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Bioorganic & Medicinal Chemistry Letters

Asmita Magotra, Abhishek Gour, Deepak K Sharma, Ashutosh K Dash, Gurdarshan Singh, Debaraj Mukherjee, Utpal Nandi
An improved route for the synthesis of N,N'-diindolyl methane (DIM) glycosides has been developed by using Fe/Al pillared clay catalyst. In-silico pharmacokinetics followed by in-vitro studies like aqueous solubility, lipophilicity, P-glycoprotein (P-gp) dependent ATPase activity, permeability, plasma protein binding, RBC partitioning, metabolic stability in different liver microsomes and its in-vitro-in-vivo extrapolation were conducted for the most potent derivative namely NGD16. The compound was found to have low solubility, optimum lipophilicity, no P-gp inhibitory activity, intermediate permeability, high plasma protein binding, low RBC partitioning, acceptable metabolic stability in rat liver microsomes (RLM) as well as human liver microsomes (HLM) with intermediate hepatic extraction ratio...
February 11, 2019: Bioorganic & Medicinal Chemistry Letters
Hongna Wu, Jun Wu, Wenxuan Zhang, Zhongwen Li, Jinhui Fang, Xu Lian, Tong Qin, Jie Hao, Qi Zhou, Song Wu
Aberrant Wnt signaling has been implicated in a variety of disease. Inhibition of the Wnt pathway is an attractive approach for developing new therapeutics for the treatment of various types of fibrosis and cancers. We have discovered the phthalimide-phenylpyridine conjugate as a novel hit compound for the Wnt pathway inhibitors from cellular screening. The structure-activity relationship of these compounds suggested both of the substituent group on the phthalimide fragment and the structure of the linker were critical to the inhibitory activity...
February 8, 2019: Bioorganic & Medicinal Chemistry Letters
Marco Masi, Ramesh Dasari, Antonio Evidente, Veronique Mathieu, Alexander Kornienko
Ophiobolin A is a fungal secondary metabolite that was found to have significant activity against apoptosis-resistant glioblastoma cells through the induction of a non-apoptotic cell death, offering an innovative strategy to combat this aggressive cancer. The current article aims to make the bridge between the anti-cancer effects of ophiobolin A and its unique reaction with primary amines and suggests that pyrrolylation of lysine residues on its intracellular target protein(s) and/or phosphatidylethanolamine lipid is responsible for its biological effects...
February 7, 2019: Bioorganic & Medicinal Chemistry Letters
Kazutaka Ikegashira, Taku Ikenogami, Takayuki Yamasaki, Takahiro Oka, Yasunori Hase, Naoki Miyagawa, Koji Inagaki, Iichiro Kawahara, Yoshihisa Koga, Hiromasa Hashimoto
Optimization of novel azetidine compounds, which we had found as colony stimulating factor-1 receptor (CSF-1R) Type II inhibitors, provided JTE-952 as a clinical candidate with high cellular activity (IC50  = 20 nM) and good pharmacokinetics profile. JTE-952 was also effective against a mouse collagen-induced model of arthritis (mouse CIA-model). Additionally, the X-ray co-crystal structure of JTE-952 with CSF-1R protein was shown to be a Type II inhibitor, and the kinase panel assay indicated that JTE-952 had high kinase selectivity...
February 7, 2019: Bioorganic & Medicinal Chemistry Letters
Chaobin Jin, Rawaf Alenazy, Yinhu Wang, Rumana Mowla, Yinhui Qin, Jin Quan Eugene Tan, Natansh Deepak Modi, Xinjie Gu, Steven W Polyak, Henrietta Venter, Shutao Ma
A series of novel 5-methoxy-2,3-naphthalimide derivatives were designed, synthesized and evaluated for their biological activities. In particular, the ability of the compounds to synergize with antimicrobials, to inhibit Nile Red efflux, and to target AcrB was assayed. The results showed that the most of the tested compounds more sensitized the Escherichia coli BW25113 to the antibiotics than the parent compounds 7c and 15, which were able to inhibit Nile Red efflux. Significantly, compound A5 possessed the most potent antibacterial synergizing activity in combination with levofloxacin by 4 times and 16 times at the concentration of 8 and 16 µg/mL, respectively, whilst A5 could effectively abolish Nile Red efflux at 100 μM...
