Synthesis of Tetrahydrobenzo[b]thiophene-3-carbohydrazide Derivatives as Potential Anti-cancer Agents and Pim-1 Kinase Inhibitors

2019 ◽  
Vol 19 (14) ◽  
pp. 1737-1753 ◽  
Author(s):  
Rafat M. Mohareb ◽  
Wagnat W. Wardakhan ◽  
Nermeen S. Abbas
Keyword(s):  
Kinase Inhibitors ◽  
Ethyl Cyanoacetate ◽  
Biologically Active ◽  
Thiazole Derivatives ◽  
Wide Range ◽  
Anti Cancer ◽  
Target Molecules ◽  
Thiophene Derivatives ◽  
Ht 29

Background: Tetrahydrobenzo[b]thiophene derivatives are well known to be biologically active compounds and many of them occupy a wide range of anticancer agent drugs. Objective: One of the main aim of this work was to synthesize target molecules not only possessing anti-tumor activities but also kinase inhibitors. To achieve this goal, our strategy was to synthesize a series of 4,5,6,7- tetrahydrobenzo[b]thiophene-3-carbohydrazide derivatives using cyclohexan-1,4-dione and cyanoacetylhydrazine to give the 2-amino-6-oxo-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carbohydrazide (3) as the key starting material for many heterocyclization reactions. Methods: Compound 3 was reacted with some aryldiazonium salts and the products were cyclised when reacted with either malononitrile or ethyl cyanoacetate. Thiazole derivatives were also obtained through the reaction of compound 3 with phenylisothiocyanate followed by heterocyclization with α-halocarbonyl derivatives. Pyrazole, triazole and pyran derivatives were also obtained. Results: The compounds obtained in this work were evaluated for their in-vitro cytotoxic activity against c-Met kinase, and the six typical cancer cell lines (A549, H460, HT-29, MKN-45, U87MG, and SMMC-7721). The results of anti-proliferative evaluations and c-Met kinase, Pim-1 kinse inhibitions revealed that some compounds showed high activities. Conclusion: The most promising compounds 5b, 5c, 7c, 7d, 11b, 14a, 16b, 18b, 19, 21a, 23c, 23d and 23i against c-Met kinase were further investigated against the five tyrosin kinases (c-Kit, Flt-3, VEGFR-2, EGFR, and PDGFR). Compounds 5b, 5c, 7d, 7e, 11b, 11c, 16c, 16d, 18c, 19, 23e, 23k and 23m were selected to examine their Pim-1 kinase inhibitions activity where compounds 7d, 7e, 11b, 11c, 16d, 18c and 23e showed high activities. All of the synthesized compounds have no impaired effect toward the VERO normal cell line.

Cyclin-dependent kinase inhibitors block erythrocyte invasion and intraerythrocytic development of Babesia bovis in vitro

Parasitology ◽  
2007 ◽  
Vol 134 (10) ◽  
pp. 1347-1353 ◽  
Author(s):  
K. NAKAMURA ◽  
N. YOKOYAMA ◽  
I. IGARASHI
Keyword(s):  
Kinase Inhibitors ◽  
Specific Inhibitor ◽  
Inhibitory Effect ◽  
Eukaryotic Cell ◽  
Babesia Bovis ◽  
Cdk Inhibitors ◽  
Erythrocyte Invasion ◽  
Anti Cancer ◽  
Target Molecules

SUMMARYCyclin-dependent kinases (CDKs) are essential for the regulation of the eukaryotic cell cycle. A number of chemicals, which selectively inhibit the CDK activities, have been synthesized for the development of anti-cancer drugs. This report describes the inhibitory effect of purine derivatives known to be CDK inhibitors on the asexual growth of Babesia bovis. The 4 compounds, roscovitine, purvalanol A, CGP74514A, and CDK2 Inhibitor II, showed significantly suppressive effects on the in vitro growth of B. bovis. Three (roscovitine, purvalanol A, and CDK2 Inhibitor II) showed an inhibitory effect on the early stages of intraerythrocytic development of B. bovis. CGP74514A (CDK1-specific inhibitor) blocked the erythrocyte invasion by merozoites. Our data suggest the chemotherapeutic potential of the CDK inhibitors for babesiosis, and the target molecules of the compounds would participate in the process of successful erythrocyte invasion or intraerythrocytic development of B. bovis.

