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Cheong A Choi, Jung Eun Lee, Zihnil Adha Islamy Mazrad, Young Kwang Kim, Insik In, Ji Hoon Jeong, Sung Young Park
We described fluorescence resonance energy transfer for pH/redox-activatable fluorescent carbon dot (FNP) to realize "off-on" switched imaging-guided controllable photothermal therapy (PTT). The FNP is a carbonized self-crosslinked polymer that allows IR825 loading (FNP[IR825]) via hydrophobic interactions in cancer therapy. The capability for fluorescence bioimaging was achieved via the internalization of FNP(IR825) into tumor cells, wherein glutathione (GSH) disulfide bonds were reduced and benzoic imine were cleaved under acidic conditions...
May 18, 2018: ChemMedChem
Jennifer R Baker, Jayne Gilbert, Stefan Paula, Xiao Zhu, Jennette A Sakoff, Adam McCluskey
Knoevenagel condensation of 3,4-dichloro- and 2,6-dichloro- phenylacetonitriles gave a library of dichlorophenylacrylonitriles. Our leads 5 and 6 displayed 0.56±0.03 and 0.127±0.04 μM growth inhibition (GI₅₀) and 260-fold selectivity for the MCF-7 breast cancer cell line. A 2,6-dichlorophenyl moiety saw a 10-fold potency loss; additional nitrogen moieties (-NO₂) enhanced activity (26 and 27), with the corresponding -NH₂ analogues (29 and 30) more potent. Despite this, both 29 (2.8±0.03 μM) and 30 (2...
May 17, 2018: ChemMedChem
Eduardo Hernández-Vázquez, Alejandra Chávez-Riveros, Adriana Romo-Pérez, María Teresa Ramírez-Apán, Alma D Chávez-Blanco, Rocío Morales-Bárcenas, Alfonso Dueñas-González, Luis D Miranda
Cancer continues to be a worldwide health problem. Certain macrocyclic molecules have become attractive therapeutic alternatives for this disease because of their efficacy and, frequently, their novel mechanisms of action. Herein, we report the synthesis of a series of 20-, 21-, and 22-membered macrocycles containing triazole and bis(aryl ether) moieties. The compounds were prepared by a multicomponent approach from readily available commercial substrates. Notably, some of the compounds displayed interesting cytotoxicity against cancer (PC-3) and breast (MCF-7) cell lines, especially those bearing an aliphatic or a trifluoromethyl substituent on the N-phenyl moiety (IC50 <13 μm)...
May 17, 2018: ChemMedChem
Andrea Dalle Vedove, Dimitrios Spiliotopoulos, Vito Giuseppe D'Agostino, Jean-Rémy Marchand, Andrea Unzue, Cristina Nevado, Graziano Lolli, Amedeo Caflisch
The bromodomain-containing protein BAZ2A is a validated target in prostate cancer, while the function of its paralog BAZ2B is still undefined. The bromodomains of BAZ2A and BAZ2B have a very similar binding site for their natural ligand, the acetylated lysine side chain. Here, we present an analysis of the binding modes of eight compounds belonging to three distinct chemical classes. For all compounds, the moiety mimicking the natural ligand makes essentially identical interactions in the BAZ2A and BAZ2B bromodomains...
May 17, 2018: ChemMedChem
Chunhui Li, Peng Teng, Zhong Peng, Peng Sang, Xingmin Sun, Jianfeng Cai
Clostridium difficile infection (CDI) symptoms range from diarrhea to severe toxic megacolon and even death. Due to its rapid acquisition of resistance, C. difficile is listed as an urgent antibiotic-resistant threat, and has surpassed methicillin-resistant Staphylococcus aureus (MRSA) as the most common hospital-acquired infections in the USA. To combat the pathogen, the new structural class of pseudo peptides that exhibit antimicrobial activities could play an important role. Herein, we report that bis-cyclic guanidine compounds that exhibit potent antibacterial activity against C...
May 16, 2018: ChemMedChem
Hiroki Kanazawa, Oscar M Saavedra, Juan Pablo Maianti, Simon A Young, Luis Izquierdo, Terry K Smith, Stephen Hanessian, Jiro Kondo
Aminoglycosides (AG) are antibiotics that lower the accuracy of protein synthesis by targeting a highly-conserved RNA helix of the ribosomal A-site. The discovery of AGs that selectively target the eukaryotic ribosome, but lack activity in prokaryotes, are promising as antiprotozoals for the treatment of neglected tropical diseases, and as therapies to read-through point-mutation genetic diseases. However, a single nucleobase change A1408G in the eukaryotic A-site leads to negligible affinity for most AGs. Herein we report the synthesis of 6'-fluoro sisomicin, the first 6'-fluorinated aminoglycoside, which specifically interacts with the protozoal cytoplasmic rRNA A-site, but not the bacterial A-site, as evidenced by X-ray co-crystal structures...
