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European Journal of Medicinal Chemistry

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https://www.readbyqxmd.com/read/28923383/design-synthesis-and-structure-activity-relationship-studies-of-a-focused-library-of-pyrimidine-moiety-with-anti-proliferative-and-anti-metastasis-activities-in-triple-negative-breast-cancer
#1
Dahong Yao, Yuxin Zhou, Lingjuan Zhu, Liang Ouyang, Jin Zhang, Yingnan Jiang, Yuqian Zhao, Dejuan Sun, Shilin Yang, Yang Yu, Jinhui Wang
Triple-negative breast cancer (TNBC) is a clinical conundrum with distinct clinical and pathologic features, which is characterized by high aggression, poor prognosis, and lack of targeted therapies. In this study, based on the structural features of type II kinase inhibitors, we designed and synthesized a focused library of 41 pyrimidine derivatives possessing potent anti-proliferation activity, Y29 showed the most potent activity against MDA-MB-231 cells. Subsequently, we carried out target prediction, homology modeling, molecular docking, dynamics simulation and determination of enzymatic activity...
September 15, 2017: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28923381/synthesis-of-substituted-phenanthrene-9-benzimidazole-conjugates-cytotoxicity-evaluation-and-apoptosis-inducing-studies
#2
Niggula Praveen Kumar, Pankaj Sharma, S Sujana Kumari, Umarani Brahma, Shalini Nekkanti, Nagula Shankaraiah, Ahmed Kamal
A series of new phenanthrene-9-benzimidazole conjugates has been synthesized by condensing phenanthrene aldehydes with various substituted o-phenylenediamines. The title compounds were evaluated for their in vitro cytotoxic potential against various human cancer cell lines like breast (BT-549), prostate (PC-3 and DU145), triple negative breast cancer (MDA-MB-453), and human colon cancer (HCT-116 and HCT-15) cells. Among the tested compounds, 10o displayed significant in vitro cytotoxic activity against PC-3 prostate cancer cells with an IC50 value of 6...
September 8, 2017: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28923380/novel-deoxyvasicinone-derivatives-as-potent-multitarget-directed-ligands-for-the-treatment-of-alzheimer-s-disease-design-synthesis-and-biological-evaluation
#3
Fang Ma, Hongtao Du
A series of multitarget ligands was designed by introducing several structurally diverse aminoacetamide groups at position 6 of the deoxyvasicinone group, with the aim of obtaining novel multifunctional anti-Alzheimer's disease agents using deoxyvasicinone as the substrate. In vitro studies showed that almost all of the derivatives were potent inhibitors of human recombinant acetylcholinesterase (hAChE) and human serum butyrylcholinesterase (hBChE), with IC50 values in the low nanomolar range, and exhibited moderate to high inhibition of Aβ1-42 self-aggregation...
September 8, 2017: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28923382/synthesis-and-biological-evaluation-of-new-substituted-thioglycolurils-their-analogues-and-derivatives
#4
Galina A Gazieva, Lada V Anikina, Tatyana V Nechaeva, Sergey A Pukhov, Tatyana B Karpova, Sergey V Popkov, Yulia V Nelyubina, Natalya G Kolotyrkina, Angelina N Kravchenko
A novel series of substituted N-aminothioglycolurils was synthesized by tandem hydrazone formation - ring contraction reaction of 3-thioxoperhydroimidazo[4,5-e]-1,2,4-triazin-6-ones with (E)-3-phenyl(furan-2-yl)acrylaldehyde derivatives. S-Alkyl substituted N-aminothioglycolurils were prepared through alkylation of corresponding thioglycolurils with iodoalkane or 4-chlorobenzylchloride. Methylthio group in S-methyl derivatives can be substituted with hydroxyl group in acid medium to give N-aminoglycolurils...
September 7, 2017: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28923363/anti-inflammatory-effects-of-flavonoids-in-neurodegenerative-disorders
#5
Carmela Spagnuolo, Stefania Moccia, Gian Luigi Russo
Neuroinflammation is one of the main mechanisms involved in the progression of several neurodegenerative diseases, such as Parkinson, Alzheimer, multiple sclerosis, amyotrophic lateral sclerosis and others. The activation of microglia is the main feature of neuroinflammation, promoting the release of pro-inflammatory cytokines and resulting in the progressive neuronal cell death. Natural compounds, such as flavonoids, possess neuroprotective potential probably related to their ability to modulate the inflammatory responses involved in neurodegenerative diseases...