Properties and Biotechnological Application of mutant Derivatives of Mini-intein PRP8 from Penicillium chrysogenum with Improved Control of C-terminal Processing

2019 ◽  
Vol 35 (6) ◽  
pp. 91-101
Author(s):  
F.A. Klebanov ◽  
S.E. Cheperegin ◽  
D.G. Kozlov
Keyword(s):  
Penicillium Chrysogenum ◽  
Protein Denaturation ◽  
Biologically Active ◽  
Cultivation Temperature ◽  
Target Proteins ◽  
E Coli ◽  
Complete Inactivation ◽  
Target Molecules ◽  
Proteins And Peptides

Mutant variants of mini-intein PRP8 from Penicillium chrysogenum (Int4b) with improved control of C-terminal processing were characterized. The presented variants can serve as a basis for self-removed polypeptide tags capable of carrying an affine label and allowing to optimize the process of obtaining target proteins and peptides in E. coli cells. They allow to synthesize target molecules in the composition of soluble and insoluble hybrid proteins (fusions), provide their afnne purification, autocatalytic processing and obtaining mature target products. The presented variants have a number of features in comparison with the known prototypes. In particular the mutant mini-intein Int4bPRO, containing the L93P mutation, has temperature-dependent properties. At cultivation temperature below 30 °C it allows the production of target molecules as part of soluble fusions, but after increasing of cultivation temperature to 37 °C it directs the most of synthesized fusions into insoluble intracellular aggregates. The transition of Int4bPRO into insoluble form is accompanied by complete inactivation of C-terminal processing. Further application of standard protein denaturation-renaturation procedures enable efficiently reactivate Int4bPRO and to carry out processing of its fusions in vitro. Two other variants, Int4b56 and Int4b36, containing a point mutation T62N or combination of mutations D144N and L146T respectively, have a reduced rate of C-terminal processing. Their use in E. coli cells allows to optimize the biosynthesis of biologically active target proteins and peptides in the composition of soluble fusions, suitable for afnne purification and subsequent intein-dependent processing without the use of protein denaturation-renaturation procedures. intein, fusion, processing, processing rate, gelonin The work was supported within the framework of the State Assignment no. 595-00003-19 PR.

Ethnomedicinal uses, Phytochemistry and Pharmacological Aspects of the Genus Berberis Linn: A Comprehensive Review

2020 ◽  
Vol 23 ◽  
Author(s):  
Roohi Mohi-ud-din ◽  
Reyaz Hassan Mir ◽  
Prince Ahad Mir ◽  
Saeema Farooq ◽  
Syed Naiem Raza ◽  
...  
Keyword(s):  
Chemical Constituents ◽  
Pharmacological Activities ◽  
Traditional Use ◽  
Comprehensive Review ◽  
Wide Range ◽  
Anti Cancer ◽  
Comprehensive Survey ◽  
Ethnomedicinal Uses

Background: Genus Berberis (family Berberidaceae), which contains about 650 species and 17 genera worldwide, has been used in folklore and various traditional medicine systems. Berberis Linn. is the most established group among genera with around 450-500 species across the world. This comprehensive review will not only help researchers for further evaluation but also provide substantial information for future exploitation of species to develop novel herbal formulations. Objective: The present review is focussed to summarize and collect the updated review of information of Genus Berberis species reported to date regarding their ethnomedicinal information, chemical constituents, traditional/folklore use, and reported pharmacological activities on more than 40 species of Berberis. Conclusion: A comprehensive survey of the literature reveals that various species of the genus possess various phytoconstituents mainly alkaloids, flavonoid based compounds isolated from different parts of a plant with a wide range of pharmacological activities. So far, many pharmacological activities like anti-cancer, anti-hyperlipidemic, hepatoprotective, immunomodulatory, anti-inflammatory both in vitro & in vivo and clinical study of different extracts/isolated compounds of different species of Berberis have been reported, proving their importance as a medicinal plant and claiming their traditional use.

