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Bioorganic & Medicinal Chemistry Letters

Mei Han, Chengyan Wang, Yinchun Ji, Zilan Song, Li Xing, Yi Su, Xisheng Wang, Ao Zhang, Jing Ai, Meiyu Geng
A metabolism-based fine-tuning structure-optimization was conducted to address the oxidative metabolism and hERG blockade of our early ALK inhibitor. Compound 8 was identified showing high potency against both ALK wild type and gatekeeper mutant. In addition to the optimal PK properties and significant cell antiproliferative effects, 8 showed complete tumor growth inhibition at doses of 50 or 10mg/kg once daily in the Karpas299 xenograft model. All these results encouraged the further development of 8 as a potent and orally bioavailable ALK inhibitor...
October 14, 2016: Bioorganic & Medicinal Chemistry Letters
Wenchen Pu, Yun Yuan, Danfeng Lu, Xin Wang, Hanwei Liu, Chun Wang, Fei Wang, Guolin Zhang
Estrogen biosynthesis is pivotal to many physiological processes of human. Aberrant estrogen level is closely related to a variety of diseases, including breast cancer and osteoporosis. Previously we found that 2-phenylbenzo[b]furan glycosides could promote estrogen biosynthesis. To find high active 2-phenylbenzo[b]furans, fifty-four 2-phenylbenzo[b]furans were prepared via four strategies according to corresponding substrate scopes. Biological evaluation in HEK293A cells showed that some compounds exhibited promotive activity on estrogen biosynthesis...
October 8, 2016: Bioorganic & Medicinal Chemistry Letters
Ying Peng, Li-Li Lou, Si-Fan Liu, Le Zhou, Xiao-Xiao Huang, Shao-Jiang Song
Seven new neolignans (1-2, 7-11) and five known compounds (3-6, 12) were isolated from the 70% EtOH extract of hawthorn seeds. Their structures were determined by spectroscopic analyses. The antioxidant and anti-inflammatory activities of all the isolates were investigated. Most of the isolates showed moderate radical scavenging activity in the DPPH assay and significant activities in the ABTS and FRAP assays. Furthermore, compounds 7-12 exhibited marked nitric oxide (NO) inhibition and compounds 1-4 had a potent necrosis factor-α (TNF-α) inhibitory effect...
October 7, 2016: Bioorganic & Medicinal Chemistry Letters
Xin-Long Wang, Feng-Jiao Zhou, Man Dou, Yong-Ming Yan, Shu-Mei Wang, Lei Di, Yong-Xian Cheng
Ganoderma mushrooms are of great nutritious and medicinal values. This study was designed to characterize compounds from the fruiting bodies of Ganoderma cochlear and investigate their protective effects against kidney disorders. Six novel meroterpenoids cochlearoids F-K (1-6) were isolated by utilizing phytochemical approaches. Their structures were identified on the basis of extensive spectroscopic data and calculation methods. Biological evaluation shows that compounds 1-4 and 6 exhibit potent inhibitory activity on fibronectin overproduction in TGF-β1-induced HKC-8 cells...
October 7, 2016: Bioorganic & Medicinal Chemistry Letters
Yeohong Yoon, Jee Woong Lim, Jiyoung Kim, Younggi Kim, Keun Ho Chun
The aim of our study was to develop ursolic acid (UA) prodrugs in order to overcome UA's weakness, which has an extremely low bioavailability. UA-medoxomil (NX-201), one of our UA prodrugs, showed an improved bioavailability about 200times better than UA in rodent model. According to in vivo test performed with PANC-1 xenograft SCID mouse model, tumor growth rate decreased dose-dependently and 100mg/kg dose of NX-201 had an anticancer effect comparable to gemcitabine. Most of all the combination of NX-201 (50mg/kg, po, daily) and gemcitabine (40mg/kg, iv, 2timesperweek) even reduced tumor size after three weeks...