September 7, 2017: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28923389/1-4-naphthoquinones-as-inhibitors-of-itch-a-hect-domain-e3-ligase-and-tumor-growth-suppressors-in-multiple-myeloma
#6
Yi-Min Liu, Wei-Chun HuangFu, Han-Li Huang, Wei-Cheng Wu, Yi-Lin Chen, Yun Yen, Hsiang-Ling Huang, Chih-Ying Nien, Mei-Jung Lai, Shiow-Lin Pan, Jing-Ping Liou
A series of 1,4-naphthoquinones (10a-10q) were synthesized and evaluated for anticancer activity. Compound 10e was identified as an inhibitor of Itch, a HECT domain-E3 ligase. In an evaluation of in vivo efficacy, 10e exhibited remarkable anticancer activity with TGI values of 98.3% and 100% at 25 mg/kg and 50 mg/kg orally daily, respectively, against human RPMI-8226 multiple myeloma xenograft. Treatment with 10e also showed a decrease of Itch level in human RPMI-8226 multiple myeloma cells. Thus 10e is a lead compound for further development of inhibitors targeting E3 ligase for treatment of multiple myeloma...
September 6, 2017: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28923388/synthesis-of-cytotoxically-active-derivatives-based-on-alkylated-2-3-seco-triterpenoids
#7
Anastasia V Konysheva, Vladimir O Nebogatikov, Irina A Tolmacheva, Maxim V Dmitriev, Victoria V Grishko
Extremely low content of biologically active triterpenoids with the fragmented or contracted ring A extractable from plants is the main disadvantage of their use in drug discovery and practical pharmacology. Development of new methods for synthesis of these compounds and their structural analogs from bioavailable triterpene precursors gives an opportunity to obtain promising agents for pharmacology with excellent yields. A new approach to synthesis of alkylated A-seco-triterpenoids, including the Beckmann fragmentation of 3-methyl-substituted allobetulin or betulinic acid methyl ester with 2-hydroxyimino group in the ring A was proposed...
September 6, 2017: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28923387/characterization-and-structure-activity-relationship-study-of-iminodipyridinopyrimidines-as-novel-hepatitis-c-virus-inhibitor
#8
Dong-Sik Park, Eunji Jo, Jihyun Choi, MyungEun Lee, Soohyun Kim, Hee-Young Kim, Jiyon Nam, Sujin Ahn, Jong Yeon Hwang, Marc Peter Windisch
Upon high-throughput screening of synthetic small molecule libraries with the infectious hepatitis C virus (HCV) cell culture system, we identified an iminodipyridinopyrimidine (IDPP) scaffold. IDPP did not inhibit HCV replication, but exhibited very potent inhibitory activity on early and late steps of HCV life cycle. Applying an intensive structure-activity relationship (SAR) study, a promising IDPP Lead compound (12c) with excellent potency (EC50 = 10 nM), high safety margin (SI > 2000), and an acceptable stability in human and rat liver microsomes (t1/2 >60 min) was identified...
September 6, 2017: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28923386/structure-based-design-synthesis-and-biological-evaluation-of-withaferin-a-analogues-as-potent-apoptotic-inducers
#9
Gabriel G Llanos, Liliana M Araujo, Ignacio A Jiménez, Laila M Moujir, Jaime Rodríguez, Carlos Jiménez, Isabel L Bazzocchi
Apoptosis inducers represent an attractive approach for the discovery and development of anticancer agents. Herein, we report on the development by molecular fine tuning of a withaferin A-based library of 63 compounds (2-64), 53 of them reported for the first time. Their antiproliferative evaluation on HeLa, A-549 and MCF-7 human tumor cell lines identified fifteen analogues displaying higher activity (IC50 values ranging 0.3-4.8 μM) than the lead (IC50 values ranging 1.3-10.1 μM) either in lag or log growth phases...
September 6, 2017: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28923379/synthesis-characterization-cellular-uptake-and-apoptosis-inducing-properties-of-two-highly-cytotoxic-cyclometalated-ruthenium-ii-%C3%AE-carboline-complexes
#10
Jincan Chen, Fa Peng, Yao Zhang, Baojun Li, Ji She, Xinming Jie, Zhilin Zou, Man Chen, Lanmei Chen
Two new cyclometalated Ru(II) complexes of the general formula [Ru(N-N)2(1-Ph-βC)](PF6), where N-N = 4,4'-dimethyl-2,2'-bipyridine (dmb, Ru1), 2,2'-bipyridine (bpy, Ru2), and 1-Ph-βC (1-phenyl-9H-pyrido[3,4-b]indole) is a β-carboline alkaloids derivatives, have been synthesized and characterized. The in vitro cytotoxicities, cellular uptake and localization, cell cycle arrest and apoptosis-inducing mechanisms of these complexes have been extensively explored by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, inductively coupled plasma mass spectrometry (ICP-MS), flow cytometry, comet assay, inverted fluorescence microscope as well as western blotting experimental techniques...