Approach in improving potency and selectivity of kinase inhibitors: Allosteric kinase inhibitors

2020 ◽  
Vol 21 ◽  
Author(s):  
Shangfei Wei ◽  
Tianming Zhao ◽  
Jie Wang ◽  
Xin Zhai
Keyword(s):  
Protein Interactions ◽  
Kinase Inhibitors ◽  
Binding Modes ◽  
Allosteric Inhibitors ◽  
Wide Range ◽  
Allosteric Sites ◽  
Protein Functions ◽  
Regulate Protein

: Allostery is an efficient and particular regulatory mechanism to regulate protein functions. Different from conserved orthosteric sites, allosteric sites have distinctive functional mechanism to form the complex regulatory network. In drug discovery, kinase inhibitors targeting the allosteric pockets have received extensive attention for the advantages of high selectivity and low toxicity. The approval of trametinib as the first allosteric inhibitor validated that allosteric inhibitors could be used as effective therapeutic drugs for treatment of diseases. To date, a wide range of allosteric inhibitors have been identified. In this perspective, we outline different binding modes and potential advantages of allosteric inhibitors. In the meantime, the research processes of typical and novel allosteric inhibitors are described briefly in terms of structureactivity relationships, ligand-protein interactions and in vitro and in vivo activity. Additionally, challenges as well as opportunities are presented.

Heterocyclization of 2-(2-phenylhydrazono)cyclohexane-1,3-dione to Synthesis Thiophene, Pyrazole and 1,2,4-triazine Derivatives with Anti-Tumor and Tyrosine Kinase Inhibitions

2020 ◽  
Vol 20 (10) ◽  
pp. 1209-1220
Author(s):  
Rafat M. Mohareb ◽  
Ensaf S. Alwan
Keyword(s):  
Cell Lines ◽  
Cancer Cell ◽  
Tyrosine Kinases ◽  
Proliferative Activity ◽  
Cancer Cell Lines ◽  
Thiazole Derivatives ◽  
Wide Range ◽  
Cytotoxic Compounds ◽  
Triazine Derivatives ◽  
Target Molecules

Background: Recently tetrahydrobenzo[b]thiazole derivatives acquired a special attention due to their wide range of pharmacological activities especially the therapeutic activities. Through the market it was found that many pharmacological drugs containing the thiazole nucleus were known. Objective: This work aimed to synthesize target molecules not only possess anti-tumor activities but also kinase inhibitors. The target molecules were obtained starting from the arylhydrazonocyclohexan-1,3-dione followed by their heterocyclization reactions to produce anticancer target molecules. Methods: The arylhydrazone derivatives 3a-c underwent different heterocyclization reactions to produce thiophene, thiazole, pyrazole and 1,2,4-triazine derivatives. The anti-proliferative activity of twenty six compounds among the synthesized compounds toward the six cancer cell lines namely A549, H460, HT-29, MKN-45, U87MG, and SMMC-7721 was studied. Results: Anti-proliferative evaluations, tyrosine and Pim-1 kinase inhibitions were perform for most of the synthesized compounds where the varieties of substituent through the aryl ring and the thiophene moiety afforded compounds with high activities. Conclusion: The compounds with high anti-proliferative activity towards the cancer cell lines showed that compounds 3b, 3c, 5e, 5f, 8c, 9c, 11c, 12c, 14e, 14f and 16c were the most cytotoxic compounds. Further tests of the latter compounds toward the five tyrosine kinases c-Kit, Flt-3, VEGFR-2, EGFR, and PDGFR and Pim-1 kinase showed that compounds 3c, 5e, 5f, 8c, 9c, 12c, 14e, 14f and 16c were the most potent of the tested compounds toward the five tyrosine kinases and compounds 6d, 11a, 20b and 21e were of the highest inhibitions towards Pim-1 kinase. Pan Assay Interference Compounds (PAINS) for the most cytotoxic compounds showed zero PAINS alert and can be used as lead compounds.

Phytochemical, Analytical and Medicinal Studies of Holoptelea integrifolia Roxb. Planch - A Review

2019 ◽  
Vol 5 (4) ◽  
pp. 270-277 ◽  
Author(s):  
Vijay Kumar ◽  
Simranjeet Singh ◽  
Ragini Bhadouria ◽  
Ravindra Singh ◽  
Om Prakash
Keyword(s):  
Liquid Chromatography ◽  
Thin Layer ◽  
Thin Layer Chromatography ◽  
High Performance ◽  
Biologically Active ◽  
Toxicological Studies ◽  
Wide Range ◽  
Layer Chromatography

