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C L Charron, M S McFarland, S Dhanvantari, L G Luyt
The ghrelin receptor is a member of the growth hormone secretagogue receptor (GHS-R) family and is present at low concentrations in tissues such as the brain, kidney, cardiovascular system, and prostate. The ghrelin receptor plays an important role in cellular proliferation, apoptosis, invasion, and migration associated with the progression of many cancers, including prostate, breast, ovarian, testicular, and intestinal carcinomas. Ghrelin, the endogenous ligand, is a 28 amino acid peptide (IC50 = 3.1 nM) known to have poor in vivo stability...
October 1, 2018: MedChemComm
Zhen Yang, Syed Muhammad Usama, Feng Li, Kevin Burgess, Zheng Li
Much effort has been devoted to targeting agents for imaging and chemotherapy of tumors in cancer research, but there remain significant unmet needs in that area. We have reported a series of preclinical TrkC targeting agents for diagnoses and treatment of metastatic breast cancer; however, with respect to optical imaging, there are limitations to the agents already disclosed. In this work, a TrkC targeting fragment was equipped with a zwitterionic cyanine dye to give a near-infrared probe for in vivo imaging of metastatic breast tumors, with excitation and emission wavelengths of 760 and 780 nm, respectively, and facilitate the aqueous dissolution of the final design...
October 1, 2018: MedChemComm
Anastasiya S Sokolova, Olga I Yarovaya, Nikolay I Bormotov, Larisa N Shishkina, Nariman F Salakhutdinov
The Orthopoxvirus genus belongs to the Poxviridae family and includes variola virus (smallpox), cowpox virus, monkeypox virus and vaccinia virus (VV). Smallpox is considered one of the great epidemic disease scourges in human history. It has currently been eradicated; however, it remains a considerable threat as a biowarfare or bioterrorist weapon. The poxvirus, VV, serves as a model virus from which new antiviral therapies against Orthopoxviruses can be identified. Here, a series of nitrogen-sulphur containing heterocycles such as 1,3-thiazolidin-4-one and thiazoles containing a 1,7,7-trimethylbicyclo[2...
October 1, 2018: MedChemComm
Peter Mubanga Cheuka, Nina Lawrence, Dale Taylor, Sergio Wittlin, Kelly Chibale
3,6-Diarylated imidazopyridazines have recently been shown to possess good in vitro antiplasmodial and in vivo antimalarial activity. However, frontrunner compounds have been associated with poor solubility and a hERG (human ether-a-go-go -related gene) inhibition liability raising concerns for potential cardiotoxicity risks. Herein, we report the synthesis and structure-activity relationship studies of new imidazopyridazines aimed at improving aqueous solubility and countering hERG inhibition while maintaining antiplasmodial potency...
October 1, 2018: MedChemComm
Shan Lu, Obinna N Obianom, Yong Ai
Colorectal cancer (CRC) remains the fourth leading cause of cancer deaths around the world despite the availability of many approved small molecules for treatment. The issues lie in the potency, selectivity and targeting of these compounds. Therefore, new strategies and targets are needed to optimize and develop novel treatments for CRC. Here, a group of novel hybrids derived from aspirin and chalcones were designed and synthesized based on recent reports of their individual benefits to CRC targeting and selectivity...
October 1, 2018: MedChemComm
Xiaozheng Zhang, Jun Chen, Pan Xu, Xin Tian
The present study aimed to evaluate the protective effects of astragaloside IV (As-IV) against hypoxic pulmonary hypertension (HPH) and its mechanisms of action. Sprague-Dawley rats were used in a model of HPH induced by chronic hypoxia. After hypoxia, the mean pulmonary arterial pressure (mPAP), right ventricular pressure (RVP), and right ventricular hypertrophy index (RVHI) were monitored. Relaxation of the pulmonary artery in response to As-IV was measured. The levels of endothelin-1 (ET-1), angiotensin II (Ang II), tumor necrosis factor-α (TNF-α), and interleukin-6 (IL-6) in serum were assessed...
October 1, 2018: MedChemComm
Joanna Kurek, Patrycja Kwaśniewska-Sip, Krzysztof Myszkowski, Grzegorz Cofta, Marek Murias, Piotr Barczyński, Beata Jasiewicz, Rafał Kurczab
A series of new semi-synthetic 7-deacetyl-10-alkylthiocolchicne derivatives with ethyl, n -propyl, i-propyl and n -butyl substituents were synthesised and characterised by spectroscopic methods, elemental analysis, DFT calculations and molecular docking simulations. All the synthesized compounds have been tested for fungicidal and anticancer activities against SKOV-3, LoVo, MCF-7, MDA-MB-231 and the lung-derived fibroblast CCD39Lu. All the new colchicine derivatives exhibit significantly higher cytotoxicity towards the SKOV-3 tumour cell line than the natural product - colchicine...
