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New Drugs

Federica Alessandrini, Laura Pezzè, Daniel Menendez, Michael A Resnick, Yari Ciribilli
Breast cancer treatment often includes Doxorubicin as adjuvant as well as neoadjuvant chemotherapy. Despite its cytotoxicity, cells can develop drug resistance to Doxorubicin. Uncovering pathways and mechanisms involved in drug resistance is an urgent and critical aim for breast cancer research oriented to improve treatment efficacy. Here we show that Doxorubicin and other chemotherapeutic drugs induce the expression of ETV7, a transcriptional repressor member of ETS family of transcription factors. The ETV7 expression led to DNAJC15 down-regulation, a co-chaperone protein whose low expression was previously associated with drug resistance in breast and ovarian cancer...
July 16, 2018: Neoplasia: An International Journal for Oncology Research
Thanigaimalai Pillaiyar, Ewelina Gorska, Gregor Schnakenburg, Christa E Müller
Diindolylmethane (DIM) and its derivatives have recently been in the focus of interest due to their significant biological activities, specifically in cancer prevention and therapy. Molecular targets of DIM have been identified, e.g., the immuno-stimulatory G protein-coupled receptor GPR84. However, most of the reported and investigated DIM derivatives are symmetrical because general methods for obtaining unsymmetrical DIMs have been lacking. To optimize the interaction of DIM derivatives with their protein targets, unsymmetrical substitution is required...
July 19, 2018: Journal of Organic Chemistry
Shasha Liu, Xiaoxia Liu, Xun Zhang, Meiyun Shi, Hecheng Wang, Yajun Liu
Crizotinib, a drug for anaplastic lymphoma kinase (ALK) positive and c-ros oncogene 1 receptor tyrosine kinase (ROS1) positive non-small cell lung cancer (NSCLC), was structurally optimized via a strategy of structure based fragment replacing. Computational study showed it was beneficial for interaction of crizotinib and ALK to increase the distance between pyridyl ring and phenyl ring in crizotinib, and thus a series of novel glycol diaryl ethers were synthesized. The in vitro anti-tumor activity of synthesized compounds was studied in NSCLC cell line H2228 and neurobalstoma cell line SH-SY5Y...
July 19, 2018: Chemical Biology & Drug Design
Subha Bakthavatsalam, Mark L Sleeper, Azim Dharani, Daniel J George, Tian Zhang, Katherine J Franz
The avidity of prostate cancer cells for copper sensitizes them to cytotoxicity by disulfiram, a dithiocarbamate-containing drug approved for alcohol aversion therapy. While disulfiram has received attention as a possible therapy for various cancers, its lack of cancer specificity is a liability that limits this promise. Here we present a prodrug approach to direct copper-dependent cytotoxicity of dithiocarbamate pharmacophores to prostate cancer cells. The prochelator GGTDTC requires activation by gamma-glutamyl transferase (GGT) to release the metal chelator diethyldithiocarbamate from a linker that masks the thiol reactivity and metal binding properties of the pharmacophore prior to activation...
July 19, 2018: Angewandte Chemie
Christian Ottmann, Sebastian A Andrei, Pim de Vink, Eline Sijbesma, Ling Han, Luc Brunsveld, Nobuo Kato, Yusuke Higuchi
The natural product family of fusicoccanes are stabilizers of 14-3-3 mediated protein-protein interactions (PPIs), some of which possess antitumor activity. In this study, we present the first use of molecular dynamics (MD) to rationally design PPI stabilizers with increased potency. Synthesis of a focused library, followed by characterization by fluorescence polarization, mutational studies and X-ray crystallography confirmed the power of the MD-based design approach, revealing the potential for an additional hydrogen bond with the 14-3-3 protein which significantly increased potency...
July 19, 2018: Angewandte Chemie
Yulia Kaluzhny, Miriam W Kinuthia, Thoa Truong, Allison M Lapointe, Patrick Hayden, Mitchell Klausner
Purpose: The purpose of the current work was to develop a physiologically relevant, in vitro human three-dimensional (3D) corneal epithelial tissue model for use in ophthalmic drug development. Methods: Normal human corneal epithelial cells were cultured at the air-liquid interface to produce the 3D corneal tissue model. Corneal barrier was determined by measuring transepithelial electrical resistance (TEER). Quantitative PCR arrays were utilized to investigate expression of 84 phase I/II metabolizing enzymes and 84 drug transporter genes...
June 1, 2018: Investigative Ophthalmology & Visual Science
Liwen Chen, Mu Li, Zhaoxia Luo, Xiaoqin Yan, Ke Yao, Yin Zhao, Hong Zhang
Purpose: To investigate the roles of vasoactive intestinal peptides (VIPs) in regulating the morphology and F-actin distribution of Schlemm's canal (SC) of rat eyes. Methods: Chronic intraocular pressure (IOP) hypertension models with episcleral venous cauterization (EVC) were treated with topical VIP or PG99-465 (vasoactive intestinal peptide receptors 2 [VPAC2] antagonist). IOPs were measured with Tono-Pen, and the SC parameters, including the cross-section area, circumference, and length, were statistically evaluated by hematoxylin-eosin and CD31 immunohistochemical staining...
