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Chemical Biology & Drug Design

Yuxia Wang, Jianying Zhang, Meng Li, Ming Li, Songqiang Xie, Chaojie Wang
With the aim of up-regulating antitumor efficacy and down-regulating adverse effects, the amino group in the 3-positon of amonafide aromatic ring was modified by coupling with different amine/polyamine motifs via two linkers. Two series of naphthalimide derivatives were designed and synthesized and evaluated for their antitumor properties in vitro and in vivo. The preliminary in vitro trials revealed that compounds with urea as the linker were not active, and the presence of aspirin elevated the potency of 6k against tumor cells, wound healing and the protein expression of Cyclic D1 and MMP9...
October 19, 2016: Chemical Biology & Drug Design
Feng Zhang, Bo Yang, Kailiang Zhang, Mei-Ling Hou, Xue-Chun Lu, Yu-Xin Li
Amifostine (AMF), 2-(3-Aminopropyl) aminoethyl phosphorothioate is a broad-spectrum cytoprotective agent used to treat nuclear radiation and chemical weapon injuries. Recently, amifostine has been shown to have a profound biological influence on tumor cells. In order to examine the effects and mechanisms underlying the effects of amifostine on human acute megakaryocytic leukemia, we evaluated the efficacy of amifostine against Dami cells and observed a cell cycle arrest in G2 /M phase. Amifostine treatment also induced cell apoptosis of Dami cells which corresponds to formal studies...
October 19, 2016: Chemical Biology & Drug Design
Dejan Agić, Hrvoje Brkić, Sanja Tomić, Zrinka Karačić, Marija Špoljarević, Miroslav Lisjak, Drago Bešlo, Marija Abramić
Fifteen flavonoids were studied for their inhibitory activity against human dipeptidyl peptidase III (hDPP III) combining an in vitro assay with an in silico molecular modeling study. All analyzed flavonoids showed inhibitory effects against hDPP III with the IC50 values ranging from 22.0 to 437.2 μM. Our 3D QSAR studies indicate that the presence of hydrophilic regions at a flavonoid molecule increases its inhibitory activity while the higher percentage of hydrophobic surfaces have negative impact on enzyme inhibition...
October 18, 2016: Chemical Biology & Drug Design
G Bharath Kumar, Syed Nasir Abbas Bukhari, Hua-Li Qin
A new series of arylisoxazole-oxindole derivatives (6a-r) was synthesized and evaluated for their antiproliferative activity against human cancer cell lines including non-small cell lung (A549), cervical (HeLa), breast (MCF-7) and prostate (DU-145) cancer cell lines. The synthesized compounds (6a-r) demonstrated excellent to moderate cytotoxicity with IC50 values ranging from 0.82-3.69 μM. Some new compounds (6m-r) exhibited profound cytotoxicity better or similar to positive control. More particularly, the compound 6q possess donating substituent like methoxy group presented at 5-position on D-ring exhibited remarkable antiproliferative activity against A-549 (lung cancer) with an IC50 value 0...
October 17, 2016: Chemical Biology & Drug Design
Denise Hübner, Milena R Kaluđerović, Santiago Gómez-Ruiz, Goran N Kaluđerović
Two ionic triphenyltin(IV) chloride carboxylato compounds of the formula [NHEt3 ][Ph3 SnCl(L)] (LH = N-phthaloylglycine (P-GlyH), 1; 1,2,4-benzenetricarboxylic 1,2-anhydride (BTCH), 2) were tested for the in vitro activity against 518A2 (melanoma), FaDu (head and neck carcinoma), HT-29 (colon cancer), MCF-7 (breast carcinoma) and SW1736 (thyroid cancer) cell lines. The ammonium salts of carboxylic acids are found to be not active, while anionic [Ph3 SnCl(L)](-) exhibited high cytotoxicity in nM range, higher both activity and selectivity than cisplatin...
