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Bioorganic & Medicinal Chemistry

Britt Paulsen, Kim Alex Fredriksen, Dirk Petersen, Louis Maes, An Matheeussen, Ali-Oddin Naemi, Anne Aamdal Scheie, Roger Simm, Rui Ma, Baojie Wan, Scott Franzblau, Lise-Lotte Gundersen
(+)-N6 -Hydroxyagelasine D, the enantiomer of the proposed structure of (-)-ageloxime D, as well as N6 -hydroxyagelasine analogs were synthesized by selective N-7 alkylation of N6 -[tert-butyl(dimethyl)silyloxy]-9-methyl-9H-purin-6-amine in order to install the terpenoid side chain, followed by fluoride mediated removal of the TBDMS-protecting group. N6 -Hydroxyagelasine D and the analog carrying a geranylgeranyl side chain displayed profound antimicrobial activities against several pathogenic bacteria and protozoa and inhibited bacterial biofilm formation...
January 4, 2019: Bioorganic & Medicinal Chemistry
Ting Zhang, Zhenglan Han, Xuerui Shi, Weidong Zhao, Zilong Wang, Run Zhang, Biao Xu, Mengna Zhang, Qinqin Zhang, Jian Xiao, Hanwen Zhu, Ting Zheng, Quan Fang
It is well known that opioid analgesics produce side effects including tolerance and constipation. Since neuropeptide FF (NPFF) receptor antagonists reversed opioid-induced hyperalgesia and analgesic tolerance, the present work was performed to synthetize two branched peptidomimetics, EKR and RKE, containing the opioid peptide endomorphin-2 (EM-2) and the NPFF receptor antagonist RF9. Our data obtained from the in vitro cyclic adenosine monophosphate experiment demonstrated that EKR functioned as a mixed mu-, delta-opioid receptors agonist and NPFF1 receptor antagonist/NPFF2 receptor partial agonist, whereas RKE acted as a multi-functional peptidomimetic with the mu-opioid agonism and the NPFF1 antagonism/NPFF2 partial agonism...
January 4, 2019: Bioorganic & Medicinal Chemistry
Subramani Muthuraman, Shweta Sinha, C S Vasavi, Kamran Manzoor Waidha, Biswarup Basu, Punnagai Munussami, M M Balamurali, Mukesh Doble, Rajendran Saravana Kumar
5-Lipoxygenase (5-LOX) is a key enzyme involved in the biosynthesis of pro-inflammatory leukotrienes, leading to asthma. Developing potent 5-LOX inhibitors especially, natural product based ones, are highly attractive. Coumaperine, a natural product found in white pepper and its derivatives were herein developed as 5-LOX inhibitors. We have synthesized twenty four derivatives, characterized and evaluated their 5-LOX inhibition potential. Coumaperine derivatives substituted with multiple hydroxy and multiple methoxy groups exhibited best 5-LOX inhibition...
January 3, 2019: Bioorganic & Medicinal Chemistry
Ivan Romero-Estudillo, José Luis Viveros-Ceballos, Obed Cazares-Carreño, Angelina González-Morales, Berenice Flores de Jesús, Misael López-Castillo, Rodrigo Said Razo-Hernández, Gabriela Castañeda-Corral, Mario Ordóñez
In this paper, we report the synthesis of a new series of α-aminophosphonates derivatives based in an efficient three-component reaction. All compounds prepared showed significant anti-inflammatory activity, being the compounds 1a, 1c, 1d, 1f, 2b and 2c the most promising ones, in terms of maximal efficacy (over 95%), potency (ED50 range between 0.7 and 10.1 mg/ear) and relative potency (range from 0.04 to 0.67). Compounds 1a, 1c, 1d and 1f significantly decrease the number of neutrophils (range from 46...
December 31, 2018: Bioorganic & Medicinal Chemistry
Qi Zhang, Ping Bai, Cheng Zheng, Yao Cheng, Tao Wang, Xiaoxia Lu
A series of new doramectin derivatives containing carbamate, ester and sulfonate were synthesized, and their structures were characterized by 1 H and 13 C nuclear magnetic resonance (NMR) and high-resolution mass spectrum (HRMS). Their insecticidal activities against oriental armyworm, diamondback moth, and corn borer were evaluated and compared with the parent doramectin and commercial avermectins, metolcarb, fenpropathrin. Among all compounds, three compounds (3a, 3g and 3h) showed excellent insecticidal effect...