September 6, 2017: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28926764/synthesis-antimicrobial-antiquorum-sensing-antitumor-and-cytotoxic-activities-of-new-series-of-cyclopenta-hepta-b-thiophene-and-fused-cyclohepta-b-thiophene-analogs
#11
Somaya A Abdel-Rahman, Nadia S El-Gohary, Eman R El-Bendary, Saadia M El-Ashry, Mona I Shaaban
New series of cyclopenta(hepta)[b]thiophene and fused cyclohepta[b]thiophene analogs were synthesized. The new analogs were assessed for antibacterial efficacy toward Escherichia coli ATCC 12435, Bacillus cereus UW 85 and Staphylococcus aureus. Compounds 5a, 6b and 12 showed eminent activity toward all selected bacterial strains compared to ampicillin. The antifungal efficacy of the same analogs was also examined toward Candida albicans and Aspergillus fumigatus 293, whereas 5a,b and 12 showed excellent efficacy toward both of the tested fungi...
September 4, 2017: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28926763/synthesis-and-2d-qsar-studies-of-neolignan-based-diaryl-tetrahydrofuran-and-furan-analogues-with-remarkable-activity-against-trypanosoma-cruzi-and-assessment-of-the-trypanothione-reductase-activity
#12
Ana Paula Hartmann, Marcelo Rodrigues de Carvalho, Lilian Sibelle Campos Bernardes, Milena Hoehr de Moraes, Eduardo Borges de Melo, Carla Duque Lopes, Mario Steindel, João Santana da Silva, Ivone Carvalho
Two series of diaryl-tetrahydrofuran and -furan were synthesised and screened for anti-trypanosomal activity against trypomastigote and amastigote forms of Trypanosoma cruzi, the causative agent of Chagas disease. Based on evidence that modification of a natural product may result in a more effective drug than the natural product itself, and using known neolignan inhibitors veraguensin 1 and grandisin 2 as templates to synthesise simpler analogues, remarkable anti-trypanosomal activity and selectivity were found for 3,5-dimethoxylated diaryl-furan 5c and 2,4-dimethoxylated diaryl-tetrahydrofuran 4e analogues with EC50 0...
September 4, 2017: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28923390/tnf-%C3%AE-and-il-6-inhibitors-conjugates-of-n-substituted-indole-and-aminophenylmorpholin-3-one-as-anti-inflammatory-agents
#13
Palwinder Singh, Sukhmeet Kaur, Anuradha Sharma, Gurcharan Kaur, Rajbir Bhatti
The conjugates obtained by the combination of indole and aminophenyl morpholinone were screened for TNF-α and IL-6 inhibition in microglial cells. Compound 4 was found to be the most potent anti-inflammatory agent as it reduced LPS induced level of inflammatory cytokines TNF-α and IL-6 by 71% and 53%, respectively. A significant decrease in NO and MMPs release from BV2 cells in culture pretreated with this compound as well as inhibition of nuclear translocation of NF-κB and AP-1 was observed. 75% inhibition of acetic acid induced algesia in swiss albino mice was noticed in the presence of compound 4...
September 4, 2017: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28923384/synthesis-and-structure-elucidation-of-novel-salophen-based-dioxo-uranium-vi-complexes-in-vitro-and-in-silico-studies-of-their-dna-bsa-binding-properties-and-anticancer-activity
#14
S Yousef Ebrahimipour, Maryam Mohamadi, Masoud Torkzadeh Mahani, Jim Simpson, Joel T Mague, Iran Sheikhshoaei
The synthesis and characterization of three dioxo U(VI) complexes, [UO2(L(1))(OH2)], [UO2(L(2))DMF], and [UO2(L(2))DMSO], [L(1)](2-) = 1,1'-(4-methyl-1,2-phenylenebis (nitrilomethylidyne))di-2-naphtholate: [L(2)](2-) = 1,1'-(o-phenylenebis (nitrilomethylidyne)) di-2-naphtholate, are reported. Elemental analysis, FT-IR, (1)HNMR, UV-Vis spectroscopy, molar conductivity and single crystal X-ray diffraction were used to characterize the complexes. It was found that the complexes adopt a distorted pentagonal bipyramidal coordination geometry...
September 4, 2017: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28911822/structural-insights-of-cyclin-dependent-kinases-implications-in-design-of-selective-inhibitors
#15
REVIEW
Sourav Kalra, Gaurav Joshi, Anjana Munshi, Raj Kumar
There are around 20 Cyclin-dependent kinases (CDKs) known till date, and various research groups have reported their role in different types of cancer. The X-ray structures of some CDKs especially CDK2 was exploited in the past few years, and several inhibitors have been found, e.g., flavopiridol, indirubicin, roscovitine, etc., but due to the specificity issues of these inhibitors (binding to all CDKs), these were called as pan inhibitors. The revolutionary outcome of palbociclib in 2015 as CDK4/6 inhibitor added a new charm to the specific inhibitor design for CDKs...
