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Bioorganic & Medicinal Chemistry

Ehsan Ullah Mughal, Amina Sadiq, Shahzad Murtaza, Hummera Rafique, Muhammad Naveed Zafar, Tauqeer Riaz, Bilal Ahmad Khan, Abdul Hameed, Khalid Mohammed Khan
The present study describes efficient and facile syntheses of varyingly substituted 3-thioaurones from the corresponding 3-oxoaurones using Lawesson's reagent and phosphorous pentasulfide. In comparison, the latter methodology was proved more convenient, giving higher yields and required short and simple methodology. The structures of synthetic compounds were unambiguously elucidated by IR, MS and NMR spectroscopy. All synthetic compounds were screened for their inhibitory potential against in vitro acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) enzymes...
October 14, 2016: Bioorganic & Medicinal Chemistry
Russell Dahl
Endoplasmic reticulum (ER) stress is intimately linked to Parkinson's disease (PD) pathophysiology. Disrupted intracellular calcium homeostasis is a major cause of the ER stress seen in dopaminergic neurons, leading to the cell death and subsequent loss of movement and coordination in patients. Dysfunctional calcium handling proteins play a major role in the promulgation of ER stress in PD. Specifically, compromised sarco/endoplasmic reticulum Ca(2+)-ATPase (SERCA) has been identified as a major cause of ER stress and neuron loss in PD...
October 12, 2016: Bioorganic & Medicinal Chemistry
E V Shchegol'kov, I V Shchur, Ya V Burgart, V I Saloutin, A N Trefilova, G A Ljushina, S Yu Solodnikov, L N Markova, V V Maslova, O P Krasnykh, S S Borisevich, S L Khursan
We have developed the convenient methods for synthesis of polyfluorosalicylic acids and their derivatives. For the first time the biological properties of polyfluorosalicylates were investigated in vitro (permeability through the biological membranes, COX-1 inhibitory action) and in vivo (anti-inflammatory, analgesic activities, acute toxicity). Molecular docking of polyfluorinated salicylates confirmed in vitro and in vivo experiments.
October 12, 2016: Bioorganic & Medicinal Chemistry
Yazhou Wang, Wei Huang, Minhang Xin, Pan Chen, Li Gui, Xinge Zhao, Feng Tang, Jia Wang, Fei Liu
Janus kinases inhibitor is considered to have therapeutic potential for the treatment of oncology and immune-inflammatory diseases. Two series of 4-(2-benzofuranyl)pyrimidin-2-amine and 4-(4,5,6,7-tetrahydrofuro[3,2-c]pyridin-2-yl)pyrimidin-2-amine derivatives have been designed and synthesized. Primary SAR studies resulted in the discovery of a novel class of 4,5,6,7-tetrahydrofuro[3,2-c]pyridine based JAK2 inhibitors with higher potency (IC50 of 0.7nM) and selectivity (>30 fold) to JAK3 kinase than tofacitinib...
October 11, 2016: Bioorganic & Medicinal Chemistry
J Phillip Turner, Shelby E Chastain, Dongwon Park, Melissa A Moss, Shannon L Servoss
Alzheimer's disease (AD) is characterized by the buildup of insoluble aggregated amyloid-β protein (Aβ) into plaques that accumulate between the neural cells in the brain. AD is the sixth leading cause of death in the United States and is the only cause of death among the top ten that cannot currently be treated or cured (Alzheimer's Association, 2011; Selkoe, 1996). Researchers have focused on developing small molecules and peptides to prevent Aβ aggregation; however, while some compounds appear promising in vitro, the research has not resulted in a viable therapeutic treatment...
