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Christopher Meier, Tamara N Steinhauer, Fabian Koczian, Birte Plitzko, Katharina Jarolim, Ulrich Girreser, Simone Braig, Doris Marko, Angelika M Vollmar, Bernd Clement
Classic cytotoxic drugs constantly remain an indispensable instrument in antitumor therapy due to their effectiveness and a more prevalent insensibility against tumor resistance mechanisms. We describe the favorable properties of P8-D6, a powerful inductor of apoptosis caused by an equipotent inhibition of human topoisomerase I and II activities. A broad spectrum effect against human tumor cell lines in nanomolar concentrations as well as strong anti-leukemic effects were shown and proven to be superior to marketed topo-targeting drugs and dual topoisomerase inhibitors in clinical trials...
January 18, 2017: ChemMedChem
Alessia Carocci, Alessia Catalano, Domenico Iacopetta, Maria Stefania Sinicropi
Thalidomide was firstly used as morning sickness relief in pregnant women and then withdrawn from market because of its dramatic effects on fetal normal development. Over the last decades, it has been successfully used for the care of several pathologies, including cancer. Many analogues with improved activity were synthesized and tested. Herein, we report some effects on MCF-7 and MDA-MB-231 breast cancer cells growth and progression of a small series of thalidomide correlated compounds, very effective in inducing cancer cells death by triggering TNFα-mediated apoptosis...
January 18, 2017: ChemMedChem
Zixin Xie, Zaikui Zhang, Shufang Yu, Donghua Cheng, Huan Zhang, Chao Han, Handeng Lv, Faqing Ye
A total of 24 N-substituted 3,5-bis(2-(trifluoromethyl)benzylidene)piperidin-4-one derivatives were synthesized via aldol condensation, and their anti-inflammatory activities were evaluated. These compounds were found to have no significant cytotoxicity against mouse bone marrow cells in vitro. However, some compounds, such as c6 (N-(3-methylbenzoyl)-3,5-bis-(2-(trifluoromethyl)benzylidene)piperidin-4-one) and c10 (N-(2-chlorobenzoyl)-3,5-bis-(2-(trifluoromethyl)benzylidene)piperidin-4-one), displayed potent anti-inflammatory activity by inhibiting lipopolysaccharide (LPS)-stimulated tumor necrosis factor (TNF)-α, interleukin-6 (IL-6), IL-1β, prostaglandin E2 (PGE2), and nitric oxide (NO) production in RAW 264...
January 18, 2017: ChemMedChem
Yong Bo Peng, Zi Long Zhao, Teng Liu, Guo Jian Xie, Cheng Jin, Tang Gang Deng, Yang Sun, Xiong Li, Xiao Xiao Hu, Xiao Bing Zhang, Mao Ye, Wei Hong Tan
Mitochondria are double-membrane-bound organelles involved mainly in supplying cellular energy, but also play roles in signaling, cell differentiation, and cell death. Mitochondria are implicated in carcinogenesis, and therefore dozens of lethal signal transduction pathways converge on these organelles. Accordingly, mitochondria provide an alternative target for cancer management. In this study, F16, a drug that targets mitochondria, and chlorambucil (CBL), which is indicated for the treatment of selected human neoplastic diseases, were covalently linked, resulting in the synthesis of a multi-mitochondrial anticancer agent, FCBL...
January 18, 2017: ChemMedChem
Sharrol Bachas, Bryan Kohrs, Herschel V Wade
BmrR is a multidrug resistance regulator that responds to diverse ligands. To obtain insights into signal recognition, allosteric control and cooperativity, we employed a quantitative in vitro transcription assay to determine the ligand-dependent activation profiles for a diverse set of cations, zwitterions and uncharged ligands. Like many other biological switch systems, the data are well described by a modified Hill equation. Parameters extracted from curve fits to the data include, L50, RMAX and N. We find that L50 directly correlates to Gbind suggesting that the parameter reflects binding, whereas RMAX and N reflect allosteric control and cooperativity, respectively...
January 16, 2017: ChemMedChem
Borkova Lucie, Richard Adamek, Petr Kalina, Pavel Drašar, Petr Dzubak, Sona Gurska, Jiri Rehulka, Marian Hajduch, Milan Urban, Jan Sarek
41 New triterpenoids were prepared from allobetulon, methyl betulonate, methyl oleanonate, and oleanonic acid to study their influence on cancer cells. Each 3-oxo triterpene was brominated at C-2, substituted with thiocyanate; following cyclization with appropriate ammonium salts gave N-substituted thiazoles. All compounds were tested for their in vitro cytotoxic activity on eight cancer cell lines and two non-cancer fibroblasts. 2-Bromoallobetulon (2b) methyl 2-bromobetulonate (3b), 2-bromooleanonic acid (5b), and 2-thiocyanooleanonic acid (5c) were best with IC50 < 10 μM to CCRF-CEM cells (e...
