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Uwe Seibold, Björn Wängler, Carmen Wängler
89Zr is a positron-emitting radionuclide being of high interest for medical imaging applications with Positron Emission Tomography. For the introduction of this radiometal into biologically active targeting vectors, the chelating agent desferrioxamine B (DFO) is commonly applied which is however known to form 89Zr-complexes of limited in vivo stability. We herein describe the rational design and chemical development a new, macrocyclic, four hydroxamates-bearing chelating agent (CTH36) for the stable complexation of Zr4+...
July 17, 2017: ChemMedChem
Sören Reinhard, Wei Zhang, Ernst Wagner
Cationic lipo-oligomers containing unsaturated oleic acid are potent siRNA carriers based on electrostatic and hydrophobic lipo-polyplex formation and endosomal membrane destabilization. Lipo-oligomers can be produced by solid-phase supported synthesis in sequence-defined form. However, the trifluoroacetic acid (TFA)-mediated removal of acid-labile protecting groups and cleavage from the resin can be accompanied by side products caused by addition of TFA to the double bonds of oleic acid. Under aqueous conditions, these TFA adducts of oleic acid are converted into hydroxystearic acid derivatives...
July 17, 2017: ChemMedChem
Emanuele Amata, Agostino Marrazzo, Maria Dichiara, Maria N Modica, Loredana Salerno, Orazio Prezzavento, Giovanni Nastasi, Antonio Rescifina, Giuseppe Romeo, Valeria Pittalà
Due to the increasing interest in the field of heme oxygenases (HOs), we have built a ligand database named HemeOxDB that includes the entire set of known HO-1 and HO-2 inhibitors, resulting in more than 400 compounds. The HemeOxDB is available online at, and having a robust search engine allows the end-users to build complex queries, sort tabulated results, generate color coded 2D (two dimension) and 3D (three dimension) graphs, and is will grow to be a tool for the design of potent and selective HO-1 or HO-2 inhibitors...
July 14, 2017: ChemMedChem
Suraj Toraskar, Madhuri Gade, Sivakoti Sangabathuni, Hirekodathakallu V Thulasiram, Raghavendra Kikkeri
To investigate the effects of the heterogeneity and shape of glyco-nanoprobes on carbohydrate-protein interactions (CPIs), α-d-mannose- and β-d-galactose-linked homo- and heterogeneous glycodendrons were synthesized and immobilized on spherical and rod-shaped gold nanoparticles (AuNPs). Lectin and bacterial binding studies of these glyco-AuNPs clearly illustrate that multivalency and shape of AuNPs contribute significantly to CPIs than the heterogeneity of glycodendrons. Finally, bacterial infection of HeLa cells was effectively inhibited by the homogeneous glycodendron-conjugated rod-shaped AuNPs relative to their heterogeneous counterparts...
July 5, 2017: ChemMedChem
Horst Kunz, Natascha Stergiou, Markus Glaffig, Helmut Jonuleit, Edgar Schmitt
Breaking the tolerance is crucial for an effective tumor immunotherapy. We showed that vaccines containing tumor-associated human MUC1 glycopeptides induce strong humoral anti-tumor responses in mice. The question remained whether such vaccines work in humans, in systems where huMUC1 is a self-antigen. To clarify the question, mice transgenic in expressing huMUC1, mimicking the self-tolerant environment, and wild-type mice were vaccinated with a synthetic vaccine. This vaccine comprised STn and Tn antigens bound to a MUC1 tandem repeat peptide coupled to Tetanus Toxoid...
July 4, 2017: ChemMedChem
Jie Zhou, Hanchun Yao, Lingchang Meng, Chong Sun, Weiran Ye, Qiuzheng Du
To develop a multifunctional nanomaterial for dual-mode imaging and synergetic chemotherapy, curcumin (CUR) was physically entrapped into hollow upconversion NaGdF4, then attached AFn loaded with doxorubicin (DOX) to the surface of NaGdF4. Followed modifying targeting reagent folic acid (FA), obtaining the CUR/NaGdF4-DOX/AFn-FA conjugate for cancer treatment. X-ray diffraction, SEM and TEM and FT-IR proved the successful preparation of hexagonal-phase NaGdF4 and NaGdF4-AFn-FA. And NaGdF4-AFn-FA had no evident toxicity...