May 15, 2018: ChemMedChem
Mayibongwe J Lunga, Ruramai L Chisango, Carli Weyers, Michelle Isaacs, Dale Taylor, Adrienne L Edkins, Setshaba D Khanye, Heinrich C Hoppe, Clinton Veale
Despite major strides in reducing Plasmodium falciparum infections, this parasite still accounts for roughly half a million annual deaths. This problem is compounded by reduced efficacy of artemisinin combination therapies (ACT). Therefore, the development and optimisation of novel antimalarial chemotypes is critical. In this study, we describe our strategic approach to optimise a class of previously reported antimalarials, resulting in the discovery compounds 13 and 14 whose activity was equipotent to chloroquine against the P...
May 13, 2018: ChemMedChem
Celine Bolwerk, Larissa P M W D Govers, Hanna Knol, Thom F Oostendorp, Roland Brock
The blood brain barrier (BBB) limits the access of drugs to the brain. Intensive research is being conducted on the development of nanoparticulate drug carriers that mediate transfer across the BBB. A question that has been neglected so far is the potential accumulation of the carrier in the brain upon long-term exposure. Here, we address this question by implementing a kinetic model to relate drug loading, required concentration of drug in the brain and drug clearance to the degradation half-life of the carrier...
May 11, 2018: ChemMedChem
Nadine Schneider, Richard A Lewis, Nikolas Fechner, Peter Ertl
Chirality is understood by many as a binary concept: a molecule is either chiral or it is not. In terms of the action of a structure on polarized light, this is indeed true. When examined through the prism of molecular recognition, the answer becomes more nuanced. In this work, we investigated chiral behavior on protein-ligand binding: when does chirality make a difference in binding activity? Chirality is a property of the 3D structure, so recognition also requires an appreciation of the conformation. In many situations, the bioactive conformation is undefined...
May 11, 2018: ChemMedChem
Ramon Vilar, Tiffany G Chan, Sophie V Morse, Matthew J Copping, James J Choi
Nanoparticles have been widely studied as versatile platforms for in vivo imaging and therapy. However, their use to image and/or treat the brain is limited as they are often unable to cross the blood-brain barrier (BBB). To overcome this problem, herein we report the use of focused ultrasound in vivo to successfully deliver DNA-coated gold nanoparticles to specific locations in the brains of mice.
May 9, 2018: ChemMedChem
Deepti Goyal, Amandeep Kaur, Bhupesh Goyal
Alzheimer's disease (AD) is a progressive neurodegenerative disease with no clinically accepted treatment to cure or halt its progression. The Food and Drug Administration (FDA) approved drugs (rivastigmine, donepezil, galantamine and memantine) at best provide marginal benefits thus emphasize the urgent need to explore other molecular entities as future drug candidates for AD. Looking at the wide pharmaceutical applications of heterocyclic compounds and particularly those containing benzofuran and indole ring system; these molecular frameworks draw special attention of the medicinal chemists for further evaluation in numerous diseases...
May 9, 2018: ChemMedChem
Suzanne J F Kaptein, Paolo Vincetti, Emmanuele Crespan, Jorge I Armijos-Rivera, Gabriele Costantino, Giovanni Maga, Johan Neyts, Marco Radi
Social and demographic changes over the past 50 years resulted in important outbreaks of arboviruses such as dengue virus (DENV) and Zika virus (ZIKV) all over the world. Despite such potential threat, no approved drugs or fully protective vaccines are available to counteract DENV and ZIKV spreading. The development of "broad spectrum" antivirals (BSAs) targeting common components of multiple viruses, can be a more effective strategy to limit the rapid rise of emerging viral pathogens than the classic "one-bug/one-drug" approach...
May 9, 2018: ChemMedChem
Joel Wahl, Martin Smiesko
Computational methods, namely Molecular Dynamics Simulations (MD simulations) in combination with Inhomogeneous Fluid Solvation Theory (IFST) were used to retrospectively investigate various cases of ligand structure modifications that led to the displacement of binding site water molecules. Our findings are that the water displacement per se is energetically unfavorable in the discussed examples, and that it is merely the fine balance between change in protein-ligand interaction energy, ligand solvation free energies and binding site solvation free energies that determine if water displacement is favorable or not...
May 4, 2018: ChemMedChem
Yann Ayotte, Francois Bilodeau, Albert Descoteaux, Steven Laplante
A rapid and practical approach for the discovery of new chemical matter for targeting pathogens and diseases is described. Fragment-based phenotypic lead discovery (FPLD) combines aspects of traditional fragment-based lead discovery (FBLD), which employs the screening of small-molecule fragment libraries to target specific proteins, with phenotypic lead discovery (PLD), which typically involves the screening of drug-like compounds in cell-based assays. To enable FPLD, a diverse library of fragments was first designed, assembled and curated...