January 13, 2017: ChemMedChem
Daniele Castagnolo, Rosemary Bass, Sarah Jenkinson, Jennifer Wright, Tora Smulders-Srinivasan, Jamie C Marshall
A series of novel amidinourea derivatives has been synthesised and the new compounds have been evaluated as inhibitors of MDA-MB-231 human breast cancer cell proliferation. In addition, a second series of triazine derivatives designed as rigid congeners of the amidinoureas was synthesised as well and the compounds were evaluated for their antiproliferative activity. Among the two series, the amidinourea 3d emerged as a potent anticancer hit compound with IC50 = 0.76 micormolar comparable to tamoxifen.
January 11, 2017: ChemMedChem
Danielle Wilson, Jason Li, Neil Branda
A photoresponsive small molecule undergoes a ring-opening reaction when exposed to visible light and becomes an active inhibitor of the enzyme, protein kinase C. This "turning on" of enzyme inhibition with light puts the control into the hands of the user, creating the opportunity to regulate when and where enzyme catalysis takes place.
January 10, 2017: ChemMedChem
Tingjunhong Ni, Ran Li, Fei Xie, Jing Zhao, Xin Huang, Maomao An, Chengxu Zang, Zhan Cai, Dazhi Zhang, Yuanying Jiang
Based on the structures of the reported compounds G884 [N-(3-(pentan-2-yloxy)phenyl)nicotinamide], E1210 [3-(3-(4-((pyridin-2-yloxy)methyl)benzyl)isoxazol-5-yl)pyridin-2-amine], and 10 b [2-amino-N-((5-(3-fluorophenoxy)thiophen-2-yl)methyl)nicotinamide], which inhibit the biosynthesis of glycosylphosphatidylinositol (GPI)-anchored proteins in fungi, a series of novel 2-aminonicotinamide derivatives were designed, synthesized, and evaluated for in vitro antifungal activity. Most of these compounds were found to exhibit potent in vitro antifungal activity against Candida albicans, with MIC80 values ranging from 0...
January 10, 2017: ChemMedChem
Benedetta Del Secco, Giulia Malachin, Lorenzo Milli, Nicola Zanna, Emanuele Papini, Andrea Cornia, Regina Tavano, Claudia Tomasini
Some hybrid foldamers of various length, all containing the (4R,5S)-4-carboxy-5-methyloxazolidin-2-one (d-Oxd) moiety alternating with an l-amino acid (l-Val, l-Lys, or l-Ala), were prepared in order to study their preferred conformations and to evaluate their biological activity. Surprisingly, only the longer oligomers containing l-Ala fold into well-established helices, whereas all the other oligomers give partially unfolded turn structures. Nevertheless, they all show good biocompatibility, with no detrimental effects up to 64 μm...
January 9, 2017: ChemMedChem
Martin Perreault, René Maltais, Jenny Roy, Raphaël Dutour, Donald Poirier
Anticancer structure-activity relationship studies on aminosteroid (5α-androstane) derivatives have emerged with a promising lead candidate: RM-133 (2β-[1-(quinoline-2-carbonyl)pyrrolidine-2-carbonyl]-N-piperazine-5α-androstane-3α,17β-diol), which possesses high in vitro and in vivo activities against several cancer cells, and selectivity over normal cells. However, the relatively weak metabolic stability of RM-133 has been a drawback to its progression toward clinical trials. We investigated the replacement of the androstane backbone by a more stable mestranol moiety...
January 6, 2017: ChemMedChem
Natalia Molchanova, Paul Robert Hansen, Peter Damborg, Hanne Mørck Nielsen, Henrik Franzyk
Multidrug-resistant bacteria pose a serious threat to public health worldwide. Previously, α-peptide/β-peptoid hybrid oligomers were found to display activity against Gram-negative multidrug-resistant bacteria. In the present work, the influence of hydrophobicity, fluorination and distribution of cationic/hydrophobic residues on antimicrobial, hemolytic and cytotoxic properties of α-peptide/β-peptoid hybrids were investigated. An array of 22 peptidomimetics was tested. Analogues with enhanced hydrophobicity exhibited increased activity against Gram-positive bacteria...
January 4, 2017: ChemMedChem
Lu Yang, Sohini Bose, Anh H Ngo, Loi H Do
We demonstrate that nontoxic organoiridum complexes can selectively chemosensitize cancer cells toward platinum antiproliferative agents. Treatment of human cancer cells (breast, colon, eye/retina, head/neck, lung, ovary, and blood) with the iridium chemosensitizers led to lowering of the 50 % growth inhibition concentration (IC50 ) of the Pt drug carboplatin by up to ∼30-50 %. Interestingly, non-cancer cells were mostly resistant to the chemosensitizing effects of the iridium complexes. Cell culture studies indicate that cancer cells that were administered with Ir show significantly higher reactive oxygen species concentrations as well as NAD(+) /NADH ratios (oxidized vs...
January 4, 2017: ChemMedChem
Christa E Müller, Dominik Thimm, Karl-Heinz Baringhaus
Pushing the frontiers of medicinal chemistry: Christa Müller, Dominik Thimm, and Karl-Heinz Baringhaus look back at the events of the 2016 Frontiers in Medicinal Chemistry (FiMC) Conference held in Bonn, Germany. The report highlights the themes & talks in the annual conference hosted by the Joint Division of Medicinal Chemistry of the German Pharmaceutical Society (DPhG) and German Chemical Society (GDCh). It is also an invitation to the 2017 conference in Bern, Switzerland this February 12-15.