July 4, 2017: ChemMedChem
Cosimo Damiano Altomare, Maria Majellaro, Angela Stefanachi, Piero Tardia, Chiara Vicenti, Angelina Boccarelli, Alessandra Pannunzio, Federica Campanella, Mauro Coluccia, Nunzio Denora, Francesco Leonetti, Modesto de Candia, Saverio Cellamare
A number of trimethoxybenzoic acid anilides, previously studied as P-gp modulators, were screened with the aim of identifying new anticancer agents. One of these compounds, which showed antiproliferative activity against resistant MCF-7 cell line, was selected as the hit structure. The replacement of the trimethoxybenzoyl moiety with the nicotinoyl one, for overcoming solubility issues, led to synthesize a new series of N-biphenyl nicotinoyl anilides, among which a nitro derivative (3) displayed antiproliferative activity against MCF7 and MDA-MB231 cells in the nanomolar range...
June 30, 2017: ChemMedChem
Riccardo Rondanin, Daniele Simoni, Martina Maccesi, Romeo Romagnoli, Stefania Grimaudo, Rosaria Maria Pipitone, Maria Meli, Antonio Cascio, Manlio Tolomeo
STAT5 is a transcription factor, component of the STAT family of signalling proteins. STAT-5 is involved in many types of cancer, including chronic myelogenous leukemia (CML), where this protein is found constitutively activated as a consequence of the BCR-ABL expression. Recently, literature has reported that neuroleptic drug pimozide can act as inhibitor of STAT5 phosphorylation and is capable to induce apoptosis in CML cells in vitro. Our group has synthesized simple derivatives of pimozide, with cytotoxic activity and able to reduce the levels of phosphorylated STAT5...
June 28, 2017: ChemMedChem
Garrett C Moraski, Ryan Bristol, Natalie Seeger, Helena I Boshoff, Patricia Siu-Yee Tsang, Marvin J Miller
The global fight to stop tuberculosis (TB) remains a great challenge, particularly with the increase in drug-resistant strains and a lack of funding to support the development of new treatments. To bolster a precarious drug pipeline, we prepared a focused panel of eight pentafluorosulfanyl (SF5 ) compounds which were screened for their activity against Mycobacterium tuberculosis (Mtb) H37Rv in three different assay conditions and media. All eight compounds had sub-micromolar potency, and four displayed MICs <100 nm...
June 27, 2017: ChemMedChem
Michael Withnall, Hongming Chen, Igor V Tetko
A matched molecular pair (MMP) analysis was used to examine the change in melting point (MP) between pairs of similar molecules in a set of ca. 275k compounds. We found many cases where the change of MP (ΔMP) of compounds correlates with respect to changes in functional groups. In line with a previous study of Schultes et al, correlations between ΔMP and simple molecular descriptors, such as the number of hydrogen bond donors were identified. In using a larger dataset, covering a wider chemical space and range of melting points, we observed that this method remains stable and scales well with larger datasets: This MMP based method presents the opportunity for its use as a simple privacy-preserving technique to analyse large proprietary databases and share findings between participating groups...
June 26, 2017: ChemMedChem
Luca Mologni, Martina Dalla Via, Adriana Chilin, Manlio Palumbo, Giovanni Marzaro
Oncogenic activation of the RET kinase has been found in several neoplastic diseases, like medullary thyroid carcinoma, multiple endocrine neoplasia, papillary thyroid carcinoma and non-small cells lung cancer. Currently approved RET inhibitors were not originally designed to be RET inhibitors and their potency against RET kinase has not been optimized. Hence, novel compounds able to inhibit both wtRET and its mutants (e.g. V804MRET) are needed. Herein we present the development and the preliminary evaluation of a new sub-micromolar wtRET/V804MRET inhibitor (69) endowed with 4-anilinopyridine structure, starting from our previously identified 4-anilinopyrimidine hit compound...
