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1.
J Org Chem ; 87(24): 16676-16690, 2022 12 16.
Article in English | MEDLINE | ID: mdl-36469658

ABSTRACT

Regioselective functionalization of gem-difluoroalkenes enables convergent late-stage access to fluorinated functional groups, though most functionalization reactions proceed through defluorinative functionalization processes that deliver mono-fluorovinyl products. In contrast, fewer reactions undergo net hydrofunctionalization to generate difluorinated products. Herein, we report a photocatalytic hydrothiolation of gem-difluoroalkenes that enables access to a broad spectrum of α,α-difluoroalkylthioethers. Notably, the reaction successfully couples nonactivated substrates, which expands the scope of accessible molecules relative to previously reported reactions involving organo- or photocatalytic strategies. Further, this reaction successfully couples biologically relevant molecules under aqueous conditions, highlighting potential applications in both late-stage and biorthogonal functionalizations.


Subject(s)
Catalysis
2.
Bioorg Chem ; 94: 103405, 2020 01.
Article in English | MEDLINE | ID: mdl-31806156

ABSTRACT

This report describes the synthesis of a library of fluorogenic carbapenemase substrates consisting of carbapenem derivatives, fluorescence dyes, and active cleavable linkers and their evaluation for specifically detecting carbapenemase-producing organisms (CPOs). We synthesized a series of compounds having three different types of linkers such as benzyl ether, carbamate, and amine using hydroxymethyl carbapenem 7a and hydroxyallyl carbapenem 7b as key intermediates. Probe 1b exhibited high stability and a prompt turn-on fluorescence signal upon hydrolysis by carbapenemases. In particular, the screening of clinical samples indicated that the probe 1b exhibited excellent selectivity to the CPOs over other ß-lactamases or non-carbapenemase producing bacteria, which may be of clinical use for the rapid and accurate detection of CPOs for timely diagnosis and treatment.


Subject(s)
Bacteria/pathogenicity , Bacterial Proteins/chemistry , Carbapenems/chemistry , Fluorescent Dyes/therapeutic use , beta-Lactamases/chemistry , Humans , Models, Molecular
3.
Molecules ; 23(2)2018 Jan 31.
Article in English | MEDLINE | ID: mdl-29385071

ABSTRACT

A new series of 1-phenyl-3-(4-(pyridin-3-yl)phenyl)urea derivatives were synthesized and subjected to in vitro antiproliferative screening against National Cancer Institute (NCI)-60 human cancer cell lines of nine different cancer types. Fourteen compounds 5a-n were synthesized with three different solvent exposure moieties (4-hydroxylmethylpiperidinyl and trimethoxyphenyloxy and 4-hydroxyethylpiperazine) attached to the core structure. Substituents with different π and σ values were added on the terminal phenyl group. Compounds 5a-e with a 4-hydroxymethylpiperidine moiety showed broad-spectrum antiproliferative activity with higher mean percentage inhibition values over the 60-cell line panel at 10 µM concentration. Compound 5a elicited lethal rather than inhibition effects on SK-MEL-5 melanoma cell line, 786-0, A498, RXF 393 renal cancer cell lines, and MDA-MB-468 breast cancer cell line. Two compounds, 5a and 5d showed promising mean growth inhibitions and thus were further tested at five-dose mode to determine median inhibitory concentration (IC50) values. The data revealed that urea compounds 5a and 5d are the most active derivatives, with significant efficacies and superior potencies than paclitaxel in 21 different cancer cell lines belonging particularly to renal cancer and melanoma cell lines. Moreover, 5a and 5d had superior potencies than gefitinib in 38 and 34 cancer cell lines, respectively, particularly colon cancer, breast cancer and melanoma cell lines.