October 10, 2016: Bioorganic & Medicinal Chemistry
Chao Ding, Shaopeng Chen, Cunlong Zhang, Guangnan Hu, Wei Zhang, Lulu Li, Yu Zong Chen, Chunyan Tan, Yuyang Jiang
By merging the critical pharmacophore of EGFR/HER2 and HDAC inhibitors into one compound, a novel series of EGFR, HER-2, and HDAC multitarget inhibitors were synthesized. Compounds 9a-l contained 4-anilinoquinazolines with C-6 triazole-linked long alkyl chains of hydroxamic acid and displayed excellent inhibition against these enzymes (compound 9d exhibited the best inhibitory potency on wild-type EGFR, HDAC1, and HDAC6 with IC50 values 0.12nM, 0.72nM and 3.2nM individually). Furthermore, compounds 9b and 9d potently inhibited proliferation of five human cancer cell lines (with IC50 values between 0...
October 10, 2016: Bioorganic & Medicinal Chemistry
Sanjib K Shrestha, Liliia M Kril, Keith D Green, Stefan Kwiatkowski, Vitaliy M Sviripa, Justin R Nickell, Linda P Dwoskin, David S Watt, Sylvie Garneau-Tsodikova
The emergence of multidrug-resistant bacterial and fungal strains poses a threat to human health that requires the design and synthesis of new classes of antimicrobial agents. We evaluated bis(N-amidinohydrazones) and N-(amidino)-N'-aryl-bishydrazones for their antibacterial and antifungal activities against panels of Gram-positive/Gram-negative bacteria as well as fungi. We investigated their potential to develop resistance against both bacteria and fungi by a multi-step resistance-selection method, explored their potential to induce the production of reactive oxygen species, and assessed their toxicity...
October 10, 2016: Bioorganic & Medicinal Chemistry
Aurélie Stallivieri, Ludovic Colombeau, Gulim Jetpisbayeva, Albert Moussaron, Bauyrzhan Myrzakhmetov, Philippe Arnoux, Samir Acherar, Régis Vanderesse, Céline Frochot
Recent researches in photodynamic therapy have focused on novel techniques to enhance tumour targeting of anticancer drugs and photosensitizers. Coupling a photosensitizer with folic acid could allow more effective targeting of folate receptors which are over-expressed on the surface of many tumour cells. In this study, different folic acid-OEG-conjugated photosensitizers were synthesized, characterized and their photophysical properties were evaluated. The introduction of an OEG does not significantly improve the hydrophilicity of the FA-porphyrin...
October 10, 2016: Bioorganic & Medicinal Chemistry
Shan Qian, Tao He, Wei Wang, Yanying He, Man Zhang, Lingling Yang, Guobo Li, Zhouyu Wang
Indoleamine 2,3-dioxygenase 1 (IDO1)-mediated kynurenine pathway of tryptophan degradation is identified as an important immune effector pathway in the tumor cells to escape a potentially effective immune response. IDO1 is an attractive target for anticancer therapy and the discovery of IDO1 inhibitors has been intensely ongoing in both academic research laboratories and pharmaceutical organizations. Our study discovered that 1H-indazole was a novel key pharmacophore with potent IDO1 inhibitory activity. A series of new 1H-indazole derivatives were synthesized and determined the enzyme inhibitory activities, and the compound 2g exhibited the highest activity with an IC50 value of 5...
October 6, 2016: Bioorganic & Medicinal Chemistry
Jiankang Zhang, Lixin Gao, Jianjun Xi, Li Sheng, Yanmei Zhao, Lei Xu, Yidan Shao, Shourong Liu, Rangxiao Zhuang, Yubo Zhou, Jia Li
A series of novel non-covalent piperidine-containing dipeptidyl derivatives were designed, synthesized and evaluated as proteasome inhibitors. All target compounds were tested for their proteasome chymotrypsin-like inhibitory activities, and selected derivatives were evaluated for the anti-proliferation activities against two multiple myeloma (MM) cell lines RPMI 8226 and MM-1S. Among all of these compounds, eight exhibited significant proteasome inhibitory activities with IC50 less than 20nM, and four are more potent than the positive control Carfilzomib...