January 3, 2017: ChemMedChem
Xiaoliang Qi, Junjian Li, Wei Wei, Ting Su, Gancheng Zuo, Xihao Pan, Jianfa Zhang, Wei Dong
Salecan is a water-soluble bacterial polysaccharide consisting of glucopyranosyl units linked by α-1,3 and β-1,3 glycosidic bonds. salecan is suitable for the development of hydrogels for biomedical applications, given its outstanding physicochemical and biological profiles. In this study we designed a new semi-interpenetrating polymer network hydrogel that introduces the salecan polysaccharide into a stimuli-responsive poly(2-acrylamido-2-methylpropanosulfonic acid-co-[2-(methacryloxy)ethyl]trimethylammonium chloride) (PAM) hydrogel matrix for controlled insulin release...
January 3, 2017: ChemMedChem
Saleh E Al-Khalifa, Megan C Jennings, William M Wuest, Kevin P C Minbiole
A series of 18 bis- and tris-pyridinium amphiphiles were prepared and tested for both antimicrobial activity and lytic capability, in comparison to the commercially available pyridinium antiseptic cetylpyridinium chloride (CPC). Assessments were made against Gram-positive and Gram-negative bacteria, including two methicillin-resistant Staphylococcus aureus (MRSA) strains. While 2Pyr-11,11 was identified as one of the most potent antimicrobial QACs reported to date, boasting nanomolar inhibition against 5 of 6 bacteria tested, no significant improvement in bioactivity of tris-pyridinium amphiphiles over their bis-pyridinium counterparts was observed...
December 29, 2016: ChemMedChem
Andrew McIver, Weihe Zhang, Qingyang Liu, Xinpeng Jiang, Michael Stashko, James Nichols, Michael Miley, Jacqueline Norris-Drouin, Mischa Machius, Deborah DeRyckere, Edgar Wood, Douglas Graham, H Shelton Earp, Dmitri Kireev, Stephen Frye, Xiaodong Wang
Macrocycles have attracted significant attention in drug discovery recently. In fact, a few de novo designed macrocyclic kinases inhibitors are currently in clinical trials with good potency and selectivity for their intended target. In this paper, we have successfully engaged a structure-based drug design approach to discover macrocyclic pyrimidines as potent Mer tyrosine kinase (MerTK)-specific inhibitors. An enzyme-linked immunosorbent assay (ELISA) in a 384-well format was employed to evaluate the inhibitory activity of macrocycles in a cell-based assay assessing tyrosine phosphorylation of MerTK...
December 28, 2016: ChemMedChem
Siew Qi Yap, Chee Fei Chin, Agnes Hwee Hong Thng, Yi Yun Pang, Han Kiat Ho, Wee Han Ang
Pt(IV) bis-carboxylates are highly versatile prodrug scaffolds with different axial ligands that can be functionalised while maintaining intact the Pt(II) pharmacophore. Using a sequential acylation strategy, we developed a class of Pt(IV) prodrugs of cisplatin with contrasting lipophilic and hydrophilic ligands. We investigated their stability, reduction rates, lipophilicity, aqueous solubility, and antiproliferative efficacies, and assessed for correlations among the parameters that could be useful in drug design...
December 27, 2016: ChemMedChem
Asta Zubrienė, Alexey Smirnov, Virginija Dudutienė, David D Timm, Jurgita Matulienė, Vilma Michailovienė, Audrius Zakšauskas, Elena Manakova, Saulius Gražulis, Daumantas Matulis
The goal of rational drug design is to understand structure-thermodynamics correlations in order to predict the chemical structure of a drug that would exhibit excellent affinity and selectivity for a target protein. In this study we explored the contribution of added functionalities of benzenesulfonamide inhibitors to the intrinsic binding affinity, enthalpy, and entropy for recombinant human carbonic anhydrases (CA) CA I, CA II, CA VII, CA IX, CA XII, and CA XIII. The binding enthalpies of compounds possessing similar chemical structures and affinities were found to be very different, spanning a range from -90 to +10 kJ mol(-1) , and are compensated by a similar opposing entropy contribution...
December 21, 2016: ChemMedChem
Wojciech Streciwilk, Alessio Terenzi, Rainer Misgeld, Corazon Frias, Peter G Jones, Aram Prokop, Bernhard Keppler, Ingo Ott
Naphthalimide-based N-heterocyclic carbene (NHC) complexes of the type [(COD)(NHC)RhCl) (4a-c), [(p-cymene)(NHC)RuCl2) (5a-c) and [(NHC)CuBr] (6a-c) were synthesised and investigated as antiproliferative agents that target DNA. The cytotoxic effects were largely driven by the naphthalimide structure, which represents a DNA intercalating moiety. Regarding the metal centre, the highest activities were observed with the rhodium complexes and the cytotoxic activity was strongly decreased for the ruthenium derivatives...
December 20, 2016: ChemMedChem
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