June 1, 2018: Investigative Ophthalmology & Visual Science
Paul Meyvisch, Chrispin Kambili, Koen Andries, Nacer Lounis, Myriam Theeuwes, Brian Dannemann, An Vandebosch, Wim Van der Elst, Geert Molenberghs, Ariel Alonso
The emergence of multidrug resistant-tuberculosis (MDR-TB), defined as Mycobacterium tuberculosis strains with in vitro resistance to at least isoniazid and rifampicin, has necessitated evaluation and validation of appropriate surrogate endpoints for treatment response in drug trials for MDR-TB. The trial that has demonstrated efficacy of bedaquiline, a diarylquinoline that inhibits mycobacterial ATP synthase, possesses the requisite features to conduct this evaluation. Approval of bedaquiline for use in MDR-TB was based primarily on the results of the controlled C208 Stage II study (ClinicalTrials...
2018: PloS One
Brady P Horn, Xiaoxue Li, Saleh Mamun, Barbara McCrady, Michael T French
BACKGROUND: The US has the highest incarceration rate in the world and spends $40-$80 billion to house inmates per year. It is well-known that a significant correlation is present between substance use and crime, especially over recent years as opioid use disorder (OUD) has grown exponentially. To mitigate OUD, methadone maintenance treatment (MMT) has demonstrated effectiveness in numerous randomized and quasi-experimental studies. A potentially fruitful environment for MMT is correctional facilities, particularly short-term facilities, such as city and county jails...
July 19, 2018: American Journal of Drug and Alcohol Abuse
Jitendra Wankar, Francesca Bonvicini, Gabor Benkovics, Valentina Marassi, Milo Malanga, Eva Fenyvesi, Giovanna Angela Gentilomi, Pierluigi Reschiglian, Barbara Roda, Ilse Manet
Clofazimine (CLZ) is an antibiotic with promising behavior against gram positive bacteria however the drug is completely insoluble in water and accumulates in fat tissues. We explored nanocarriers, labeled and not with rhodamine, consisting of negatively charged sulfobutylether-β-cyclodextrins for CLZ loading. A new oligomeric carrier was obtained crosslinking βCyD with epichlorohydrin followed by sulfonation in strongly alkaline aqueous medium. The oligomeric carrier has MW of 53 kDa, and forms small nanoparticles of few tens of nm...
July 19, 2018: Molecular Pharmaceutics
Pranav Tiwari, Navpreet Kaur, Vinay Sharma, Shaikh M Mobin
The direct exfoliation of graphite (Gr) is highly desirable and feasible compared to conventional processes owing to its non-oxidative, facile and controlled synthesis conditions. Herein, gelatin (gel), a hydrolysed form of collagen, was used as an exfoliant to directly exfoliate Gr. The main advantages of exploring gel as an exfoliant is its easy availability, low cost and high biocompatibility, which alleviate the drawbacks of previous exfoliation methods. The effect of the exfoliation parameters such as temperature, ratio of interacting species and pH of the solution offers a high yield of graphene (G) with the added advantages of good solubility, easy dispersibility and high stability...
July 19, 2018: Physical Chemistry Chemical Physics: PCCP
Sumit Kumar, Issac J Michael, Juhee Park, Steve Granick, Yoon-Kyoung Cho
Exosomes-nanosized extracellular vesicles (EVs) naturally secreted from cells-have emerged as promising biomarkers and potential therapeutic vehicles, but methods to manipulate them for engineering purposes remain elusive. Among the technical obstacles are the small size and surface complexity of exosomes and the complex processing steps required, which reduce the biocompatibility of currently available methods. The encapsulation of exosomes with a nanofilm of supramolecular complexes of ferric ions (Fe3+ ) and tannic acid is demonstrated here...
July 19, 2018: Small
Aleix Gimeno, Andrea Ardid-Ruiz, María José Ojeda-Montes, Sarah Tomás-Hernández, Adrià Cereto-Massagué, Raúl Beltrán-Debón, Miquel Mulero, Cristina Valls, Gerard Aragonès, Manuel Suárez, Gerard Pujadas, Santiago Garcia-Vallvé
Protein tyrosine phosphatase 1B (PTP1B) is a potential drug target for diabetes and obesity. However, designing PTP1B inhibitors that combine potency and bioavailability is a great challenge and new leads are needed to circumvent this problem. Virtual screening (VS) workflows can be used to find new PTP1B inhibitors with little chemical similarity to existing ones. Unfortunately, previous VS workflows for the identification of PTP1B inhibitors have several limitations, such as a small number of experimentally tested compounds and the low bioactivity of those compounds...