December 31, 2018: Bioorganic & Medicinal Chemistry
Chutima Kaewpiboon, Nawong Boonnak, Natpaphan Yawut, Sirichat Kaowinn, Young-Hwa Chung
Our recent study reported that multidrug-resistant (MDR) human A549 lung cancer cells (A549RT-eto) with the elevated expression of NF-κB showed epithelial-mesenchymal transition (EMT), increasing spheroid formation and elevating the expression levels of stemness-related factors, including Oct4, Nanog, Sox2, Bmi1, and Klf4. Therefore, when new therapeutic agents targeting these malignant cancer cells were explored, we found that caged-xanthone (CX) isolated from the roots of Cratoxylum formosum ssp. pruniflorum diminished the expression of NF-κB, P-glycoprotein (P-gp) protein levels, cell migration and invasion, and sphere-forming ability of A549RT-eto cells...
December 31, 2018: Bioorganic & Medicinal Chemistry
Zhao Wang, Zhao Yu, Dongwei Kang, Jian Zhang, Ye Tian, Dirk Daelemans, Erik De Clercq, Christophe Pannecouque, Peng Zhan, Xinyong Liu
A novel series of acetamide-substituted derivatives and two prodrugs of doravirine were designed and synthesized as potent HIV-1 NNRTIs by employing the structure-based drug design strategy. In MT-4 cell-based assays using the MTT method, it was found that most of the new compounds exhibited moderate to excellent inhibitory potency against the wild-type (WT) HIV-1 strain with a minimum EC50 value of 54.8 nM. Among them, the two most potent compounds 8i (EC50  = 59.5 nM) and 8k (EC50  = 54.8 nM) displayed robust activity against WT HIV-1 with double-digit nanomolar EC50 values, being superior to lamivudine (3TC, EC50  = 12...
December 30, 2018: Bioorganic & Medicinal Chemistry
Bo Li, Li Li, Zonggen Peng, Dong Liu, Longlong Si, Jing Wang, Bochuan Yuan, Jian Huang, Peter Proksch, Wenhan Lin
Two new sesquiterpene-based analogues, namely harzianoic acids A (1) and B (2), were isolated from a sponge-associated fungus Trichoderma harzianum. Their structures were determined on the basis of the extensive spectroscopic analyses in association with the ECD data for the configurational assignment. Harzianoic acids A and B were structurally characterized as a sesquiterpene and a norsesquiterpene with a cyclobutane nucleus, which is uncommonly found from nature. Both compounds exhibited the inhibitory activity to reduce the HCV RNA levels with low cytotoxicity...
December 29, 2018: Bioorganic & Medicinal Chemistry
Chunfeng Xie, Xiaoting Li, Jianyun Zhu, Jieshu Wu, Shanshan Geng, Caiyun Zhong
Magnesium Isoglycyrrhizinate (MgIG), a novel molecular compound extracted from licorice root, has exhibited greater anti-inflammatory activity and hepatic protection than glycyrrhizin and β-glycyrrhizic acid. In this study, we investigated the anti-inflammatory effect and the potential mechanism of MgIG on Lipopolysaccharide (LPS)-treated RAW264.7 cells. MgIG down-regulated LPS-induced pro-inflammatory mediators and enzymes in LPS-treated RAW264.7 cells, including TNF-α, IL-6, IL-1β, IL-8, NO and iNOS. The generation of reactive oxygen species (ROS) in LPS-treated RAW264...