Holoptelea integrifolia Roxb. Planch (HI) has been used to treat various ailments including obesity, osteoarthritis, arthritis, inflammation, anemia, diabetes etc. To review the major phytochemicals and medicinal properties of HI, exhaustive bibliographic research was designed by means of various scientific search engines and databases. Only 12 phytochemicals have been reported including biologically active compounds like betulin, betulinic acid, epifriedlin, octacosanol, Friedlin, Holoptelin-A and Holoptelin-B. Analytical methods including the Thin Layer Chromatography (TLC), High-Performance Thin Layer Chromatography (HPTLC), High-Performance Liquid Chromatography (HPLC) and Liquid Chromatography With Mass Spectral (LC-MS) analysis have been used to analyze the HI. From medicinal potency point of view, these phytochemicals have a wide range of pharmacological activities such as antioxidant, antibacterial, anti-inflammatory, and anti-tumor. In the current review, it has been noticed that the mechanism of action of HI with biomolecules has not been fully explored. Pharmacology and toxicological studies are very few. This seems a huge literature gap to be fulfilled through the detailed in-vivo and in-vitro studies.

scholarly journals Isobornylchalcones as Scaffold for the Synthesis of Diarylpyrazolines with Antioxidant Activity

Molecules ◽  
2021 ◽  
Vol 26 (12) ◽  
pp. 3579
Author(s):  
Svetlana A. Popova ◽  
Evgenia V. Pavlova ◽  
Oksana G. Shevchenko ◽  
Irina Yu. Chukicheva ◽  
Aleksandr V. Kutchin
Keyword(s):  
Antioxidant Activity ◽  
Antioxidant Properties ◽  
Biological Properties ◽  
High Reactivity ◽  
Biologically Active ◽  
Brain Lipids ◽  
Wide Range ◽  
Privileged Structure ◽  
Vitro Model

The pyrazoline ring is defined as a “privileged structure” in medicinal chemistry. A variety of pharmacological properties of pyrazolines is associated with the nature and position of various substituents, which is especially evident in diarylpyrazolines. Compounds with a chalcone fragment show a wide range of biological properties as well as high reactivity which is primarily due to the presence of an α, β-unsaturated carbonyl system. At the same time, bicyclic monoterpenoids deserve special attention as a source of a key structural block or as one of the pharmacophore components of biologically active molecules. A series of new diarylpyrazoline derivatives based on isobornylchalcones with different substitutes (MeO, Hal, NO2, N(Me)2) was synthesized. Antioxidant properties of the obtained compounds were comparatively evaluated using in vitro model Fe2+/ascorbate-initiated lipid peroxidation in the substrate containing brain lipids of laboratory mice. It was demonstrated that the combination of the electron-donating group in the para-position of ring B and OH-group in the ring A in the structure of chalcone fragment provides significant antioxidant activity of synthesized diarylpyrazoline derivatives.

scholarly journals Production of biologically active human interleukin-10 by Bifidobacterium bifidum BGN4

2021 ◽  
Vol 20 (1) ◽  
Author(s):  
Nayoun Hong ◽  
Seockmo Ku ◽  
Kyungjin Yuk ◽  
Tony V. Johnston ◽  
Geun Eog Ji ◽  
...  
Keyword(s):  
Culture Supernatant ◽  
Shuttle Vector ◽  
Sodium Dodecyl ◽  
Interleukin 10 ◽  
Biologically Active ◽  
Enzyme Linked Immunosorbent Assay ◽  
Functional Evaluation ◽  
Ht 29 ◽  
Cell Free Culture Supernatant

Abstract Background Bifidobacterium spp. are representative probiotics that play an important role in the health of their hosts. Among various Bifidobacterium spp., B. bifidum BGN4 exhibits relatively high cell adhesion to colonic cells and has been reported to have various in vivo and in vitro bio functionalities (e.g., anti-allergic effect, anti-cancer effect, and modulatory effects on immune cells). Interleukin-10 (IL-10) has emerged as a major suppressor of immune response in macrophages and other antigen presenting cells and plays an essential role in the regulation and resolution of inflammation. In this study, recombinant B. bifidum BGN4 [pBESIL10] was developed to deliver human IL-10 effectively to the intestines. Results The vector pBESIL10 was constructed by cloning the human IL-10 gene under a gap promoter and signal peptide from Bifidobacterium spp. into the E. coli-Bifidobacterium shuttle vector pBES2. The secreted human IL-10 from B. bifidum BGN4 [pBESIL10] was analyzed by sodium dodecyl sulphate-polyacrylamide gel electrophoresis (SDS-PAGE), Western Blotting, and enzyme-linked immunosorbent assay (ELISA). More than 1,473 ± 300 ng/mL (n = 4) of human IL-10 was obtained in the cell free culture supernatant of B. bifidum BGN4 [pBESIL10]. This productivity is significantly higher than other previously reported human IL-10 level from food grade bacteria. In vitro functional evaluation of the cell free culture supernatant of B. bifidum BGN4 [pBESIL10] revealed significantly inhibited interleukin-6 (IL-6) production in lipopolysaccharide (LPS)-induced Raw 264.7 cells (n = 6, p < 0.0001) and interleukin-8 (IL-8) production in LPS-induced HT-29 cells (n = 6, p < 0.01) or TNFα-induced HT-29 cells (n = 6, p < 0.001). Conclusion B. bifidum BGN4 [pBESIL10] efficiently produces and secretes significant amounts of biologically active human IL-10. The human IL-10 production level in this study is the highest of all human IL-10 production reported to date. Further research should be pursued to evaluate B. bifidum BGN4 [pBESIL10] producing IL-10 as a treatment for various inflammation-related diseases, including inflammatory bowel disease, rheumatoid arthritis, allergic asthma, and cancer immunotherapy.