October 1, 2018: MedChemComm
Liyun Zhao, Hongxin Liu, Luqiong Huo, Miaomiao Wang, Bao Yang, Weimin Zhang, Zhifang Xu, Haibo Tan, Sheng-Xiang Qiu
Methicillin-resistant Staphylococcus aureus (MRSA) infections are well-known as a significant global health challenge. In this study, twenty-two congeners of the natural antibiotic rhodomyrtosone B (RDSB) were synthesized with the aim of specifically enhancing the structural diversity through modifying the pendant acyl moiety. The structure-activity relationship study against various MRSA strains revealed that a suitable hydrophobic acyl tail in the phloroglucinol scaffold is a prerequisite for antibacterial activity...
October 1, 2018: MedChemComm
Katarina Jakovljević, Milan D Joksović, Ivana Z Matić, Nina Petrović, Tatjana Stanojković, Dušan Sladić, Miroslava Vujčić, Barbara Janović, Ljubinka Joksović, Snežana Trifunović, Violeta Marković
Hybrid compounds that combine the 1,3,4-thiadiazole-containing catechol moiety with a chalcone motif were synthesized and examined for their antioxidant activity, cytotoxicity, and DNA-binding activity. A series of thirteen compounds showed strong antioxidant and cytotoxic effects on human acute promyelocytic leukemia HL-60 cells. Several compounds exerted good cytotoxic activities on cervical adenocarcinoma HeLa cells. The treatment of HeLa cells with IC50 and double IC50 concentrations of the compounds 5a , 5c , 5f , and 5m induced a statistically significant increase in the percentage of cells within a subG1 cell cycle phase...
October 1, 2018: MedChemComm
Oliver John V Belleza, Jortan O Tun, Gisela P Concepcion, Aaron Joseph L Villaraza
Nobilamide B, a TRPV1 antagonist, and a series of Ala-substituted analogues were synthesized and their neuroactivity was assessed in a primary culture of dorsal root ganglion (DRG) neurons. Analogues 4 , 6 , and 7 showed comparable activity, affecting capsaicin response in neurons, in contrast to 2 , 3 , and 5 which showed minimal blocking. Compounds 2 , 3 , and 5 correspond to analogues in which d-Phe, d-Leu and d- allo -Thr have been substituted with Ala, respectively. The observed loss of bioactivity in these three analogues highlights the importance of d amino acids in the primary structure of nobilamide B...
October 1, 2018: MedChemComm
Kun Hu, Chensi Liu, Jingui Li, Fupei Liang
Three copper(ii) complexes, [Cu(L1)(NO3 )2 ] ( C1 ), [Cu(L2)Cl2 ] ( C2 ) and [Cu(L2)SO4 ]2 ·H2 O ( C3 ), were designed and synthesized by the reaction of Cu(NO3 )2 ·3H2 O, CuCl2 ·2H2 O and CuSO4 ·5H2 O with a quinoline-derived Schiff base ligand, L1 or L2, prepared by the condensation of quinoline-8-carbaldehyde with 4-aminobenzoic acid methyl ester or 4-aminobenzoic acid ethyl ester (benzocaine). The efficient bindings of the C1 - C3 complexes with human serum albumin (HSA) and calf thymus DNA (CT-DNA) were analyzed by spectroscopy and molecular docking...
October 1, 2018: MedChemComm
Casey J Maguire, Zhi Chen, Vani P Mocharla, Madhavi Sriram, Tracy E Strecker, Ernest Hamel, Heling Zhou, Ramona Lopez, Yifan Wang, Ralph P Mason, David J Chaplin, Mary Lynn Trawick, Kevin G Pinney
The natural products colchicine and combretastatin A-4 ( CA4 ) have provided inspiration for the discovery and development of a wide array of derivatives and analogues that inhibit tubulin polymerization through a binding interaction at the colchicine site on β-tubulin. A water-soluble phosphate prodrug salt of CA4 (referred to as CA4P ) has demonstrated the ability to selectively damage tumor-associated vasculature and ushered in a new class of developmental anticancer agents known as vascular disrupting agents (VDAs)...
October 1, 2018: MedChemComm
Qi-Pin Qin, Bi-Qun Zou, Fei-Long Hu, Guo-Bao Huang, Shu-Long Wang, Yun-Qiong Gu, Ming-Xiong Tan
Four new platinum(ii) complexes, [Pt(Rut)(DMSO)Cl2 ] ( Rut-Pt ), [Pt(Try)(DMSO)Cl2 ] ( Try-Pt ), [Pt(ITry)(DMSO)Cl2 ] ( ITry-Pt ) and [Pt(BrTry)(DMSO)Cl2 ] ( BrTry-Pt ), with rutaecarpine (Rut), tryptanthrin (Try), 8-iodine-tryptanthrin (ITry) and 8-bromo-tryptanthrin (BrTry) as ligands were synthesized and fully characterized. In these complexes, the platinum(ii) adopts a four-coordinated square planar geometry. The inhibitory activity evaluated by the MTT assay showed that BrTry-Pt (IC50 = of 0.21 ± 0.25 μM) could inhibit the growth of T-24 tumor cells (human bladder cancer cell line) more so than the other three complexes...
