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Han-Yue Qiu, Fang Wang, Xue Wang, Wen-Xue Sun, Jin-Liang Qi, Yan-Jun Pang, Rong-Wu Yang, Gui-Hua Lu, Xiao-Ming Wang, Yong-Hua Yang
The biological importance of microtubules in mitosis makes them an interesting target for the development of anticancer agents. In this study, a series of novel chalcone-containing shikonin derivatives was designed, synthesized, and evaluated for biological activities. Among them, derivative PMMB-259 [(R)-1-(5,8-dihydroxy-1,4-dioxo-1,4-dihydronaphthalen-2-yl)-4-methylpent-3-en-1-yl (E)-2-(4-(3-oxo-3-(3-(trifluoromethoxy)phenyl)prop-1-en-1-yl)phenoxy)acetate] was identified as a potent inhibitor of tubulin polymerization...
February 17, 2017: ChemMedChem
Dan Gibson, Benjamin Harper, Aviva Friedman-Ezra, Roman Sirota, Emanuele Emanuele Petruzzella, Janice R Aldrich-Wright
The discrepancy between the in vitro cytotoxic results and the in vivo performance of Pt56MeSS, prompted us to look into its interactions and those of its Pt(IV) derivatives with human serum, HSA, lipoproteins and serum supplemented cell culture medium. The Pt(II) complex, Pt56MeSS, binds non-covalently and reversibly to slow tumbling proteins in human serum and in cell culture medium and interacts through the phenanthroline with HSA with a Kd of about 1.5 × 10-6. All Pt(IV) complexes were stable to reduction in HS but those with axial carboxylate ligands, cct-[Pt(1S,2S-DACH)(5,6-dimethyl-1,10-phenantroline)(acetato)2](TFA)2 (Pt56MeSS(OAc)2) and cct-[Pt(1S,2S-DACH)(5,6-dimehtyl-1,10-phenantroline)(phenylbutyrate)2](TFA)2 (Pt56MeSS(PhB)2), were spontaneously reduced at pH=7 or higher in phosphate buffer, but not in tris buffer (pH=8)...
February 16, 2017: ChemMedChem
Ming Bu, Tingting Cao, Hongxia Li, Mingzhou Guo, Burton B Yang, Chengchu Zeng, Liming Hu
By inspiration of significant anticancer activity of our previously screened natural ergosterol peroxide (1), a series of novel ergosterol peroxide 3-carbamate derivatives were synthesized and characterized. The anti-proliferative activity of synthesized compounds against human hepatocellular carcinoma cells (HepG2, SK-Hep1) and human breast cancer cells (MCF-7, MDA-MB231) were investigated. Compound 3d, 3f and their hydrochloride exhibited significant in vitro anti-proliferative activity against the tested tumor cell lines, with IC50 values ranging from 0...
February 15, 2017: ChemMedChem
Yushu Ge, Qianqian Han, Wenxiu Duan, Jiaqi Zhang, Kai Chen, Jiajia Wan, Yi Liu, Dan Liu
Cdc25 phosphatase has been studied as an attractive target for cancer therapy. Multiple pharmacophore models with unique core features of classic quinone inhibitors and novel inhibitors were used to discover novel lead inhibitor. 21 compounds with qualified physical properties were screened out from Maybridge hitfinderTM database containing 14400 compounds by pharmacophore models. 4 compounds inhibit the Cdc25A activity more than 50% at concentration of 100 μM. Among them, compound KM10389 (N-(2-((furan-2-ylmethyl)thio)ethyl)-2-((4-hydroxy-6-propylpyrimidin-2-yl)thio)acetamide) shows high enzyme inhibition activity with IC₅₀ of 7...