June 22, 2017: ChemMedChem
Filipe Vultos, Célia Fernandes, Filipa Mendes, Fernanda Marques, João Correia, Isabel Santos, Lurdes Gano
A straightforward synthetic route for a new multifunctional DOTA derivative is described. To prove the versatility of this prochelator to prepare radiolabelled hybrid compounds containing two different biological targeting moieties, an antitumoral agent (e.g. DNA intercalating agent) and an Estrogen Receptor ligand (e.g. LXXLL based peptide) were regiospecifically conjugated to the DOTA derivative. The bifunctional probe was radiolabelled with the Auger electron emitter Indium-111 and the radioconjugate demonstrated to induce DNA damage in vitro which along with the nuclear internalization exhibited in breast cancer cells might enhance its therapeutic activity...
June 19, 2017: ChemMedChem
Martin Maxmilian Kaiser, Ondřej Baszczyňski, Dana Hocková, Lenka Poštová-Slavětínská, Martin Dračínský, Dianne T Keough, Luke W Guddat, Zlatko Janeba
Acyclic nucleoside phosphonates (ANPs) are an important class of therapeutic drugs that act as antiviral agents by inhibiting viral DNA polymerases and reverse transcriptases. ANPs containing a 6-oxopurine instead of 6-aminopurine or pyrimidine bases are inhibitors of the purine salvage enzyme, hypoxanthine-guanine-[xanthine]-phosphoribosyltransferase (HG[X]PRT). Such compounds, and their prodrugs, are able to arrest the growth of Plasmodium falciparum (Pf) in cell culture. A new series of ANPs has been synthesized and tested as inhibitors of human HGPRT, PfHGXPRT and Plasmodium vivax (Pv) HGPRT...
June 19, 2017: ChemMedChem
Melanie Göth, Volker Badock, Jörg Weiske, Kevin Pagel, Benno Kuropka
Fragment-based screening presents a promising alternative to high-throughput screening and has gained great attention over the last years. So far, only a few studies discuss mass spectrometry as a screening technology for fragments. Here, we applied native electrospray ionization mass spectrometry (ESI-MS) for screening defined sets of fragments against four different target proteins. Fragments were selected from a primary screen conducted by thermal shift assay (TSA) and represent different binding categories...
June 15, 2017: ChemMedChem
Durairaj Thiyagarajan, Gopal Das, Ramesh Aiyagari
A pyridinium amphiphile-loaded Poly(lactic-co-glycolic acid) (PLGA) nanocarrier (C1-PNC) was developed as an adjuvant in order to break the resistance and restore susceptibility of methicillin-resistant Staphylococcus aureus (MRSA) cells to therapeutic antibiotics. Notably, against a clinical MRSA strain, C1-PNC could render 8 × and 6 × reduction of the minimum biofilm eradication concentration (MBEC90) of gentamicin and ciprofloxacin, respectively. Mechanistic studies on MRSA planktonic cells revealed that in case of gentamicin, C1-PNC promoted enhanced cellular uptake of the antibiotic, while the propensity of C1-PNC to inhibit efflux pump activity could be leveraged to enhance cellular accumulation of ciprofloxacin leading to effective killing of MRSA cells...