October 6, 2016: Bioorganic & Medicinal Chemistry
Yoshiaki Manse, Kiyofumi Ninomiya, Ryosuke Nishi, Iyori Kamei, Yushi Katsuyama, Takahito Imagawa, Saowanee Chaipech, Osamu Muraoka, Toshio Morikawa
An aqueous acetone extract from the fruit of Alpinia galanga (Zingiberaceae) demonstrated inhibitory effects on melanogenesis in theophylline-stimulated murine B16 melanoma 4A5 cells (IC50=7.3μg/mL). Through bioassay-guided separation of the extract, a new 7-O-9'-linked neolignan, named galanganol D diacetate (1), was isolated along with 16 known compounds including 14 phenylpropanoids (2-15). The structure of 1, including its absolute stereochemistry in the C-7 position, was elucidated by means of extensive NMR analysis and total synthesis...
October 6, 2016: Bioorganic & Medicinal Chemistry
Rebecca J Hron, Branko S Jursic, Donna M Neumann
Six structural motifs based on the initial (lead) structure of merbarone were designed, prepared, and tested against the glioblastoma LN-229 cell line. Three different structural moieties were modified in the search for optimal glioblastoma activity: the 1,3-diazinane moiety, the aryl moiety, and the heteroatom linker. Calculated molecular descriptors such as lipophilicity (ClogP), acidic strength (calculated pKa), and polar surface area (PSA) were used to design a diverse structural library of these compounds...
October 4, 2016: Bioorganic & Medicinal Chemistry
Haroon Ur Rashid, Marco Antonio Utrera Martines, Juliana Jorge, Paula Martin de Moraes, Muhammad Naveed Umar, Kamin Khan, Hanif Ur Rehman
Magnetic Resonance Imaging (MRI) is a noninvasive radiology technique used to examine the internal organs of human body. It is useful for the diagnosis of structural abnormalities in the body. Contrast agents are used to increase the sensitivity of this technique. 1,4,7,10-Tetraazacyclododecane (cyclen) is a macrocyclic tetraamine. Its derivatives act as useful ligands to produce stable complexes with Gd(3+) ion. Such chelates are investigated as MRI contrast agents. Free Gd(3+) ion is extremely toxic for in vivo use...
October 1, 2016: Bioorganic & Medicinal Chemistry
Dong-Dong Li, Zhi-Hui Wang, Wei-Lin Chen, Yi-Yue Xie, Qi-Dong You, Xiao-Ke Guo
WDR5 is an essential protein for enzymatic activity of MLL1. Targeting the protein-protein interaction (PPI) between MLL1 and WDR5 represents a new potential therapeutic strategy for MLL leukemia. Based on the structure of reported inhibitor WDR5-0103, a class of ester compounds were designed and synthetized to disturb MLL1-WDR5 PPI. These inhibitors efficiently inhibited the histone methyltransferase activity in vitro. Especially, WL-15 was one of the most potent inhibitors, blocking the interaction of MLL1-WDR5 with IC50 value of 26...
October 1, 2016: Bioorganic & Medicinal Chemistry
Ho Shin Kim, Mannkyu Hong, Jihyae Ann, Suyoung Yoon, Cong-Truong Nguyen, Su-Chan Lee, Ho-Young Lee, Young-Ger Suh, Ji Hae Seo, Hoon Choi, Jun Yong Kim, Kyu-Won Kim, Joohwan Kim, Young-Myeong Kim, So-Jung Park, Hyun-Ju Park, Jeewoo Lee
Based on the lead compound L-80 (compound 2), a potent heat shock protein 90 (HSP90) inhibitor, a series of C-ring truncated deguelin analogs were designed, synthesized and evaluated for Hypoxia Inducible Factor-1α (HIF-1α) inhibition as a primary screening method. Their structure-activity relationship was investigated in a systematic manner by varying the A/B ring, linker and D/E ring, respectively. Among the synthesized inhibitors, compound 5 exhibited potent HIF-1α inhibition in a dose-dependent manner and significant antitumor activity in human non-small cell lung carcinoma (H1299), with better activities than L-80...