February 14, 2017: ChemMedChem
Shutao Ma, Ziteng Zhou
The treatment of the infections caused by Pseudomonas aeruginosa, an opportunistic Gram-negative bacterium, is very difficult. High intrinsic tolerance towards common antibiotics and the development of new resistant strains challenge us to find a new treatment as soon as possible. PqsD is an enzyme essential for Pseudomonas aeruginosa quorum sensing apparatus, which catalyzes the last and key step in the biosynthesis of HHQ that is a signal molecule of the P. aeruginosa quorum sensing system. In this review, following an outline on their structures, we present a brief introduction of the PqsD inhibitors including their mechanisms of action, inhibitory activity and structure-activity relationships...
February 14, 2017: ChemMedChem
Zisis V Peitsinis, Achilleas G Mitrakas, Eirini A Nakiou, Dafni A Melidou, Dimitra Kalamida, Christos Kakouratos, Michael I Koukourakis, Alexandros E Koumbis
The synthesis of four new analogues of marine nucleoside trachycladine A was accomplished via direct regio- and stereoselective Vorbrüggen glycosylations of 2,6-dichloropurine and 2-chloropurine with a D-ribose derived chiron. Naturally occurring trachycladines (A and B) and a series of analogues were examined for their cytotoxic activity against a number of cancer cell lines (glioblastoma, lung and cervical cancer). Parent trachycladine A and two analogues (the diacetate of 2,6-dichloropurine derivative and N-cyclopropyl trachycladine A) were found to result in a significant reduction of cell viability, with the latter exhibiting a stronger effect...
February 14, 2017: ChemMedChem
Masood Fereidoonnezhad, Maryam Niazi, Mahnaz Shahmohammadi Beni, Shima Mohammadi, Zeinab Faghih, Zahra Faghih, Hamid R Shahsavari
A series of cyclometalated rollover complexes [PtMe(κ²N,C-bipyO-H)(L)], 2a-2c, bipyO-H = cyclometalated 2,2'-bipyridine N-oxide, L = PCy₃ (2a), PPh₂py (2-(diphenylphosphino)pyridine, 2b), P(OPh)₃ (2c), was synthesized by reacting of complex [PtMe(κ²N,C-bipyO-H)(SMe₂)], 1, with various monodentate phosphine and phosphite ligands. These complexes were characterized by means of NMR spectroscopy and the structures of 2a confirmed by single-crystal X-ray diffraction. 1 was treated with bis(diphenylphosphino)methane (dppm) in a 1 : 1 ratio to give corresponding complex [PtMe(κ²N,C-bipyO-H)(η¹P-dppm)], 3b, in which dppm ligand acts as a monodentate pendant ligand...
February 14, 2017: ChemMedChem
Peng Zhao, David O Nettleton, Rajeshri G Karki, Frederic J Zecri, Shih-Yuan Liu
The first examples of biologically active monocyclic 1,2- azaborines have been synthesized and demonstrated to exhibit not only improved in vitro aqueous solubility in comparison to the corresponding carbonaceous analogues, but in the context of a CDK2 inhibitor, also improved biological activity and better in vivo oral bioavailability. This proof-of-concept study establishes the viability of monocyclic 1,2-azaborines as a novel pharmacophore with distinct pharmacological profiles that can help address challenges associated with solubility in drug development research...
February 8, 2017: ChemMedChem
Raffael Vorberg, Erick M Carreira, Klaus Müller
In a series of partially fluorinated N-propyl- and N-butylpiperidine derivatives three compounds exhibit unexpected instability under mild biophysical assay conditions. These compounds carry a single terminal fluorine in delta-position of a N-butyl group as a common structural feature. An adjacent fluorine substituent in gamma-position significantly slows down the reactivity. All other compounds, having either no or more than one fluorine substituents in delta-position are chemically inert under all assay conditions...
January 31, 2017: ChemMedChem
Yao Wang, Yen Chin Koay, Shelli Renee McAlpine
Selectively inhibiting target proteins in cancer cells over normal cells is one of the most critical features of a successful protein inhibitor for clinical applications. By evaluating and comparing the impact of a clinical N-terminal Hsp90 inhibitor, AUY922, on Hsp90 inhibition-associated cellular events in cancer cells versus normal cells, we find that it produces similar phenotype characteristics in both cell types, indicating that AUY922 is not selective for targeting tumor Hsp90. By comparison, the C-terminal Hsp90 modulator SM258 suppresses cell proliferation, triggers apoptosis, regulates the expression of Hsp90-associated heat shock proteins, and enhances the degradation of Hsp90's client proteins preferentially in cancer cells over normal cells...