June 15, 2017: ChemMedChem
Monica Piras, Andrea Testa, Ian N Fleming, Sergio Dall'Angelo, Alexandra Andriu, Sergio Menta, Mattia Mori, Gavin D Brown, Duncan Forster, Kaye J Williams, Matteo Zanda
Non-peptidic RGD-mimic ligands were designed and synthesized by click chemistry between an arginine-azide mimic and an aspartic acid-alkyne mimic. Some of these molecules combine excellent in vitro properties (high αvβ3 affinity, selectivity, drug-like logD, high metabolic stability) with a variety of radiolabeling options (e.g. tritium and [18F]fluorine, plus compatibility with radio-iodination), not requiring the use of chelators or prosthetic groups. The binding mode of the resulting triazole RGD-mimics to αvβ3 or αIIbβ3 receptors was investigated by molecular modeling simulations...
June 13, 2017: ChemMedChem
Nagham Alatrash, Eugenia S Narh, Abhishek Yadav, Mahn-Jong Kim, Thamara Janaratne, James Gabriel, Frederick M MacDonnell
Four mononuclear [(L-L)2 Ru(tatpp)](2+) and two dinuclear [(L-L)2 Ru(tatpp)Ru(L-L)2 ](4+) ruthenium(II) polypyridyl complexes (RPCs) containing the 9,11,20,22-tetraazatetrapyrido[3,2-a:2',3'-c:3'',2''-l:2''',3'''-n]pentacene (tatpp) ligand were synthesized, in which L-L is a chelating diamine ligand such as 2,2'-bipyridine (bpy), 1,10-phenanthroline (phen), 3,4,7,8-tetramethyl-1,10-phenanthroline (Me4 phen) or 4,7-diphenyl-1,10-phenanthroline (Ph2 phen). These Ru-tatpp analogues all undergo reduction reactions with modest reducing agents, such as glutathione (GSH), at pH 7...
June 12, 2017: ChemMedChem
Tian-Long Yan, Li-Fei Bai, Hai-Liang Zhu, Wei-Ming Zhang, Peng-Cheng Lv
Vascular endothelial growth factor receptor 2 (VEGFR2) has been proven to play a major role in the regulation of tumor angiogenesis. A series of novel glycyrrhetic acid derivatives were synthesized and evaluated for their VEGFR2 inhibitory activity as well as their antiproliferative properties against four cancer cell lines (MCF-7, HeLa, HepG2, and A549). In vitro biological evaluations against these human tumor cell lines indicate that most of the prepared compounds have antiproliferative activities; compound 3 a (3β-hydroxy-30-(4-phenyl-1-piperazinyl)olean-12-ene-11,30-dione) exhibited the best inhibitory activity against MCF-7 cells, with an IC50 value of 1...
June 9, 2017: ChemMedChem
Tommaso Felicetti, Rolando Cannalire, Maria Sole Burali, Serena Massari, Giuseppe Manfroni, Maria Letizia Barreca, Oriana Tabarrini, Bryan D Schindler, Stefano Sabatini, Glenn W Kaatz, Violetta Cecchetti
Bacterial resistance to antimicrobial agents has become an increasingly serious health problem in recent years. Among the strategies by which resistance can be achieved, overexpression of efflux pumps such as NorA of S. aureus leads to a sub-lethal concentration of the antibacterial at the active site that in turn may predispose the organism to the development of high-level target-based resistance. With the aim to improve both the chemical stability and the potency of our previously reported 3-phenyl-1,4-benzothiazine NorA inhibitors, we replaced the benzothiazine core with different nuclei...
June 9, 2017: ChemMedChem
Maria Dichiara, Agostino Marrazzo, Orazio Prezzavento, Simona Collina, Antonio Rescifina, Emanuele Amata
Human African trypanosomiasis (HAT), Chagas disease and leishmaniasis, belong to a group of infectious diseases defined as neglected tropical diseases, induced by infection with protozoan parasites named trypanosomatids. Current drugs present several issues and the development of new candidates appears to be needed. The majority of the current therapeutic trypanosomatid targets are represented by enzymes or cell surface receptors. Among these, eukaryotic protein kinases represent a major group of protein targets whose modulation may be beneficial for the treatment of neglected tropical protozoan diseases...
June 7, 2017: ChemMedChem
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