October 6, 2016: Bioorganic & Medicinal Chemistry Letters
Jie Gao, Narasimha Midde, Jun Zhu, Alvin V Terry, Campbell McInnes, James M Chapman
Using molecular modeling and rationally designed structural modifications, the multi-target structure-activity relationship for a series of ranitidine analogs has been investigated. Incorporation of a variety of isosteric groups indicated that appropriate aromatic moieties provide optimal interactions with the hydrophobic and π-π interactions with the peripheral anionic site of the AChE active site. The SAR of a series of cyclic imides demonstrated that AChE inhibition is increased by additional aromatic rings, where 1,8-naphthalimide derivatives were the most potent analogs and other key determinants were revealed...
October 6, 2016: Bioorganic & Medicinal Chemistry Letters
Ruo-Kai Lin, Yuh-Feng Lin, Ming-Jen Hsu, Chang-Lin Hsieh, Chen-Yu Wang, Chih-Chiang Huang, Wei-Jan Huang
Some hydroxamate compounds induce cancer cell death by intracellular reactive oxygen species (ROS). This study introduced the hydroxamate core into lovastatin, a fungus metabolite clinically used for the treatment of hypercholesterolemia. The resulting compounds were evaluated for the activity for inducing ROS production. Most compounds exhibited higher activity than original lovastatin. Of these compounds, compound 3c had the most potent activity. Test of cytotoxicity in a panel of human cancer cell lines indicated compound 3c had activities superior to cisplatin in prostate cancer PC-3 cells and breast cancer T47D cells...
October 6, 2016: Bioorganic & Medicinal Chemistry Letters
Yeon Sun Lee, Michael Remesic, Cyf Ramos-Colon, Sara M Hall, Alexander Kuzmin, David Rankin, Frank Porreca, Josephine Lai, Victor J Hruby
Nerve injury and inflammation cause up-regulation of an endogenous opioid ligand, dynorphin A (Dyn A), in the spinal cord resulting in hyperalgesia via the interaction with bradykinin receptors (BRs). This is a non-opioid neuroexcitatory effect that cannot be blocked by opioid antagonists. Our systematic structure-activity relationships study on Dyn A identified lead ligands 1 and 4, along with the key structural feature (i.e. amphipathicity) for the BRs. However, the ligands showed very low metabolic stability in plasma (t1/2 <1h) and therefore, in order to improve their metabolic stabilities with retained biological activities, various modifications were performed...
October 6, 2016: Bioorganic & Medicinal Chemistry Letters
Ramu Guda, Sirassu Narsimha, Ramavath Babu, Srujana Muthadi, Harikiran Lingabathula, Rambabu Palabindela, Narsimha Reddy Yellu, Girijesh Kumar, Mamatha Kasula
A series of novel substituted hydrazono indolo[2,1-b]quinazoline-6,12-dione analogues have been synthesized and screened for their in vitro cytotoxic and antimicrobial activities. Among all the target compounds, 3c exhibited the most potent inhibitory activity against three cancer cell lines MCF-7, A549, HeLa with IC50 values 07.14±1.285μM, 09.18±0.968μM and 10.57±0.581μM respectively, while maintaining low toxicity towards non-cancer originated cell line, HEK-293. The detailed studies about molecular interactions with probable target protein indoleamine 2,3-dioxygenase (IDO1) were done by using docking simulations...
October 5, 2016: Bioorganic & Medicinal Chemistry Letters
Rick Morrison, Zhaohua Zheng, Ian G Jennings, Philip E Thompson, Jasim M A Al-Rawi
To continue our study of 2-morpholino-benzoxazine based compounds, which show useful activity against PI3K family enzymes or antiplatelet activity, we designed and synthesized a series of linear 6.7-fused, 5,6-angular fused and 7,8-angular fused-aryl-morpholino-naphth-oxazines. The compounds were prepared from substituted 2-hydroxynaphthoic acid to give the corresponding thioxo analogues 8, 9, 15 and 19. The thioxo products were then converted to the morpholino substituted analogue. The aryl group was introduced by Suzuki coupling of bromo precursors...
