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Wenjia Wang, Matthew R Groves, Alexander Dömling
Interleukin 17(A) is a pro-inflammatory cytokine involved in several auto-immune and inflammatory diseases. Current antagonists against IL17(A) or its receptor (IL17R) that show efficacy in clinical trials are monoclonal-antibodies (mAbs). However, recently designed artificial macrocyles are potent IL17-IL17R antagonists. Based on Co-crystal structures, a better understanding the biological activity and SAR of the macrocycles has been elucidated, demonstrating that macrocycles can compete with mAbs for difficult targets such as PPIs...
January 1, 2018: MedChemComm
Youhui Si, Yi Wen, Jianjun Chen, Rebecca R Pompano, Huifang Han, Joel Collier, Anita S Chong
Self-assembled peptide nanofibers raise significant antibody and T cell responses without adjuvants, but the mechanism by which they achieve this has not been fully elucidated. Myeloid differentiation primary response gene 88 (MyD88) previously has been shown to be critical for the antibody response to antigens presented by peptide nanofibers. The present study sought to determine the cell subset in which MyD88 is essential for T cell responses. Mice deficient in MyD88 or CD11c+ cells had severely attenuated T cell responses...
2018: MedChemComm
Vitaliy M Sviripa, Liliia M Kril, Wen Zhang, Yanqi Xie, Przemyslaw Wyrebek, Larissa Ponomareva, Xifu Liu, Yaxia Yuan, Chang-Guo Zhan, David S Watt, Chunming Liu
Fluorinated, phenylethynyl-substituted heterocycles that possessed either an N -methylamino or N,N -dimethylamino group attached to heterocycles including pyridines, indoles, 1 H -indazoles, quinolines, and isoquinolines inhibited the proliferation of LS174T colon cancer cells in which the inhibition of cyclin D1 and induction of the cyclin-dependent kinase inhibitor-1 ( i.e ., p21Wif1/Cip1 ) served as a readout for antineoplastic activity at a cellular level. On a molecular level, these agents, particularly 4-((2,6-difluorophenyl)ethynyl)- N -methylisoquinolin-1-amine and 4-((2,6-difluorophenyl)ethynyl)- N , N -dimethylisoquinolin-1-amine, bound and inhibited the catalytic subunit of methionine S-adenosyltransferase-2 (MAT2A)...
2018: MedChemComm
Roberta J Melander, Daniel V Zurawski, Christian Melander
While broad spectrum antibiotics play an invaluable role in the treatment of bacterial infections, there are some drawbacks to their use, namely selection for and spread of resistance across multiple bacterial species, and the detrimental effect they can have upon the host microbiome. If the causitive agent of the infection is known, the use of narrow-spectrum antibacterial agents has the potential to mitigate some of these issues. This review outlines the advantages and challenges of narrow-spectrum antibacterial agents, discusses the progress that has been made toward developing diagnostics to enable their use, and describes some of the narrow-spectrum antibacterial agents currently being investigated against some of the most clinically important bacteria including Clostridium difficile, Mycobacterium tuberculosis and several ESKAPE pathogens...
2018: MedChemComm
Satya Prakash Shukla, D Gomika Udugamasooriya
We recently identified a peptide-peptoid hybrid, PPS1, which specifically recognized lipid-phosphatidylserine (PS). PPS1 consists of distinct positively charged and hydrophobic residue-containing regions. PPS1 monomer was inactive, but the dimeric form, PPS1D1, displayed strong cytotoxicity for lung cancer cells compared to normal cells in vitro, and reduced the tumor growth in vivo. The minimum pharmacophore of PPS1D1 showed that the first (methionine) and fourth (N-lysine) residues were not important for PPS1D1 cytotoxic activity...
December 1, 2017: MedChemComm
Wiktoria Jedwabny, Szymon Kłossowski, Trupta Purohit, Tomasz Cierpicki, Jolanta Grembecka, Edyta Dyguda-Kazimierowicz
Development and binding affinity predictions of inhibitors targeting protein-protein interactions (PPI) still represent a major challenge in drug discovery efforts. This work reports application of a predictive non-empirical model of inhibitory activity for PPI inhibitors, exemplified here for small molecules targeting the menin-mixed lineage leukemia (MLL) interaction. Systematic ab initio analysis of menin-inhibitor complexes was performed, revealing the physical nature of these interactions. Notably, the non-empirical protein-ligand interaction energy comprising electrostatic multipole and approximate dispersion terms ( E (10)El,MTP + E Das ) produced a remarkable correlation with experimentally measured inhibitory activities and enabled accurate activity prediction for new menin-MLL inhibitors...
December 1, 2017: MedChemComm
Kiran S Toti, Shanu Jain, Antonella Ciancetta, Ramachandran Balasubramanian, Saibal Chakraborty, Ryan Surujdin, Zhen-Dan Shi, Kenneth A Jacobson
Both agonists and antagonists of the UDP-activated P2Y6 receptor (P2Y6 R) have been proposed for therapeutic use, in conditions such as cancer, inflammation, neurodegeneration and diabetes. Uracil nucleotides containing a South-bicyclo[3.1.0]hexane ((S)-methanocarba) ring system in place of the ribose ring were synthesized and shown to be potent P2Y6 R agonists in a calcium mobilization assay. The (S)-methanocarba modification was compatible with either a 5-iodo or 4-methoxyimino group on the pyrimidine, but not with a α,β-methylene 5´-diphosphate...