October 1, 2018: MedChemComm
Xiaojie Huang, Junsong Guo, Qi Liu, Qiong Gu, Jun Xu, Huihao Zhou
Discovery of new drug binding sites on well-established targets is of great interest as it facilitates the design of new mechanistic inhibitors to overcome the acquired drug resistance. Small chemical fragments can easily enter and bind to the cavities on the protein surface. Thus, they can be used to probe new druggable pockets in proteins. DNA gyrase plays indispensable roles in DNA replication, and both its GyrA and GyrB subunits are clinically validated antibacterial targets. New mechanistic GyrB inhibitors are urgently desired since the withdrawal of novobiocin from the market by the FDA due to its reduced efficiency and other reasons...
October 1, 2018: MedChemComm
Parteek Prasher, Mousmee Sharma
'Acridine' along with its functional analogue 'Acridone' is the most privileged pharmacophore in medicinal chemistry with diverse applications ranging from DNA intercalators, endonuclease mimics, ratiometric selective ion sensors, and P-glycoprotein inhibitors in countering the multi-drug resistance, enzyme inhibitors, and reversals of neurodegenerative disorders. Their interaction with DNA and ability of selectively identifying numerous biologically useful ions has cemented exploitability of the acridone nucleus in modern day therapeutics...
October 1, 2018: MedChemComm
Edgar Aguilar-Ortíz, Amir R Jalilian, Miguel A Ávila-Rodríguez
Porphyrins and 64 Cu have emerged as a novel synergic option for applications in PET molecular imaging. Both the characteristics and photophysical properties of macrocyclic porphyrins and the relatively long half-life of the copper isotope, in addition to the increased tumor-specific uptake of porphyrins compared to normal cells, make this complex an attractive option not only for diagnosis but also for therapeutic applications. Herein, we present an overview of the latest results on the development of PET agents based on porphyrins and 64 Cu, including methods used to improve the selectivity of these macrocycles when conjugated with biological units such as monoclonal antibodies, peptides or proteins...
October 1, 2018: MedChemComm
Antonella Giancristofaro, Arménio J M Barbosa, Alessandra Ammazzalorso, Pasquale Amoia, Barbara De Filippis, Marialuigia Fantacuzzi, Letizia Giampietro, Cristina Maccallini, Rosa Amoroso
FXR is a member of the nuclear receptor superfamily, which regulates the expression of various genes involved in bile acid, lipid and glucose metabolism. Targeting FXR with small molecules has been exploited to treat lipid-related disorders and diseases such as cholestasis, gallstones and hepatic disorders. In this work, we expand the existing pool of known FXR agonists using a fast hit-to-lead structure-based pharmacophore and docking screening protocol. A set of 25 molecules was selected after screening a large database of commercial chemicals, and experimental tests were carried out to demonstrate their ability to activate FXR...
October 1, 2018: MedChemComm
Yongkai Cao, Ningning Sun, Jiumei Zhang, Zhiguo Liu, Yi-Zhe Tang, Zhengzhi Wu, Kyeong-Man Kim, Seung Hoon Cheon
[This corrects the article DOI: 10.1039/C8MD00237A.].
September 1, 2018: MedChemComm
Vinicius Vendrusculo, Vanessa P de Souza, Luiz Antônio M Fontoura, Marcelo G M D'Oca, Thais P Banzato, Paula A Monteiro, Ronaldo A Pilli, João Ernesto de Carvalho, Dennis Russowsky
A series of fifteen novel dihydropyrimidinone hybrid compounds were synthesized in good yields via a multicomponent reaction combined with the Huisgen reaction. The antiproliferative activity was investigated against nine tumor cell lines, and four hybrid compounds (TGI < 10 μM) showed promising antiproliferative activity against the tumor cell lines OVCAR-3 (ovarian), UACC-62 (melanoma) and U251 (glioma). Several hybrid compounds assayed have high TGI values (TGI 147.92-507.82) for the human keratinocyte cell line (HaCat), which reveals selectivity to cancer cells...
September 1, 2018: MedChemComm
William M Huggins, T Vu Nguyen, Nicholas A Hahn, James T Baker, Laura G Kuo, Darpan Kaur, Roberta J Melander, John S Gunn, Christian Melander
Serovars within the species Salmonella enterica are some of the most common food and water-borne pathogens worldwide. Some S. enterica serovars have shown a remarkable ability to persist both inside and outside the human body. Salmonella enterica serovar Typhi can cause chronic, asymptomatic infection of the human gallbladder. This organism's ability to survive inside the gallbladder centers around its ability to form biofilms on gallstone surfaces. Currently, chronic carriage of S. Typhi is treated by invasive methods, which are not well suited to areas where Salmonella carriage is prevalent...
September 1, 2018: MedChemComm
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