October 5, 2016: Bioorganic & Medicinal Chemistry Letters
Katherine C Faulkner, Katherine A Hurley, Douglas B Weibel
Antibiotic adjuvant therapy represents an exciting opportunity to enhance the activity of clinical antibiotics by co-dosing with a secondary small molecule. Successful adjuvants decrease the concentration of antibiotics used to defeat bacteria, increase activity (in some cases introducing activity against organisms that are drug resistant), and reduce the frequency at which drug-resistant bacteria emerge. We report that 5-alkyloxytryptamines are a new class of broad-spectrum antibacterial agents with exciting activity as antibiotic adjuvants...
October 5, 2016: Bioorganic & Medicinal Chemistry Letters
Jordan G Sheppard, Timothy E Long
Thiolated fluoroquinolones were synthesized from ciprofloxacin and evaluated for antimicrobial activity against a panel of pathogenic bacteria. Gram-positive species including methicillin-resistant Staphylococcus aureus (MRSA) exhibited the highest level of increased sensitivity toward ciprofloxacin bound with a N-propylthio substituent. Evidence was found that the antibiotics form disulfides with low molecular weight thiols in bacteria and potentiate generation of cytosolic reactive oxygen species (ROS). In final analysis, the enhanced anti-MRSA activity of thiolated fluoroquinolones was attributed to increased cell permeability and reaction with cytosolic thiols that yields an inactive disulfide metabolite and the parent drug ciprofloxacin as an inhibitor of DNA synthesis...
October 4, 2016: Bioorganic & Medicinal Chemistry Letters
Andrea Cappelli, Chiara Nannicini, Alessia Chelini, Marco Paolino, Germano Giuliani, Maurizio Anzini, Antonio Giordani, Chiara Sabatini, Gianfranco Caselli, Laura Mennuni, Francesco Makovec, Gianluca Giorgi, Salvatore Vomero, Maria Cristina Menziani
Two new fluorophenylindenone derivatives were designed as potential p38α MAPK modulators by preserving the key interactions of the vicinal pyridine/fluorophenyl pharmacophore with the enzyme protein. Interestingly, these two fluorophenylindenone isomers showed divergent activities, with compound 6 behaving as an inhibitor and 5 as a putative activator. These results were rationalized by docking studies and molecular dynamics simulations in terms of stabilization of DFG loop, by compound 5 in a conformation more accessible to phosphorylation...
October 4, 2016: Bioorganic & Medicinal Chemistry Letters
Pradeep S Jadhavar, Sreekanth A Ramachandran, Eduardo Riquelme, Ashu Gupta, Kevin P Quinn, Devleena Shivakumar, Soumya Ray, Dnyaneshwar Zende, Anjan K Nayak, Sandeep K Miglani, Balaji D Sathe, Mohd Raja, Olivia Farias, Ivan Alfaro, Sebastián Belmar, Javier Guerrero, Sebastián Bernales, Sarvajit Chakravarty, David T Hung, Jeffrey N Lindquist, Roopa Rai
While enzalutamide and abiraterone are approved for treatment of metastatic castration-resistant prostate cancer (mCRPC), approximately 20-40% of patients have no response to these agents. It has been stipulated that the lack of response and the development of secondary resistance to these drugs may be due to the presence of AR splice variants. HDAC6 has a role in regulating the androgen receptor (AR) by modulating heat shock protein 90 (Hsp90) acetylation, which controls the nuclear localization and activation of the AR in androgen-dependent and independent scenarios...
October 4, 2016: Bioorganic & Medicinal Chemistry Letters
Zhanzhan Du, Fang Shi, Dong Liu, Hongling Ye, Maheen Mahwish Surhio, Jinglei Li, Ming Ye
A sulfated polysaccharide, designated as SLEP-1, was obtained after sulfation of the exopolysaccharide (LEP-1) which was isolated from Lachnum. The degree of substitution (DS) of sulfate group of SLEP-1 was 1.97. SEM images of SLEP-1 revealed laminated structure in mesh. UV, FT-IR and (13)C NMR spectra indicated that the LEP-1 was sulfated successfully. The result of the anticoagulant activity in vitro showed that both of LEP-1 and SLEP-1 could effectively prolong activated partial thromboplastin time (APTT) and thrombin time (TT) of the normal mice plasma, in which SLEP-1 was more effectively than those of LEP-1, and dose-effect relationships were found...