October 17, 2016: Chemical Biology & Drug Design
Silvana Opp, Thomas Fricke, Caitlin Shepard, Dmytro Kovalskyy, Akash Bhattacharya, Frank Herkules, Dmitri N Ivanov, Kim Baek, Jose Valle-Casuso, Felipe Diaz-Griffero
The small molecule 6-(tert-butyl)-4-phenyl-4-(trifluoromethyl)-1H,3H-1,3,5-triazin-2-one (3G11) inhibits HIV-1 replication in the human T cell line MT-2. Here we showed that 3G11 specifically and potently blocks HIV-1 infection. By contrast, 3G11 did not block other retroviruses such as HIV-2, simian immunodeficiency virus (SIVmac ), bovine immunodeficiency virus (BIV), feline immunodeficiency virus (FIV), equine infectious anemia virus (EIAV), N-tropic murine leukemia virus (N-MLV), B-tropic murine leukemia virus (B-MLV) and Moloney murine leukemia virus (Mo-MLV)...
October 17, 2016: Chemical Biology & Drug Design
Akira Kawamura, Ilyas Washington, Doina M Mihai, Francesca Bartolini, Gregg G Gundersen, Milica Tesic Mark, Koji Nakanishi
Ginkgolides are terpene trilactones in Ginkgo biloba, a popular medicinal herb for memory disorders. Although ginkgolides are known for various neurobiological effects, their macromolecular target in brain is unknown. In this work, we employed benzophenone derivatives of ginkgolides to identify their binding-target in brain. Photolabeling of bovine hippocampus homogenates identified a series of α-tubulin isotypes. Selective photolabeling of α-tubulin over β-tubulin, which is equally abundant in brain, suggested that ginkgolides might modulate microtubule (MT) biology differently than typical MT-binding agents, such as taxol...
October 15, 2016: Chemical Biology & Drug Design
Anderson H Lima, Alberto M Dos Santos, Cláudio Nahum Alves, Jerônimo Lameira
UDP-N-acetylglucosamine enolpyruvyl transferase (MurA) is one of the key enzymes involved in peptidoglycan biosynthesis. The peptide HESFWYLPHQSY (called PEP 1354) is an inhibitor of MurA with an IC50 value of 200 μM. In this paper, we have used the FlexPepDock ab-initio protocol from the Rosetta program Homology Modeling and Molecular dynamics simulations to analyze, for the first time, the interaction of the PEP 1354 peptide with MurA enzyme from Pseudomonas aeruginosa (MurA-PA). Our modeling results suggest that the peptide binds to the same active site as the natural substrate UDP-N-acetylglucosamine (UNAG)...
October 13, 2016: Chemical Biology & Drug Design
Sen Ji, Shuang Ma, Wen-Jing Wang, Shen-Zhen Huan, Tian-Qi Wang, Rong Xiang, Yi-Guo Hu, Qiang Chen, Lin-Li Li, Sheng-Yong Yang
PRMT5 is an important protein arginine methyltransferase that catalyzes the symmetric dimethylation of arginine resides on histones or non-histone substrate proteins. It has been thought as a promising target for many diseases, particularly cancer. Despite the potential applications of PRMT5 inhibitors in cancer treatment, very few of PRMT5i have been publicly reported. In this investigation, virtual screening and structure-activity relationship (SAR) studies were carried out to discovery novel PRMT5i, which finally led to the identification of a number of new PRMT5i...
October 7, 2016: Chemical Biology & Drug Design
María Sánchez-Peris, Juan Murga, Eva Falomir, Miguel Carda, Alberto J Marco
A group of 36 biphenyl derivatives structurally related to honokiol were synthesised by means of Suzuki coupling reactions. Their cytotoxicities were evaluated and compared to that of honokiol. Some of the compounds were then evaluated for their ability to downregulate the secretion of the VEGF protein and the expression of the VEGF, hTERT and c-Myc genes, the two latter involved in the activation of telomerase in tumoral cells. Some of the synthetized derivatives showed promising pharmacological features as they exhibited IC50 values in low micromolar range, good therapeutic margins and a multiple mode of action on tumor cells based on the inhibition of VEGF and, at the same time, of the expression of genes related to the activation of telomerase...