September 30, 2016: Bioorganic & Medicinal Chemistry
Jon K Chen, Dong Yang, Ben Shen, Brett A Neilan, Vincent Murray
Bleomycin (BLM) is used clinically in combination with a number of other agents for the treatment of several types of tumours. Members of the BLM family of drugs include zorbamycin (ZBM), phleomycin D1, BLM A2 and BLM B2. By manipulating the BLM biosynthetic machinery, we have produced two new BLM analogues, BLM Z and 6'-deoxy-BLM Z, with the latter exhibiting significantly improved DNA cleavage activity. Here we determined the DNA sequence specificity of BLM Z, 6'-deoxy-BLM Z and ZBM, in comparison with BLM, with high precision using purified plasmid DNA and our recently developed technique...
September 30, 2016: Bioorganic & Medicinal Chemistry
Anna C Giddens, Ho H Lee, Guo-Liang Lu, Christian K Miller, Jun Guo, Gail D Lewis Phillips, Thomas H Pillow, Moana Tercel
A Pd-catalysed amination method is used to convert seco-CBI, a synthetic analogue of the alkylating subunit of the duocarmycin natural products, from the phenol to amino form. This allows efficient enantioselective access to the more potent S enantiomer of aminoCBI and its incorporation into analogues of DNA minor groove cross-linking agents. Evaluation in a panel of nine human tumour cell lines shows that the bifunctional agents containing aminoCBI are generally less cytotoxic than their phenolCBI analogues and more susceptible to P-glycoprotein-mediated resistance...
September 30, 2016: Bioorganic & Medicinal Chemistry
Wei-Lin Chen, Zhi-Hui Wang, Tao-Tao Feng, Dong-Dong Li, Chu-Hui Wang, Xiao-Li Xu, Xiao-Jin Zhang, Qi-Dong You, Xiao-Ke Guo
Protein lysine methyltransferase G9a is widely considered as an appealing antineoplastic target. Herein we present an integrated workflow combining shape-based virtual screening and structure-based molecular modification for the identification of novel G9a inhibitors. The shape-based similarity screening through ROCS overlay on the basis of the structure of UNC0638 was performed to identify CPUY074001 contained a 6H-anthra[1,9-cd]isoxazol-6-one scaffold as a hit. Analysis of the binding mode of CPUY074001 with G9a and 3D-QSAR results, two series compounds were designed and synthesized...
September 30, 2016: Bioorganic & Medicinal Chemistry
Edyta Łukowska-Chojnacka, Jolanta Mierzejewska, Małgorzata Milner-Krawczyk, Małgorzata Bondaryk, Monika Staniszewska
With the appearance of the antifungal resistance, novel antifungal agents need to be identified. In this context new 2,5-disubstituted tetrazole derivatives containing benzothiazole, benzoxazole or phenylsulfonyl moiety were synthesized by N-alkylation of aryltetrazole with 2-[(3-chloropropyl)sulfanyl]-1,3-benzothiazole or 2-[(3-chloropropyl)sulfanyl]-1,3-benzoxazole and Michael-type addition of aryltetrazole to phenyl vinyl sulfone. The chemical structures of the synthesized compounds were confirmed by means of (1)H NMR, (13)C NMR, IR and HRMS spectral data...
September 28, 2016: Bioorganic & Medicinal Chemistry
Shenqi Wei, Wei Chen, Jingfang Qin, Yingzi Huangli, Li Wang, Yue Shen, Huang Tang
A series of 8- and 11-substituted oxoisoaporphine derivatives have been designed, synthesized, and tested for their ability to inhibit cholinesterase (ChE) in vitro and in vivo, and self-induced β-amyloid (Aβ) aggregation. Their autophagy activity and blood-brain barrier (BBB) permeability were also assessed. The new derivatives exhibited high AChE inhibitory activity in vivo and in intro. Over half the derivatives exhibited a significant in vitro inhibitory activity toward the self-induced Aβ aggregation...
September 28, 2016: Bioorganic & Medicinal Chemistry
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