October 1, 2017: MedChemComm
Renato Ferreira de Freitas, Matthieu Schapira
As the protein databank (PDB) recently passed the cap of 123 456 structures, it stands more than ever as an important resource not only to analyze structural features of specific biological systems, but also to study the prevalence of structural patterns observed in a large body of unrelated structures, that may reflect rules governing protein folding or molecular recognition. Here, we compiled a list of 11 016 unique structures of small-molecule ligands bound to proteins - 6444 of which have experimental binding affinity - representing 750 873 protein-ligand atomic interactions, and analyzed the frequency, geometry and impact of each interaction type...
October 1, 2017: MedChemComm
J A H Inkster, S Zhang, V Akurathi, A Belanger, S Dubey, T Treves, A B Packard
New chemical and radiochemical syntheses are described for the preparation of [18 F]Rho6G-DEG-F, an18 F-labeled analogue of the fluoresecent dye rhodamine 6G, which has shown promise as myocardidal perfusion imaging agent. Tosylated precursors of [18 F]Rho6G-DEG-F amenable to18 F-labeling were obtained either through a two-step synthesis from rhodamine 6G lactone (33% yield), or in one step from rhodamine 575 (64% yield), then purified by preparative C18 chromatography. Manual synthesis of [18 F]Rho6G-DEG-F was achieved in a single radiochemical step from either the tosylate salt or the tosylate/formate double salt in DMSO under standard nucleophillic aliphatic18 F-fluorination conditions (K[18 F]F/K2 CO3 /Kryptofix 2...
October 1, 2017: MedChemComm
Romain Duroux, Antonella Ciancetta, Philip Mannes, Jinha Yu, Shireesha Boyapati, Elizabeth Gizewski, Said Yous, Francisco Ciruela, John A Auchampach, Zhan-Guo Gao, Kenneth A Jacobson
A pyrazolo[4,3- e ][1,2,4]triazolo[1,5- c ]pyrimidin-5-amine antagonist of the A2A adenosine receptor (AR) was functionalized as amine congeners, fluorescent conjugates and a sulfonate, and the A2A AR binding modes were predicted computationally. The optimal n -butyl spacer was incorporated into the following A2A AR-selective ( K i , nM) conjugates: BODIPY630/650 derivative 11 (MRS7396, 24.6) and AlexaFluor488 derivative 12 (MRS7416, 30.3). Flow cytometry of 12 in hA2A AR-expressing HEK-293 cells displayed saturable binding (low nonspecific) and inhibition by known A2A AR antagonists...
August 1, 2017: MedChemComm
Sandeep Sundriyal, Patty B Chen, Alexandra S Lubin, Gregor A Lueg, Fengling Li, Andrew J P White, Nicholas A Malmquist, Masoud Vedadi, Artur Scherf, Matthew J Fuchter
Plasmodium falciparum HKMTs (PfHKMTs) play a key role in controlling Plasmodium gene expression and represent exciting new anti-malarial epigenetic targets. Using an inhibitor series derived from the diaminoquinazoline HKMT inhibitory chemotype, we have previously identified compounds with highly promising antimalarial activity, including irreversible asexual cycle blood stage-independent cytotoxic activity at nM concentrations, oral efficacy in in vivo models of disease, and the unprecedented ability to reactivate dormant liver stage parasites (hypnozoites)...
May 1, 2017: MedChemComm
S Shaabani, C G Neochoritis, A Twarda-Clapa, B Musielak, T A Holak, A Dömling
Using the pharmacophore-based virtual screening platform ANCHOR.QUERY, we morphed our recently described Ugi-4CR scaffold towards a β-lactam scaffold with potent p53-MDM2 antagonizing activities. 2D-HSQC and FP measurements confirm potent MDM2 binding. Molecular modeling studies are used to understand the observed SAR in the β-lactam series.
May 1, 2017: MedChemComm
Exequiel O J Porta, Sebastián N Jäger, Isabel Nocito, Galina I Lepesheva, Esteban C Serra, Babu L Tekwani, Guillermo R Labadie
A series of prenyl 1,2,3-triazoles were prepared from isoprenyl azides and different alkynes. The dipolar cycloaddition reaction provided exclusively primary azide products as regioisomeric mixtures that were separated by column chromatography and fully characterized. Most of the compounds displayed antiparasitic activity against Trypanosoma cruzi and Leishmania donovani . The most active compounds were assayed as potential Tc CYP51 inhibitors.