January 30, 2017: ChemMedChem
Ugo Perricone, Marcus Wieder, Thomas Seidel, Thierry Langer, Alessandro Padova, Anna Maria Almerico, Marco Tutone
Molecular Dynamics (MD) simulations can be used, prior to virtual screening, to add flexibility to proteins, and study them in a dynamical way. Furthermore, the use of multiple crystal structures of the same protein containing different co-crystallised ligands, can help to better elucidate the role of the ligand on protein active conformation, and then explore the most common interactions between small molecules and the receptor. In this work, we evaluated the contribution of the combined use of MD on crystal structures containing the same protein but different ligands to examine the crucial ligand-protein interactions within the complexes...
January 30, 2017: ChemMedChem
Pascale Hazel, Sebastian H B Kroll, Alexander Bondke, Marion Barbazanges, Hetal Patel, Matthew J Fuchter, R Charles Coombes, Simak Ali, Anthony G M Barrett, Paul Freemont
Deregulation of the cell cycle by mechanisms that lead to elevated activities of cyclin-dependent kinases (CDK) is a feature of many human diseases, in particular cancer. We have identified small molecule inhibitors that selectively inhibit CDK7, the kinase that phosphorylates cell cycle CDKs to promote their activities. To investigate the selectivity of these inhibitors we have used a combination of structural, biophysical and modelling approaches. We have determined crystal structures of the CDK7 selective compounds ICEC0942 and ICEC0943 bound to CDK2, and used these to build models of inhibitor binding to CDK7...
January 26, 2017: ChemMedChem
Toni Lutz, Thomas Wein, Georg Höfner, Klaus Theodor Wanner
A new scaffold of highly potent and mGAT1 selective inhibitors has been developed which are characterized by an alkyne-type spacer interconnecting nipecotic acid with an aromatic moiety. From preliminary evaluation, it was apparent that a nipecotic acid derivative with an attached N-butinyl linker and a terminal 2-biphenyl residue exhibiting binding affinity of 7.61±0.03 (pKi) to mGAT1 and uptake inhibition of 7.00±0.06 (pIC50) selective for mGAT1 could serve as a hit compound. Docking calculations for compounds based on this basic structure in a hGAT1 homology modeling study indicated binding affinities similar to or even higher than that of the well-known mGAT1 inhibitor Tiagabine...
January 26, 2017: ChemMedChem
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
Domenico Iacopetta, Alessia Carocci, Maria Stefania Sinicropi, Alessia Catalano, Giovanni Lentini, Jessica Ceramella, Rosita Curcio, Maria Cristina Caroleo
Thalidomide was first used for relief of morning sickness in pregnant women and then withdrawn from the market because of its dramatic effects on normal fetal development. Over the last decades, it has been used successfully for the treatment of several pathologies, including cancer. Many analogues with improved activity have been synthesized and tested. Herein we report some effects on the growth and progression of MCF-7 and MDA-MB-231 breast cancer cells by a small series of thalidomide-correlated compounds, which are very effective at inducing cancer cell 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
Lucie Borkova, Richard Adamek, Petr Kalina, Pavel Drašar, Petr Dzubak, Sona Gurska, Jiri Rehulka, Marian Hajduch, Milan Urban, Jan Sarek
A total of 41 new triterpenoids were prepared from allobetulone, methyl betulonate, methyl oleanonate, and oleanonic acid to study their influence on cancer cells. Each 3-oxotriterpene was brominated at C2 and substituted with thiocyanate; subsequent cyclization with the 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-Bromoallobetulone (2 b) methyl 2-bromobetulonate (3 b), 2-bromooleanonic acid (5 b), and 2-thiocyanooleanonic acid (5 c) were best, with IC50 values less than 10 μm against 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
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