September 4, 2017: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28923385/targeting-breast-cancer-stem-cells-by-novel-hdac3-selective-inhibitors
#16
Hao-Yu Hsieh, Hsiao-Ching Chuang, Fang-Hsiu Shen, Kinjal Detroja, Ling-Wei Hsin, Ching-Shih Chen
Although histone deacetylase (HDAC) inhibitors have been known to suppress the cancer stem cell (CSC) population in multiple types of cancer cells, it remains unclear which HDAC isoforms and corresponding mechanisms contribute to this anti-CSC activity. Pursuant to our previous finding that HDAC8 regulates CSCs in triple-negative breast cancer (TNBC) cells by targeting Notch1 stability, we investigated related pathways and found HDAC3 to be mechanistically linked to CSC homeostasis by increasing β-catenin expression through the Akt/GSK3β pathway...
September 1, 2017: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28918098/identifying-novel-factor-xiia-inhibitors-with-pca-ga-svm-developed-vhts-models
#17
Jonathan Jun Feng Chen, Donald P Visco
There currently is renewed interest in blood clotting Factor XII as a potential target for thrombosis inhibition. Historically untargeted, there is little drug information with which to start drug candidate searches. Typical high-throughput screening can identify potential drug candidates, but is inefficient. Virtual high-throughput screening can be used to raise efficiency by focusing experimental efforts on compounds predicted to be active and is applied here to identify new Factor XIIa inhibitors. We combine principal component analysis, genetic algorithm and support vector machine to create the models used in the virtual high-throughput screening...
September 1, 2017: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28881289/efficacy-of-a-series-of-alpha-pyrone-derivatives-against-leishmania-l-infantum-and-trypanosoma-cruzi
#18
Andre Gustavo Tempone, Daiane Dias Ferreira, Marta Lopes Lima, Thais Alves Costa Silva, Samanta E T Borborema, Juliana Quero Reimão, Mariana K Galuppo, Juliana Mariotti Guerra, Angelie J Russell, Graham M Wynne, Roy Y L Lai, Melissa M Cadelis, Brent R Copp
The neglected tropical diseases Chagas disease and leishmaniasis affect together more than 20 million people living mainly in developing countries. The mainstay of treatment is chemotherapy, however the drugs of choice, which include benznidazole and miltefosine, are toxic and have numerous side effects. Safe and effective therapies are urgently needed. Marine alpha-pyrones have been previously identified as scaffolds with potential antiprotozoan activities. In this work, using a phenotypic screen, twenty-seven examples of 3-substituted 4-hydroxy-6-methyl alpha-pyrones were synthesized and their antiparasitic efficacy evaluated against Leishmania (L...
September 1, 2017: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28869891/synthesis-and-biological-effect-of-chrom-4-one-derivatives-as-functional-inhibitors-of-heat-shock-protein-27
#19
Soo-Yeon Hwang, Soo Yeon Kwak, Youngjoo Kwon, Yun-Sil Lee, Younghwa Na
Heat Shock Protein 27 (HSP27) is a member of small heat shock proteins with a highly-conserved α-crystalline domain. It inhibits aggregation of damaged proteins through a complex structural systems of phosphorylation-dependent oligomerization and self-assembly. It has been demonstrated that HSP27 is involved in a variety of pathophysiological pathways with negative or positive protective activities. In this study, we synthesized six chromone analogs possessing thiiran-2-ylmethoxy or oxyran-2-ylmethoxy substituents and evaluated their biological activities against HSP27 protein...
September 1, 2017: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28881285/structures-and-biochemical-evaluation-of-silver-i-5-5-diethylbarbiturate-complexes-with-bis-diphenylphosphino-alkanes-as-potential-antimicrobial-and-anticancer-agents
#20
Veysel T Yilmaz, Ceyda Icsel, Jenaidullah Batur, Seyma Aydinlik, Pinar Sahinturk, Muhittin Aygun
New silver(I) 5,5-diethylbarbiturate (barb) complexes with a series of bis(diphenylphosphino)alkanes such as 1,1-bis(diphenylphosphino)methane (dppm), 1,2-bis(diphenylphosphino)ethane (dppe), 1,3-bis(diphenylphosphino)propane (dppp) and 1,4-bis(diphenylphosphino)butane (dppb) were synthesized and characterized. [Ag2(barb)2(μ-dppm)2] (1), [Ag2(barb)2(μ-dppe)(DMSO)2] (2) and [Ag2(barb)2(μ-dppp)2] (3) were binuclear, while [Ag(barb)(μ-dppb)]n (4) was a coordination polymer. 1-4 effectively bind to the G/C rich region of the major groove of DNA and interact with BSA via hydrophobic interactions in accordance with molecular docking studies...
August 31, 2017: European Journal of Medicinal Chemistry
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