May 1, 2017: MedChemComm
Neeraj N Patwardhan, Laura R Ganser, Gary J Kapral, Christopher S Eubanks, Janghyun Lee, Bharathwaj Sathyamoorthy, Hashim M Al-Hashimi, Amanda E Hargrove
Diversification of RNA-targeted scaffolds offers great promise in the search for selective ligands of therapeutically relevant RNA such as HIV-1 TAR. We herein report the establishment of amiloride as a novel RNA-binding scaffold along with synthetic routes for combinatorial C(5)- and C(6)-diversification. Iterative modifications at the C(5)- and C(6)- positions yielded derivative 24 , which demonstrated a 100-fold increase in activity over the parent dimethylamiloride in peptide displacement assays. NMR chemical shift mapping was performed using the 2D SOFAST- [1 H-13 C] HMQC NMR method, which allowed for facile and rapid evaluation of binding modes for all library members...
May 1, 2017: MedChemComm
Behnam Nazari, Clarissa C Forneris, Marcus I Gibson, Kyuho Moon, Kelsey R Schramma, Mohammad R Seyedsayamdost
Glycopeptide antibiotics (GPAs) have served as potent clinical drugs and as an inspiration to chemists in various disciplines. Among known GPAs, complestatin, chloropeptin, and kistamicin are unique in that they contain an unusual indole-phenol crosslink. The mechanism of formation of this linkage is unknown, and to date, the biosynthetic gene cluster of only one GPA with an indole-phenol crosslink, that of complestatin, has been identified. Here, we report the genome sequence of the kistamicin producer Nonomuraea sp...
April 1, 2017: MedChemComm
Klaas Verschueren, Mathias Cobbaut, Joachim Demaerel, Lina Saadah, Arnout R D Voet, Johan Van Lint, Wim M De Borggraeve
In this study, we set out to rationally optimize PKD inhibitors based on the pyrazolo[3,4-d]pyrimidine scaffold. The lead compound for this study was 1-NM-PP1, which was previously found by us and others to inhibit PKD. In our screening we identified one compound (3-IN-PP1) displaying a 10-fold increase in potency over 1-NM-PP1, opening new possibilities for specific protein kinase inhibitors for kinases that show sensitivity towards pyrazolo[3,4-d]pyrimidine derived compounds. Interestingly the observed SAR was not in complete agreement with the commonly observed binding mode where the pyrazolo[3,4-d]pyrimidine compounds are bound in a similar fashion as PKD's natural ligand ATP...
March 1, 2017: MedChemComm
Rachel E Davis, Zheng Zhang, Brian S J Blagg
Inhibition of the Hsp90 C-terminus is an attractive therapeutic paradigm for the treatment of cancer, however the developmental space of C-terminal inhibitors is limited. It was hypothesized that the combination of two previously identified scaffolds into a single structure could provide a platform for which to probe the three-dimensional space within the Hsp90 C-terminal binding pocket. The resulting chimeric compounds displayed anti-proliferative activity at low micromolar concentrations and manifested inhibitory activity in an Hsp90-dependent rematuration assay...
March 1, 2017: MedChemComm
Jing Zhang, Kun Qian, Chunli Yan, Maomao He, Brenson A Jassim, Ivaylo Ivanov, Yujun George Zheng
Protein arginine methyltransferase 1 (PRMT1) is a key player for the dynamic regulation of arginine methylation. Its dysregulation and aberrant expression are implicated in various pathological conditions, and a plethora of evidence suggests that PRMT1 inhibition is of significant therapeutic value. Herein, we reported the modification of a series of diamidine compounds with varied lengths in the middle alkyl linker for PRMT1 inhibition. Decamidine ( 2j ), which possesses the longest linker in the series, displayed 2- and 4- fold increase in PRMT1 inhibition (IC50 = 13 μM), as compared with furamdine and stilbamidine...
February 1, 2017: MedChemComm
Amandeep Singh, Nisha, Trpta Bains, Hye Jee Hahn, Nicole Liu, Christina Tam, Luisa W Cheng, Jong Kim, Anjan Debnath, Kirkwood M Land, Vipan Kumar
A series of N -alkyl tethered C-5 functionalized bis-isatins were synthesized and evaluated for antimicrobial activity against pathogenic microorganisms. The preliminary evaluation studies revealed the compound 4t , with an optimal combination of bromo-substituent at the C-5 position of isatin ring along with propyl chain linker being most active among the synthesized series exhibiting an IC50 value of 3.72 μM against Trichomonas vaginalis while 4j exhibited an IC50 value of 14.8 μM against Naegleria fowleri , more effective than the standard drug Miltefosine...
2017: MedChemComm
Yu Zhao, Po-Yen Liu, Kan-Yen Hsieh, Pei-Ling Hsu, Masuo Goto, Susan L Morris-Natschke, Horng-Jyh Harn, Kuo-Hsiung Lee
Z-K8 ( 2 ), the racemic form of isochaihulactone ( 1 ), previously showed significant antitumor effects in A549 and LNCaP tumor-bearing mice. In the present study, 17 derivatives of 2 , were designed, synthesized and evaluated for anti-proliferative activity against four human tumor cell lines. All new derivatives exhibited high potency against A549 and P-glycoprotein (P-gp)-overexpressing KBvin. One of our new derivative exhibited greater activity against three tested tumor cells (A549, KB, and KB-VIN) than 2 , and induced cell cycle arrest in the G2 /M phase...
2017: MedChemComm
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