Subject(s)
Antineoplastic Agents , Cell Proliferation/drug effects , Neoplasms/drug therapy , Phenylurea Compounds , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Cell Line, Tumor , Humans , Neoplasms/metabolism , Neoplasms/pathology , Phenylurea Compounds/chemical synthesis , Phenylurea Compounds/chemistry , Phenylurea Compounds/pharmacology
4.
Bioorg Med Chem Lett ; 26(4): 1301-4, 2016 Feb 15.
Article in English | MEDLINE | ID: mdl-26786696

ABSTRACT

A new series of diarylamides, having a pyrimidinyl pyridine scaffold, was designed and synthesized. The target compounds were synthesized in three steps. A selected group from the target compounds was tested over a panel of 60 cancer cell lines at a single dose concentration of 10 µM, and the most active compound, 5j, was further tested in a five-dose testing mode to determine its IC50 value over the 60 cell lines. In single-dose testing mode, compound 5j showed the highest growth inhibition against the NCI-60 cancer cell lines, while other tested compounds showed a weak to moderate inhibitory activity against a range of different cancer cell lines. In five-dose testing mode, compound 5j showed strong inhibitory activity in micro molar range against many cancer cell lines. Its major activity was against melanoma cancer cell lines. Therefore, compound 5j is a promising hit compound targeting this severe form of cancer.


Subject(s)
Amides/chemistry , Antineoplastic Agents/chemical synthesis , Pyridines/chemistry , Amides/chemical synthesis , Amides/pharmacology , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Cell Line, Tumor , Cell Proliferation/drug effects , Drug Screening Assays, Antitumor , Humans , Inhibitory Concentration 50 , Pyridines/chemical synthesis , Pyridines/pharmacology , Structure-Activity Relationship
5.
J Enzyme Inhib Med Chem ; 30(2): 290-8, 2015 Apr.
Article in English | MEDLINE | ID: mdl-24939104

ABSTRACT

As a part of trials to target ROS1 kinase with potential inhibitors, a novel series of pyrimidin-4-yl-ethanol and ethanone derivatives (4a-f, 5a-f, 6a-f and 7a-f) have been designed based on previously discovered lead compounds KIST301072 and KIST301080, and synthesized on 4-5 steps according to compounds. The structures of the newly synthesized compounds have been confirmed on (1)H-NMR, (13)C-NMR and IR. Most of the tested compounds showed ROS1 kinase inhibitory activity in micromolar range.


Subject(s)
Drug Design , Protein Kinase Inhibitors/chemical synthesis , Protein-Tyrosine Kinases/antagonists & inhibitors , Proto-Oncogene Proteins/antagonists & inhibitors , Pyrimidines/chemical synthesis , Magnetic Resonance Spectroscopy , Molecular Docking Simulation , Molecular Structure , Protein Kinase Inhibitors/chemistry , Protein Kinase Inhibitors/pharmacology , Pyrimidines/chemistry , Pyrimidines/pharmacology , Spectroscopy, Fourier Transform Infrared , Structure-Activity Relationship
6.
Bioorg Med Chem ; 22(15): 3871-8, 2014 Aug 01.
Article in English | MEDLINE | ID: mdl-24997577

ABSTRACT

Recently inhibition of ROS1 kinase has proven to be a promising strategy for several indications such as glioblastoma, non-small cell lung cancer (NSCLC), and cholangiocarcinoma. Our team reported trisubstituted pyrazole-based ROS1 inhibitors by which two inhibitors showed good IC50 values in enzyme-based screening. To develop more advanced ROS1 inhibitors through SAR this trisubstituted pyrazole-based scaffold has been built. Consequently, 16 compounds have been designed, synthesized and shown potent IC50 values in the enzymatic assay, which are from 13.6 to 283 nM. Molecular modeling studies explain how these ROS1 kinase inhibitors revealed effectively the key interactions with ROS1 ATP binding site. Among these compounds, compound 9a (IC50=13.6 nM) has exerted 5 fold potency than crizotinib and exhibited high degree of selectivity (selectivity score value=0.028) representing the number of non-mutant kinases with biological activity over 90% at 10 µM.