October 7, 2016: Chemical Biology & Drug Design
Lamia W Mohamed, Azza T Taher, Ghada S Rady, Mamdouh M Ali, Abeer E Mahmoud
A new series of benzothiazole has been synthesized as cytotoxic agents. The new derivatives were tested for their cytotoxic activity towards the human breast cancer MCF-7 cell line against cisplatin as the reference drug. Many derivatives revealed good cytotoxic effect, whereas four of them 4, 5c, 5d, 6b were more potent than cisplatin, with IC50 values being 8.64, 7.39, 7.56, 5.15 μM compared to 13.33 μM of cisplatin. The four derivatives cytotoxic activity was accompanied by regulating free radicals production, by increasing the activity of superoxide dismutase and depletion of intracellular reduced glutathione, catalase and glutathione peroxidase activities, accordingly, the high production of hydrogen peroxide, nitric oxide and other free radicals causing tumor cell death as monitored by reduction in the synthesis of protein and nucleic acids...
October 4, 2016: Chemical Biology & Drug Design
Xiaowei Wu, Linyi You, Deliang Zhang, Mengna Gao, Zijing Li, Duo Xu, Pu Zhang, Lumei Huang, Rongqiang Zhuang, Hua Wu, Xianzhong Zhang
To develop a novel progesterone receptor (PR) targeting probe for positron emission tomography (PET) imaging, ethisterone derivative [(18) F]EAEF was designed and prepared in high decay-corrected radiochemical yield (30 ~ 35%) with good radiochemical purity (> 98%). [(18) F]EAEF is a lipophilic tracer (logP = 0.53 ± 0.06) with very good stability in saline and serum. In the biodistribution study, high radioactivity accumulation of [(18) F]EAEF were found in uterus (5.73 ± 1.83% ID/g) and ovary (4.05 ±0...
October 3, 2016: Chemical Biology & Drug Design
Krzysztof Siczek, Hubert Zatorski, Anna Chmielowiec-Korzeniowska, Jolanta Pulit-Prociak, Magdalena Śmiech, Radzisław Kordek, Leszek Tymczyna, Marcin Banach, Jakub Fichna
The aim of our study was to investigate the effect of newly developed silver nanoparticle aqueous suspensions NanoAg1 and NanoAg2 in the mouse models mimicking ulcerative colitis (UC) and Crohn's disease (CD). NanoAg1 and NanoAg2 were synthesized in aqueous medium with the involvement of tannic acid. To elucidate their anti-inflammatory activity, semi-chronic mouse models of inflammation induced by DSS addition to drinking water and intracolonic (i.c.) administration of TNBS were used. NanoAg1 and NanoAg2 (0...
October 3, 2016: Chemical Biology & Drug Design
Jianzhong Chen
Extracellular signal-regulated kinase 2 (ERK2) is a promising target for designs and development of anticancer drugs. Molecular dynamics (MD) simulations and molecular mechanics Poisson-Boltzmann method were applied to study binding difference of ADP and ATP to ERK2. The results prove that the binding ability of ATP to ERK2 is stronger than that of ADP. Principal component analysis performed by using MD trajectories suggest that bindings of ADP and ATP to ERK2 change motion directions of two helixes α1 and α2...
October 3, 2016: Chemical Biology & Drug Design
Cristina Trejo-Solis, Mayra A Alvarez-Lemus, Dolores Jiménez-Farfán, Isabel Anaya-Rubio, Rosendo López-González, Guadalupe Palencia, Dora M Frías-Márquez, Gerardo González-García, Carmen Rubio-Osornio, Minerva Calvillo-Velasco, Guadalupe Márquez-Chablé
Phenanthroline derivatives have been reported as potential bioactive compounds because of their ability to interact with DNA. In order to evaluate the antiproliferative effect of bis(acetylacetonate-k(2) O,O)(1,10-phenanthroline-k(2) N,N)Zn(II) or Zn(acac)2 (phen) complex, the compound was obtained in a simple manner and further characterized to determine crystal structure, thermal behavior, morphology and spectroscopic properties. The structure of the complex was confirmed by X-Ray single structure as well as by solution solid-state (13) C CP/MAS NMR...