December 28, 2018: Bioorganic & Medicinal Chemistry
Xinmiao Lu, Cheng Wang, Xiao Li, Peilin Gu, Lina Jia, Lan Zhang
Epidermal growth factor receptor (EGFR) has emerged as an attracting target in the field of imaging and treatment for non-small cell lung cancer (NSCLC). Radiolabeled EGFR-tyrosine kinase inhibitors (EGFR-TKIs) specifically targeting EGFR are deemed as promising probes for the imaging of NSCLC. This study aimed to label icotinib (one kind of EGFR-TKI) with 18 F through click reaction to develop a new EGFR-targeting PET probe-18 F-icotinib. 18 F-icotinib was obtained in 44.81% decay-corrected yield in 100 min synthesis time with 34 GBq/μmol specific activity and >99% radiochemical purity at the end of synthesis...
December 28, 2018: Bioorganic & Medicinal Chemistry
Ming-Qi Wang, Jing Xu, Lan Zhang, Yue Liao, Heng Wei, Ying-Ying Yin, Qiang Liu, Yuan Zhang
Selective and sensitive detection of G-quadruplex DNA structures is an important issue and attracts extensive interest. To this end, numerous small molecular fluorescent probes have been designed. Here, we present a series of N-alkylated styrylquinolinium dyes named Ls-1, Ls-2 and Ls-3 with varying side groups at the chain end. We found that these dyes exhibited different binding behaviors to DNAs, and Ls-2 with a sulfonato group at the chain end displayed sensitivity and selectivity to G-quadruplex DNA structures in vitro...
December 28, 2018: Bioorganic & Medicinal Chemistry
Fanjie Li, Dan Liu, Xiali Liao, Yulin Zhao, Rongtao Li, Bo Yang
The targeted or responsive systems are appealing therapeutic platforms for the development of next-generation precision medications. So, we design and prepare acid-controlled release complexes of podophyllotoxin (POD) and etoposide (VP-16) with pH-labile acyclic cucurbit[n]urils, and their characteristics and inclusion complexation behaviors were investigated via fluorescence spectroscopy, nuclear magnetic resonance and X-ray power diffraction. Cells incubated with complexes have been analyzed by high-content analysis (HCA), and cytotoxicity tests have been completed by MTT assay...
December 28, 2018: Bioorganic & Medicinal Chemistry
Xueyuan Wang, Enhe Bai, Hui Zhou, Sijia Sha, Hang Miao, Yanru Qin, Zhaogang Liu, Jia Wang, Haoyang Zhang, Meng Lei, Jia Liu, Ou Hai, Yongqiang Zhu
Valosine containing protein (VCP/p97) is a member of the AAA ATPase family involved in several essential cellular functions and plays an important role in the ubiquitin-mediated degradation of misfolded proteins. P97 has a significant role in maintaining the cellular protein homeostasis for tumor cell growth and survival and has been found overexpressed in many tumor types. No new molecule entities based on p97 target were approved in clinic. Herein, a series of novel pyrimidine structures as p97 inhibitors were designed and synthesized...
December 28, 2018: Bioorganic & Medicinal Chemistry
Toby Passioura, Bhaskar Bhushan, Anthony Tumber, Akane Kawamura, Hiroaki Suga
No abstract text is available yet for this article.
December 26, 2018: Bioorganic & Medicinal Chemistry
Yang Li, Jie Xiao, Qizhi Zhang, Wenmei Yu, Mengqin Liu, Yu Guo, Jun He, Yunmei Liu
Quinazoline was originally utilized as an anti-tumor treatment, and its various derivatives can be directly extracted from plants. In recent years, protein kinases (PK) have been well recognized in the development of tumor drugs. Functionally, PK serves a vital role in the apoptosis, proliferation, differentiation, migration and cell cycle of tumor cells. Due to its good physicochemical properties, quinazoline skeleton, a superior type of PK inhibitor, has been extensively used in anti-tumor drug design. An increasing number of studies on quinazoline synthesis have been reported and used by different groups to effectively develop novel derivatives...
December 24, 2018: Bioorganic & Medicinal Chemistry
Yan-Ting Wang, Tian-Qi Shi, Hai-Liang Zhu, Chang-Hong Liu
Tubulin-targeting drugs have increasingly become the focus of anticancer drugs research. Twenty-five novel benzimidazole grafted benzsulfamide-containing pyrazole ring derivatives were synthesized and evaluated for bioactivity as potential tubulin polymerization inhibitors. Among them, compound 30 showed the most excellent inhibition against tubulin assembly (IC50  = 1.52 μM) and in vitro growth inhibitory activity against a panel of four human cancer cell lines (IC50  = 0.15, 0.21, 0.33 and 0.17 μM, respectively for A549, Hela, HepG2 and MCF-7)...