July 19, 2018: ChemMedChem
Pablo Martin-Gago, Christian Adam Olsen
Selective covalent modification of a targeted protein is a powerful tool in chemical biology and drug discovery, with applications ranging from identification and characterization of proteins and their functions to the development of targeted covalent inhibitors. Most covalent ligands contain an "affinity motif" and an electrophilic warhead that reacts with a nucleophilic residue of the targeted protein. Because the electrophilic warhead is prone to react and modify off-target nucleophiles, its reactivity should be balanced carefully to maximize target selectivity...
July 19, 2018: Angewandte Chemie
Amandeep Singh, Grant Fong, Jenny Liu, Yun-Hsuan Wu, Kevin Chang, William Park, Jihwan Kim, Christina Tam, Luisa W Cheng, Kirkwood M Land, Vipan Kumar
In this study, we outline the synthesis of isatin-ferrocenyl chalcone and 1 H -1,2,3-triazole-tethered isatin-ferrocene conjugates along with their antimicrobial evaluation against the human mucosal pathogen Trichomonas vaginalis . The introduction of a triazole ring among the synthesized conjugates improved the activity profiles with most of the compounds in the library, exhibiting 100% growth inhibition in a preliminary susceptibility screen at 100 μM. IC50 determination of the most potent compounds in the set revealed an inhibitory range between 2 and 13 μM...
May 31, 2018: ACS Omega
Edita Sarukhanyan, Sergey Shityakov, Thomas Dandekar
After a large outbreak in Brazil, novel drugs against Zika virus became extremely necessary. Evaluation of virus-based pharmacological strategies concerning essential host factors brought us to the idea that targeting the Axl receptor by blocking its dimerization function could be critical for virus entry. Starting from experimentally validated compounds, such as RU-301, RU-302, warfarin, and R428, we identified a novel compound 2' (R428 derivative) to be the most potent for this task amongst a number of alternative compounds and leads...
May 31, 2018: ACS Omega
Kaushik Bera, Samarpan Maiti, Mritunjoy Maity, Chitra Mandal, Nakul C Maiti
With an aim to overcome multidrug resistance (MDR), nontargeted delivery, and drug toxicity, we developed a new nanochemotherapeutic system with tetrasodium salt of meso -tetrakis(4-sulfonatophenyl)porphyrin (TPPS) armored on gold nanoparticles (TPPS-AuNPs). The nanocarrier is able to be selectively internalized within tumor cells than in normal cells followed by endocytosis and therefore delivers the antitumor drug doxorubicin (DOX) particularly to the nucleus of diseased cells. The embedment of TPPS on the gold nanosurface provides excellent stability and biocompatibility to the nanoparticles...
April 30, 2018: ACS Omega
Steven Shave, Kris McGuire, Nhan T Pham, Damian J Mole, Scott P Webster, Manfred Auer
In this study, we apply a battery of molecular similarity techniques to known inhibitors of kynurenine 3-monooxygenase (KMO), querying each against a repository of approved, experimental, nutraceutical, and illicit drugs. Four compounds are assayed against KMO. Subsequently, diclofenac (also known by the trade names Voltaren, Voltarol, Aclonac, and Cataflam) has been confirmed as a human KMO protein binder and inhibitor in cell lysate with low micromolar K D and IC50 , respectively, and low millimolar cellular IC50 ...
March 31, 2018: ACS Omega
Pooja Kumari, Amogh Kulkarni, Ajay Kumar Sharma, Harinath Chakrapani
Owing to the dwindling arsenal of antibiotics, new methodologies for their effective and localized delivery are necessary. The use of optical control over delivery of drugs, also known as photopharmacology, has emerged as an important option for the spatiotemporally controlled generation of drugs and bioactive molecules. In the field of antimicrobial photopharmacology, most strategies utilize ultraviolet light for triggering release of the antibiotic. The use of such short wavelength light may have limitations such as phototoxicity...
February 28, 2018: ACS Omega
Elsa Galbis, Nieves Iglesias, Ricardo Lucas, Ernesto Tinajero-Díaz, M-Violante de-Paz, Sebastián Muñoz-Guerra, Juan A Galbis
Micelles are good devices for use as controlled drug delivery systems because they exhibit the ability to protect the encapsulated substance from the routes of degradation until they reach the site of action. The present work assesses loading kinetics of a hydrophobic drug, pilocarpine, in polymeric micellar nanoparticles (NPs) and its pH-dependent release in hydrophilic environments. The trigger pH stimulus, pH 5.5, was the value encountered in damaged tissues in solid tumors. The new nanoparticles were prepared from an amphiphilic block copolymer, [(HEMA19% -DMA31% )-(FMA5% -DEA45% )]...
January 31, 2018: ACS Omega
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