October 2, 2016: Chemical Biology & Drug Design
Panhu Zhu, Wenfeng Ye, Jiaming Li, Yanchun Zhang, Weijun Huang, Mohan Cheng, Yujun Wang, Yang Zhang, Huicai Liu, Jian Zuo
A novel class of tetrahydroisoquinoline derivatives were designed and synthesized as antitumor agents and evaluated for their in vitro and in vivo biological activities. The antiproliferative activities of all the target compounds on HUVEC, MCF-7 and HT-29 were evaluated. Compared with Colchicine (1.04×10(-2) μM), 17d and 17e exhibited outstanding activity on MCF-7 with IC50 values 0.26×10(-2) μM and 0.89×10(-3) μΜ in cell cytotoxicity assay. The tubulin polymerization assay demonstrated that 17d and 17e exhibited better inhibition rate...
September 26, 2016: Chemical Biology & Drug Design
Jérémie A Doiron, Luc M Leblanc, Martin J G Hébert, Natalie A Levesque, Aurélie F Paré, Jacques Jean-François, Marc Cormier, Marc E Surette, Mohamed Touaibia
Leukotrienes (LTs) are a class of lipid mediators implicated in numerous inflammatory disorders. Caffeic acid phenethyl ester (CAPE) possesses potent anti-LTs activity through the inhibition of 5-lipoxygenase (5-LO), the key enzyme in the biosynthesis of LTs. In this study, we describe the design and synthesis of CAPE analogs as radical scavengers and 5-LO inhibitors. Caffeic esters bearing propargyl and allyl linkers between the caffeoyl and aryl moieties (4a-i and 5a-i, respectively) were synthesized by Sonogashira and Heck cross coupling reactions to probe the effects of flexibility and aryl substitution on 5-LO inhibition...
September 26, 2016: Chemical Biology & Drug Design
Wei Zhen Jia, Feng Cheng, Yin Jun Zhang, Jin Yan Ge, Shao Q Yao, Qing Zhu
A new library of flavone derivatives targeting two active sites of monoamine oxidases ("aromatic cage" and substrate cavity) were designed and synthesized using click chemistry (CuAAC reaction) between 6-N3 -2-phenyl chromones (Az1-Az2) and a series of alkynes (k1-k20). Their inhibitory activities against MAO isoforms (MAO-A and MAO-B) are evaluated. Compounds with fluorine, amide bonds, or amino bonds have shown better inhibition. The most potent flavone MAO inhibitor studied is Az2k19 (1.6 μm for MAO-A, 2...
September 26, 2016: Chemical Biology & Drug Design
Kunbin Ke, Hongjian Li, Hong Yao, Xi-Nan Shi, Chao Dong, Ying Zhu, Xu Liu, Ling Li, Kwong-Sak Leung, Man-Hon Wong, Xiao-Dong Liu, Hsiang-Fu Kung, Marie Chia-Mi Lin
Bladder carcinoma (BC) is the 9(th) most common cause of cancer worldwide. Surgical resection and conventional chemotherapy and radiotherapy will ultimately fail due to tumor recurrence and resistance. Thus, the development of novel treatment is urgently needed. Fibroblast growth factor receptor 3 (FGFR3) is an important and well-established target for BC treatment. In this study, we utilized the free and open-source protein-ligand docking software idock to prospectively identify potential inhibitors of FGFR3 from 3167 worldwide approved small-molecule drugs using a repositioning strategy...
September 24, 2016: Chemical Biology & Drug Design
Majid Piramoon, Seyed Jalal Hosseinimehr, Kobra Omidfar, Zohreh Noaparast, Seyed Mohammad Abedi
Nanobodies are important biomolecules for tumor targeting. In this study, we synthesized and labeled anti-epidermal growth factor receptor (EGFR) nanobody OA-cb6 with (99m) Tc(CO)3 (+) and evaluated its characteristics for targeting the EGFR in the A431 human epidermal carcinoma cell line. Nanobody radiolabeling was achieved with high yield and radiochemical purity, and the radioconjugate was stable. Biodistribution results in nude mice exhibited a favorable tumor-to-muscle ratio at 4 h post-injection, and tumor location was visualized at 4 h after injection of radiolabeled nanobody...
September 21, 2016: Chemical Biology & Drug Design
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