December 23, 2018: Bioorganic & Medicinal Chemistry
Xiaoqi Liu, Yuanyuan Hu, Anhui Gao, Meng Xu, Lixin Gao, Lei Xu, Yubo Zhou, Jianrong Gao, Qing Ye, Jia Li
A series of 3-aryl-4-indolylmaleimide IDH1/R132H inhibitors with a novel structure was obtained by high-throughput screening and structure-based optimization. Most compounds such as 7a, 7d, 7h, 7i, 7k and 7o showed high inhibitory effects on IDH1/R132H and were highly selective against IDH1/WT, IDH2/WT, GDH, GK, and FBP. Evaluation of the biological activities and function at cellular level showed that compounds 7h, 7i and 7k could effectively suppress the production of 2-hydroxyglutaric acid in U87MG cells expressing IDH1/R132H...
December 23, 2018: Bioorganic & Medicinal Chemistry
Jeffrey Boehm, Roderick Davis, Claudia E Murar, Tindy Li, Brent McCleland, Shuping Dong, Hongxing Yan, Jeffrey Kerns, Christopher J Moody, Anthony J Wilson, Alan P Graves, Mary Mentzer, Hongwei Qi, John Yonchuk, Jen-Pyng Kou, Joseph Foley, Yolanda Sanchez, Patricia L Podolin, Brian Bolognese, Catherine Booth-Genthe, Marc Galop, Lawrence Wolfe, Robin Carr, James F Callahan
The antioxidant natural product sulforaphane (SFN) is an oil with poor aqueous and thermal stability. Recent work with SFN has sought to optimize methods of formulation for oral and topical administration. Herein we report the design of new analogs of SFN with the goal of improving stability and drug-like properties. Lead compounds were selected based on potency in a cellular screen and physicochemical properties. Among these, 12 had good aqueous solubility, permeability and long-term solid-state stability at 23 °C...
December 21, 2018: Bioorganic & Medicinal Chemistry
Lauren L Radford, Dionysia Papagiannopoulou, Fabio Gallazzi, Ashley Berendzen, Lisa Watkinson, Terry Carmack, Michael R Lewis, Silvia S Jurisson, Heather M Hennkens
The somatostatin receptor subtype 2 (SSTR2) is often highly expressed on neuroendocrine tumors (NETs), making it a popular in vivo target for diagnostic and therapeutic approaches aimed toward management of NETs. In this work, an antagonist peptide (sst2 -ANT) with high affinity for SSTR2 was modified at the N-terminus with a novel [N,S,O] bifunctional chelator (2) designed for tridentate chelation of rhenium(I) and technetium(I) tricarbonyl cores, [Re(CO)3 ]+ and [99m Tc][Tc(CO)3 ]+ . The chelator-peptide conjugation was performed via a Cu(I)-assisted click reaction of the alkyne-bearing chelator (2) with an azide-functionalized sst2 -ANT peptide (3), to yield NSO-sst2 -ANT (4)...
December 21, 2018: Bioorganic & Medicinal Chemistry
Naoya Tateda, Katsumi Ajisaka, Masaji Ishiguro, Tatsuo Miyazaki
Novel carbohydrate mimics were designed which contain two 5a-carba-d-glucose residues, one each at reducing and nonreducing end, and thus these mimics are 5a,5a'-dicarba-d-glucobioses. Dicarbadisaccharides have attractive features such as stability against endogenous degradative enzymes and being resistant to glycation reactions such as the Maillard reaction. For the synthesis of dicarba-β-d-isomaltose derivatives, the carbaglucosyl triflate locked in 4 C1 conformation was synthesized by protecting with butane-2,3-diacetal group or benzylidene group...
December 19, 2018: Bioorganic & Medicinal Chemistry
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