October 1, 2016: Bioorganic & Medicinal Chemistry Letters
Ryan P Wurz, Christine Sastri, Derin C D'Amico, Brad Herberich, Claire L M Jackson, Liping H Pettus, Andrew S Tasker, Bin Wu, Nadia Guerrero, J Russell Lipford, Jeffrey T Winston, Yajing Yang, Paul Wang, Yen Nguyen, Kristin L Andrews, Xin Huang, Matthew R Lee, Christopher Mohr, J D Zhang, Darren L Reid, Yang Xu, Yihong Zhou, Hui-Ling Wang
High levels of Pim expression have been implicated in several hematopoietic and solid tumor cancers, suggesting that inhibition of Pim signaling could provide patients with therapeutic benefit. Herein, we describe our progress towards this goal using a screening hit (rac-1) as a starting point. Modification of the indazole ring resulted in the discovery of a series of imidazopyridazine-based Pim inhibitors exemplified by compound 22m, which was found to be a subnanomolar inhibitor of the Pim-1 and Pim-2 isoforms (IC50 values of 0...
October 1, 2016: Bioorganic & Medicinal Chemistry Letters
Sohini Sinha, Anuja Plavuvalapil Kumaran, Debasish Mishra, Priyankar Paira
Recently a choice of fluorescent bioimaging probes have been developed as medical diagnostic tools. Herein, we have introduced a series of coumarin-based target specific probes for cancer theranostic application which play a dual role in the field of both diagnosis and therapy. A fluorogenic version of 1,3-dipolar cycloaddition between azides and alkynes (DBCO) has been introduced to develop the triazolylcoumarin based fluorescent scaffolds. These scaffolds were screened for their anticancer activity against breast cancer (MCF7) and human epitheloid cervix carcinoma (HeLa) cell line...
October 1, 2016: Bioorganic & Medicinal Chemistry Letters
Ewa Szymańska, Paulina Chałupnik, Katarzyna Szczepańska, Ana Maria Cuñado Moral, Darryl S Pickering, Birgitte Nielsen, Tommy N Johansen, Katarzyna Kieć-Kononowicz
A new series of carboxyaryl-substituted phenylalanines was designed, synthesized and pharmacologically characterized in vitro at native rat ionotropic glutamate receptors as well as at cloned homomeric kainate receptors GluK1-GluK3. Among them, six compounds bound to GluK1 receptor subtypes with reasonable affinity (Ki values in the range of 4.9-7.5μM). A structure-activity relationship (SAR) for the obtained series, focused mainly on the pharmacological effect of structural modifications in the 4- and 5-position of the phenylalanine ring, was established...
September 30, 2016: Bioorganic & Medicinal Chemistry Letters
Florian Schmitt, Heidrun Draut, Bernhard Biersack, Rainer Schobert
Three 3-(3-halo-4,5-dimethoxyphenyl)-1-(2-naphthyl)prop-2-en-1-ones 1 and three structurally related 2-pyrazolines 2 were prepared and assessed in vitro for anticancer activity. The chalcones 1 were antiproliferative with low double-digit micromolar IC50 values against six tumor cell lines whereas the pyrazolines 2 showed low single-digit micromolar IC50 values against this panel. The pyrazolines inhibited ATP-binding cassette efflux transporters of types P-gp and BCRP while the chalcones inhibited selectively BCRP...
September 30, 2016: Bioorganic & Medicinal Chemistry Letters
Min Huang, Zhongjie Chen, Lu Zhang, Zhimin Huang, Yiying Chen, Jianrong Xu, Jian Zhang, Xiaohong Shu
It is now established that the specificity in signaling of signal transducer and activator of transcription 3 (STAT3) is mediated by the SH2 domain of STAT3, which mediates its interaction with the phosphopeptide docking sites displayed by receptors and JAKs, dimerization and subsequent DNA binding. Thus, we aimed to identify and design a class of strong potential small molecular inhibitors of STAT3 for the discovery and development of novel anticancer agents. Several classes of small molecules have been identified as STAT3 inhibitors after structure-based screening of the STAT3 SH2 domain...
September 30, 2016: Bioorganic & Medicinal Chemistry Letters
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