Subject(s)
Protein Kinase Inhibitors/chemistry , Protein-Tyrosine Kinases/antagonists & inhibitors , Proto-Oncogene Proteins/antagonists & inhibitors , Pyrazoles/chemistry , Adenosine Triphosphate/chemistry , Adenosine Triphosphate/metabolism , Binding Sites , Crizotinib , Humans , Molecular Docking Simulation , Protein Binding , Protein Kinase Inhibitors/chemical synthesis , Protein Kinase Inhibitors/metabolism , Protein Structure, Tertiary , Protein-Tyrosine Kinases/metabolism , Proto-Oncogene Proteins/metabolism , Pyrazoles/metabolism , Pyridines/chemistry , Pyridines/metabolism , Structure-Activity Relationship
7.
Naunyn Schmiedebergs Arch Pharmacol ; 393(8): 1405-1417, 2020 08.
Article in English | MEDLINE | ID: mdl-32103295

ABSTRACT

Hesperidin (HD), a bioflavonoid, has been shown to exert hepatoprotective effects. Our aim is to investigate the possible protective effects of HD against methotrexate (MTX) hepatotoxicity in adult male Sprague-Dawley (SD) rats that were divided into four groups (10 rats/each) and were exposed to MTX with or without HD co-administration for consecutive 28 days. The results showed that HD significantly ameliorated MTX-induced increase in liver enzymes and histopathological changes. Hepatic oxidative stress was suppressed by HD, as evidenced by the decrease in malondialdehyde (MDA), with a concomitant increase in total antioxidant activity (TAC), catalase (CAT), and glutathione (GSH) levels. Moreover, co-administration of HD with MTX remarkably upregulated the expression of Nrf2 and HO-1 compared with the MTX group. By the decrease in nuclear factor-kB (NF-κB) pathway and tumor necrosis factor α (TNF-α), HD obviously attenuated inflammatory response in MTX-lesioned livers. Likewise, the downregulation of P53 by HD could explain its antiapoptotic effects as indicated by increase BCl2 and the significant decrease of caspase-9 mRNA expression as compared with the MTX group. Thus, these findings revealed the hepatoprotective nature of HD against MTX hepatotoxicity by attenuating the pro-inflammatory and apoptotic mediators and improving antioxidant aptitude.


Subject(s)
Anti-Inflammatory Agents/pharmacology , Antioxidants/pharmacology , Chemical and Drug Induced Liver Injury/prevention & control , Hesperidin/pharmacology , Liver/drug effects , Animals , Apoptosis/drug effects , Apoptosis Regulatory Proteins/genetics , Apoptosis Regulatory Proteins/metabolism , Chemical and Drug Induced Liver Injury/etiology , Chemical and Drug Induced Liver Injury/metabolism , Chemical and Drug Induced Liver Injury/pathology , Disease Models, Animal , Gene Expression Regulation , Heme Oxygenase (Decyclizing)/genetics , Heme Oxygenase (Decyclizing)/metabolism , Inflammation Mediators/metabolism , Liver/metabolism , Liver/pathology , Male , Methotrexate , NF-E2-Related Factor 2/genetics , NF-E2-Related Factor 2/metabolism , Oxidative Stress/drug effects , Rats, Sprague-Dawley , Signal Transduction , Tumor Suppressor Protein p53/genetics , Tumor Suppressor Protein p53/metabolism
8.
Biol Trace Elem Res ; 198(1): 177-188, 2020 Nov.
Article in English | MEDLINE | ID: mdl-31933277

