explored were predicted to better engage the affinity pocket through direct and water-mediated interactions with the enzyme, and the IC50 values decreased by ∼30-fold. Cell signalling analysis showed that some of the new PI3Kα inhibitors were more active in the H1047R mutant bearing cell lines SK-OV-3 and T47D, compared with the E545K mutant harbouring MCF-7 cell line. In conclusion, we have used a structure-based design approach to combine features from two different compound classes to create new PI3Kα-selective inhibitors. This provides new insights into the contribution of different chemical units and interactions with different parts of the active site to the selectivity and potency of PI3Kα inhibitors.

Synthesis and Molecular Modeling of Novel 3,5-Bis(trifluoromethyl)benzylamino Benzamides as Potential CETP Inhibitors

2021 ◽  
Vol 17 ◽  
Author(s):  
Reema Abu Khalaf ◽  
Mohammad Awad ◽  
Tariq Al-Qirim ◽  
Dima Sabbah
Keyword(s):  
Molecular Modeling ◽  
Cholesteryl Ester ◽  
Hdl Cholesterol ◽  
Biological Evaluation ◽  
Lead Compounds ◽  
Transfer Protein ◽  
Cetp Inhibitors ◽  
Good Target ◽  
Ic50 Values

Background: There is an alarming spread of cases of lipid-disorders in the world that occur due to harmful lifestyle habits, hereditary risk influences, or as a result of other illnesses or medicines. Cholesteryl ester transfer protein (CETP) is a 476-residue lipophilic glycoprotein that helps in the transport of cholesteryl ester and phospholipids from the atheroprotective HDL to the proatherogenic LDL and VLDL. Inhibition of CETP leads to elevation of HDL cholesterol and reduction of LDL cholesterol and triglycerides, so it's considered a good target for the treatment of hyperlipidemia and its comorbidities. Objectives: In this research synthesis, characterization, molecular modeling and biological evaluation of eight 3,5-bis(trifluoromethyl)benzylamino benzamides 9a-d and 10a-d were carried out. Methods: The synthesized molecules were characterized using 1H-NMR, 13C-NMR, IR and HR-MS. They were in vitro biologically tested to estimate their CETP inhibitory activity. Results: These compounds offered inhibitory effectiveness ranging from 42.2% to 100% at a concentration of 10 µM. Compounds bearing unsubstituted three aromatic rings (9a) or ortho-CF3 substituted (9b) were the most effective compounds among their analogs and showed IC50 values of 1.36 and 0.69 μM, respectively. The high docking scores of 9a-d and 10a-d against 4EWS imply that they might be possible CETP inhibitors. Pharmacophore mapping results demonstrate that the series approves the fingerprint of CETP active inhibitors and therefore explains their high binding affinity against CETP binding site. Conclusion: This work concludes that 3,5-bis(trifluoromethyl)benzylamino benzamides can serve as a promising CETP inhibitors lead compounds.

Syntheses of Base and Side-Chain Modified Pyrimidine 1-[2-(Phosphonomethoxy)propyl] Derivatives as Potent Inhibitors of Thymidine Phosphorylase (PD-ECGF) from SD-Lymphoma

2006 ◽  
Vol 71 (4) ◽  
pp. 595-624 ◽  
Author(s):  
Karel Pomeisl ◽  
Ivan Votruba ◽  
Antonín Holý ◽  
Radek Pohl
Keyword(s):  
Thymidine Phosphorylase ◽  
Cell Lymphoma ◽  
Inhibitory Effect ◽  
Side Chain ◽  
The Novel ◽  
Inhibitory Potency ◽  
Methyl Group ◽  
Acyclic Nucleoside Phosphonates ◽  
Acyclic Nucleoside ◽  
Trifluoromethyl Groups

In this study we synthesized a series of thymine and 5-ethyluracil acyclic nucleoside phosphonates bearing hydroxymethyl, methoxymethyl, azidomethyl, aminomethyl and (trimethylammonio)methyl group in side chain as potent inhibitors of thymidine phosphorylase. In addition, we investigated in particular the novel syntheses of fluorinated derivatives containing fluoromethyl or trifluoromethyl groups in side chain such as 5-ethyl- 1-[(S)-3-fluoro-2-(phosphonomethoxy)propyl]uracil (8) or 5-ethyl-1-[3,3,3-trifluoro-2-(phosphonomethoxy)propyl]uracil and thymine derivatives 27 and 28. Uracil acyclic nucleoside phosphonates 1-{2-[(diisopropoxyphosphoryl)methoxy]ethyl}uracil (12) and 1-{2-[(diisopropoxyphosphoryl)methoxy]-3,3,3-trifluoropropyl}uracil (19) were fluorinated to corresponding 5-fluorouracil derivatives. While the 5-fluorouracil derivatives exhibit a marginal inhibitory effect, thymine and 5-ethyluracil compound with fluorine in side chains possess considerable inhibitory potency toward thymidine phosphorylase from rat spontaneous T-cell lymphoma.

scholarly journals Effect of Bromination on the Quorum Sensing-Inhibiting Properties of Indole-3-Carboxaldehydes in Chromobacterium violaceum AHL System

2021 ◽  
Vol 12 (2) ◽  
pp. 376-382
Author(s):  
Chesley A. Kemp ◽  
Donna K. McCullough ◽  
Dobrusia Bialonska ◽  
Paul J. T. Johnson
Keyword(s):  
Escherichia Coli ◽  
Quorum Sensing ◽  
Virulence Factors ◽  
Indole Derivative ◽  
Chromobacterium Violaceum ◽  
Quorum Sensing Inhibition ◽  
Signaling Molecule ◽  
Bacterial Communication ◽  
Ic50 Value ◽  
Ic50 Values

Quorum sensing (QS) is a form of bacterial communication involved in the production of virulence factors in many species. As a result, inhibition of quorum sensing may be of use in mitigating pathogenesis. The signaling molecule indole is currently being investigated as a target for quorum sensing inhibition (QSI) and the indole derivative indole-3-carboxaldehyde (ICA) has been shown to inhibit quorum sensing-mediated behaviors in Escherichia coli. In this study, we investigate bromination as a method of increasing the QSI capabilities of indole carboxaldehydes. The IC50 values of three monobrominated indole carboxaldehydes (5-bromoindole-3-carboxaldehyde, 6-bromoindole-3-carboxaldehyde, and 7-bromoindole-3-carboxaldehyde) were determined and compared to the IC50 value of ICA. The bromination of these indole carboxaldehydes reduced the IC50 values between 2- and 13-fold, indicating that bromination significantly increases the potency of these indole carboxaldehydes.

scholarly journals NEW QUINAZOLINONE DERIVATIVES: SYTHESIS AND IN VITRO CYTOTOXIC ACTIVITY

2020 ◽  
Vol 58 (1) ◽  
pp. 12
Author(s):  
Tran Khac Vu
Keyword(s):  
Cytotoxic Activity ◽  
Cell Lines ◽  
Cancer Cell ◽  
Cytotoxic Effect ◽  
Cancer Cell Lines ◽  
Ic50 Values ◽  
Quinazolinone Derivatives ◽  
Bioassay Result ◽  
Mcf 7

The paper presents a simple synthesis of new quinazolinone derivatives 13a-i. Synthesized derivatives were tested for their cytotoxic effect against three cancer cell lines including SKLU-1, MCF-7 and HepG-2. The bioassay result showed that only compound 13e exhibited significant cytotoxic effect against cancer cell lines tested with IC50 values of 9.48, 20.39 and 18.04 µg/ mL, respectively.

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