Novel Anti-Cancer, Anti-Bacterial Coatings for Biomaterial Applications: Selenium Nanoclusters

2009 ◽  
Vol 1209 ◽  
Author(s):  
Phong Anh Tran ◽  
Erik Taylor ◽  
Love Sarin ◽  
Robert H. Hurt ◽  
Thomas J Webster
Keyword(s):  
Bone Cells ◽  
Tumor Resection ◽  
Active Agent ◽  
In Vitro Study ◽  
Biologically Active ◽  
Elemental Selenium ◽  
Orthopedic Implant ◽  
Functional Coating ◽  
Anti Cancer

AbstractTwo common problems with implantation after cancerous tumor resection are cancer recurrence and bacteria infection at the implant site. Tumor resection surgery sometimes can not remove all the cancerous cells, thus, cancer can return after implantation. In addition, bacteria infection is one of the leading causes of implant failure. Therefore, it is desirable to have anti-cancer and anti-bacterial molecules which both rapidly (for anti-infection purposes) and continuously (for anti-cancer purposes) are available at the implant site following implantation. Therefore, the objective of the present in vitro study was to create a multi-functional coating for anti-cancer and anti-bacterial orthopedic implant applications. Elemental selenium was chosen as the biologically active agent in this effort because of its known chemopreventive and anti-bacterial properties. To achieve that objective, titanium (Ti), a conventional orthopedic implant material was coated with selenium (Se) nanoclusters. Different coating densities were achieved by varying Se concentration in the reaction mixture. Titanium substrates coated with Se nanoclusters were shown to enhance healthy osteoblast (bone-forming cell) and inhibit cancerous osteoblast proliferation in co-culture experiments. Functions of S. epidermidis (one of the leading bacteria that infect implants) were inhibited on Ti coated with Se-nanoclusters compared to uncoated materials. Thus, this study provided for the first time a coating material (selenium nanoclusters) to the biomaterials’ community to promote healthy bone cells’ functions, inhibit cancer growth and prevent bacteria infection.

Przeciwnowotworowe działanie składników propolisu. Cz. 1. Ester fenyloetylowy kwasu kawowego (CAPE)

2020 ◽  
Vol 21 (3) ◽  
Author(s):  
Bogdan Kędzia ◽  
Elżbieta Hołderna-Kędzia
Keyword(s):  
Human Colon ◽  
Caffeic Acid Phenethyl Ester ◽  
Biological Properties ◽  
Biologically Active ◽  
Significant Activity ◽  
Colon Adenoma ◽  
Cancer Cell Survival ◽  
Ht 29

The paper presents a review of the publications on the anticancerogenic activity of the biologically active component of propolis – caffeic acid phenethyl ester (CAPE). Literature data indicate numerous biological properties of CAPE, namely: antioxidant, anti-inflammatory, antiviral, immunostimulatory, anti-angiogenic and others. In numerous tests, both in vitro and in vivo, the significant activity of CAPE has been confirmed, including an action against HT-29 human colon adenoma cells, and five: human, murine and other tumor cell cultures. The authors also emphasize that CAPE supports the anticancerogenic effect of drugs, including doxorubicin and cisplatin, due to the reduction of cancer cell survival by 45% and 34%, respectively, compared to the above-mentioned drugs used alone. The conducted research indicates that the induction of apoptosis in cells, i.e. programmed cell death, can be mentioned among the main mechanisms of the anticancerogenic activity of CAPE.

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