ABSTRACT

Despite the wide application of iron oxide nanoparticles (IONPs), little is known about the specific mechanism of their nephrotoxic effect. We aimed to evaluate the nephrotoxic effects of iron oxide nanoparticles (IONPs) in vivo and the protective effect of ellagic acid (EA) as a silent information regulator sirtuin 1 (SIRT1) activator against the induced nephrotoxicity. Forty male albino Wistar rats were randomly distributed into four equal groups (10 rats each): the control group (oral saline for 30 days), ellagic acid (EA) group (10 mg/kg b.w. EA, orally for 30 days), IONP group (20 mg/kg b.w. IONP I/P injection at the 24th-30th day), and EA + IONP group (10 mg/kg b.w./day EA for 30 days + 20 mg/kg b.w. IONPs at the 24th-30th day). In the present study, the potent antioxidant and antiapoptotic effects of EA were indicated by the significant overexpression of SIRT1 in renal tissues that leads to significant decreases in renal MDA content, P53 protein level and forkhead-box transcription factor1 (FOXO1) expression, and significant increases in renal GSH level, catalase activity, growth arrest and DNA damage-inducible protein 45 alpha (GADDα45), and renal inhibition of apoptosis protein (KIAP) gene expression levels in the EA + IONP-treated group. These results were confirmed by the improved histopathological renal features with EA administration. In conclusion, the present study provides the first evidence for the usefulness of EA as a sirtuin1 activator in the prevention or treatment of renal damage. Thus, EA could be used as a promising therapy for the prevention of IONP-induced nephrotoxicity.


Subject(s)
Ellagic Acid , Sirtuin 1 , Animals , Antioxidants/pharmacology , Ellagic Acid/pharmacology , Magnetic Iron Oxide Nanoparticles , Male , Prospective Studies , Rats , Rats, Wistar
9.
RSC Adv ; 10(54): 32335-32344, 2020 Sep 01.
Article in English | MEDLINE | ID: mdl-35516510

ABSTRACT

Asymmetric oxidation of prochiral sulfides is a direct means for production of enantiopure sulfoxides which are important in organic synthesis and the pharmaceutical industry. In the present study, Streptomyces glaucescens GLA.0 was employed for stereoselective oxidation of prochiral sulfides. Growing cells selectively catalyzed the oxidation of phenyl methyl sulfide to the corresponding sulfoxide. Only very little overoxidation was observed, resulting in minor amounts of the unwanted sulfone. Addition of isopropyl alcohol as a co-solvent, time of substrate addition and composition of the reaction media resulted in enhanced phenyl methyl sulfide biotransformation. The concentration of the undesired by-product (sulfone) was as low as 4% through the reaction course under optimal reaction conditions. The results show that S. glaucescens GLA.0 is a promising whole-cell biocatalyst for preparing highly enantiopure (R)-phenyl methyl sulfoxide in high yield (90%) with an enantiomeric excess (ee) exceeding 99%.

10.
Eur J Med Chem ; 90: 195-208, 2015 Jan 27.
Article in English | MEDLINE | ID: mdl-25461320

ABSTRACT

With the aim of discovering potent and selective kinase inhibitors targeting ROS1 kinase, we designed, synthesized and screened a series of new pyrazol-4-ylpyrimidine derivatives based on our previously discovered lead compound KIST301072. Compounds 6a-e and 7a-e showed good to excellent activities against ROS1 kinase, and seven out of tested compounds were more potent than KIST301072. Compound 7c was the most potent with IC50 of 24 nM. Moreover, compound 7c showed ROS1 inhibitory selectivity of about 170-fold, relative to that of ALK sharing about 49% amino acid sequence homology with ROS1 kinase in the kinase domain. In silico modeling of 7c at ROS1 active site revealed some essential features for ROS1 inhibitory activity. Based on this study as well as the previous studies, we could build a hypothetical model predicting the required essential features for ROS1 inhibitory activity. The model validity has been tested through a second set of compounds.


Subject(s)
Protein Kinase Inhibitors/pharmacology , Pyrazoles/pharmacology , Pyrimidines/pharmacology , Receptor Protein-Tyrosine Kinases/antagonists & inhibitors , Dose-Response Relationship, Drug , Humans , Models, Molecular , Molecular Structure , Protein Kinase Inhibitors/chemical synthesis , Protein Kinase Inhibitors/chemistry , Pyrazoles/chemical synthesis , Pyrazoles/chemistry , Pyrimidines/chemical synthesis , Pyrimidines/chemistry , Receptor Protein-Tyrosine Kinases/metabolism , Structure-Activity Relationship
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