May 2, 2018: ChemMedChem
Jiayao Zhang, Li Chen, Jianbo Sun
Oxoisoaporphine alkaloids are a family of oxoisoquinoline-derived alkaloids that have been firstly isolated from the rhizome of Menispermum dauricum DC. (Menispermaceae). It was demonstrated in some research that oxoisoaporphine alkaloids possess various biological properties, such as cholinesterase and β-amyloid (Aβ) inhibitory, acting as topoisomerase intercalator, monoamine oxidase A (MAO-A) inhibitory , etc, which are expected to become anti-Alzheimer's, anticancer and antidepression drugs. This review provides an overview on natural sources, synthetic route, bioactivities, structure-function relationship and modification investigation of oxoisoaporphine alkaloids, aiming to provide references of the structure-activity relationships for designing and development of oxoisoaporphine derivatives with higher efficacy and therapeutic potential...
April 25, 2018: ChemMedChem
Giuseppe Floresta, Emanuele Amata, Maria Dichiara, Agostino Marrazzo, Loredana Salerno, Giuseppe Romeo, Orazio Prezzavento, Valeria Pittalà, Antonio Rescifina
A 3D quantitative structure-activity relationship (3D-QSAR) model for predicting the heme oxygenase-1 (HO-1) inhibitors activity has been constructed with the aim of providing a useful tool for the identification, design, and optimization of novel HO-1 inhibitors. The model has been built using a set of 222 HO-1 inhibitors recovered from the Heme Oxygenase Database (HemeOxDB) and developed with the software Forge. The present model showed high statistical quality as confirmed by its robust predictive potential and satisfactory descriptive capability...
April 25, 2018: ChemMedChem
Francesca Grisoni, Claudia Neuhaus, Gisela Gabernet, Alex Müller, Jan Hiss, Gisbert Schneider
Constructive machine learning enables the automated generation of novel chemical structures without the need for explicit molecular design rules. This study presents the experimental application of such a generative model to design membranolytic anticancer peptides (ACPs) de novo. A recurrent neural network with long short-term memory cells was trained on alpha-helical cationic amphipathic peptide sequences and then fine-tuned with 26 known ACPs. This optimized model was used to generate unique and novel amino acid sequences...
April 21, 2018: ChemMedChem
Srinivas Angapelly, Andrea Angeli, Arbaj Jabbar Khan, Posa Venkata SriRamya, Claudiu Trandafir Supuran, Mohammed Arifuddin
With the aim to develop potent and selective human carbonic anhydrase inhibitors (hCAIs), we synthesized 4-sulfamoylphenyl/sulfocoumarin benzamides (5a-r and 7a-q) and evaluated for their inhibition profiles against five isoforms of zinc enzyme carbonic anhydrase (CA, EC, the cytosolic CA I and II as well as transmembrane isozymes CA IV, IX and XII. Compounds 5a-r selectively inhibited the isoform hCA II in nanomolar range, being less effective against the other isoforms. As noticeable from the literature, sulfocoumarin (1,2-benzoxathiine 2,2-dioxide) act as "prodrug" inhibitor and get hydrolysed by the esterase CA activity to form 2-hydroxyphenyl-vinylsulfonic acid, which thereafter bind to the enzyme in a similar fashion like coumarins and sulfoxocoumarins...
April 19, 2018: ChemMedChem
Luise Fiedler, Markus Kellner, Rosel Oos, Guido Böning, Sibylle Ziegler, Peter Bartenstein, Reinhard Zeidler, Franz Josef Gildehaus, Simon Lindner
64Cu is a cyclotron-produced radionuclide which offers, due to its characteristic decay scheme the possibility to combine PET investigations with radiotherapy. We evaluated the Alceo sys-tem from Comecer SpA to automatically produce 64Cu for radiolabelling purposes. We established a 64Cu production routine with high yields and radionuclide purity in combination with excellent operator radiation protection. The carbonic anhydrase XII targeting 6A10 antibody fab fragment was successfully radiolabelled with the produced 64Cu and proof of principle small animal PET experiments on mice bearing glioma xenografts were performed...
April 18, 2018: ChemMedChem
Feng Gao, Wiebke Sihver, Ralf Bergmann, Birgit Belter, Cristina Bolzati, Nicola Salvarese, Jörg Steinbach, Jens Pietzsch, Hans-Jürgen Pietzsch
α-Melanocyte stimulating hormone (α-MSH) derivatives target the melanocortin-1 receptor (MC1R) specifically and selectively. In this study, the α-MSH derived peptide NAP-NS1 (Nle-Asp-His-D-Phe-Arg-Trp-Gly-NH2) with and without linkers was conjugated with 5-(bis(pyridin-2-yl)methyl)amino)pentanoic acid (DPA-COOH) and labeled with [99mTc]Tc-tricarbonyl by two methods. With the one-pot method the labeling was faster than with the two-pots method, however obtaining similarly high yields. Negligible transchelation and high stability in physiological solutions was determined for the [99mTc]Tc-tricarbonyl-peptide conjugates...
April 16, 2018: ChemMedChem
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