February 4, 2019: Bioorganic & Medicinal Chemistry Letters
Yoshiyuki Hakata, Hiroyuki Michiue, Takashi Ohtsuki, Masaaki Miyazawa, Mizuki Kitamatsu
We synthesized a pair of compounds containing leucine zipper peptides to deliver protein cargo into cells. One is a cell-penetrating peptide (CPP) with Lz(E), a leucine zipper peptide containing negatively charged amino acids, and the other is a Nanog protein with Lz(K), a leucine zipper peptide containing positively charged amino acids. When cells were treated with these equimolar mixtures, Nanog-Lz(K) hybridized with Lz(E)-CPP was successfully delivered into the cells. Furthermore, Nanog-Lz(K) exerted its proper function after nuclear transport...
February 4, 2019: Bioorganic & Medicinal Chemistry Letters
Meizi Wang, Xinlu Li, Mengting Chen, Xiaoqing Wu, Yiduo Mi, Zhenpeng Kai, Xinling Yang
Allatostatins (AST) are neuropeptides originally described as inhibitors of juvenile hormone (JH) synthesis in insects. Consequently, they have been considered as potential lead compounds for the discovery of new insect growth regulators (IGRs). In the present work, receptor-based three-dimensional quantitative structure-activity relationship (3D-QSAR) was studied with 48 AST analogs, and a general approach for novel potent bioactive AST analogs is proposed. Hence, six novel AST analogs were designed and synthesized...
February 2, 2019: Bioorganic & Medicinal Chemistry Letters
Changwei Chen, Peichen Pan, Ziyang Deng, Dahai Wang, Qifan Wu, Lei Xu, Tingjun Hou, Sunliang Cui
A new series of 3,6-diaryl-1H-pyrazolo[3,4-b]pyridine compounds have been discovered as potent anaplastic lymphoma kinase (ALK) inhibitors. The 4-hydroxyphenyl in the 6-position of 1H-pyrazolo[3,4-b]pyridine were crucial and a fluorine atom substitution could give promising inhibitory activity. The IC50 of compound 9v against ALK was up to 1.58 nM and a binding mechanism was proposed.
February 1, 2019: Bioorganic & Medicinal Chemistry Letters
Werner J Geldenhuys, Robert Skolik, Mary E Konkle, Michael A Menze, Timothy E Long, Aaron R Robart
Nutrient-deprivation autophagy factor-1 (NAF-1, miner1; gene cisd2) is part of the [2Fe-2S]-containing protein family which includes mitoNEET (gene cisd1) and MiNT (miner2; gene cisd3). These proteins are redox active and are thought to play an important role in cellular energy homeostasis with NAF-1 playing a critical role in calcium regulation and aging. To date, no studies have investigated potential ligand interaction with NAF-1. Here we show that the thiazolidinediones pioglitazone and rosiglitazone along with the mitoNEET ligand, NL-1, bind to NAF-1 with low micromolar affinities...
February 1, 2019: Bioorganic & Medicinal Chemistry Letters
Birong Zhang, James R Kiefer, Robert A Blake, Jae H Chang, Steven Hartman, Ellen Rei Ingalla, Tracy Kleinheinz, Vidhi Mody, Michelle Nannini, Daniel F Ortwine, Yingqing Ran, Amy Sambrone, Deepak Sampath, Maia Vinogradova, Yu Zhong, Jerome C Nwachukwu, Kendall W Nettles, Tommy Lai, Jiangpeng Liao, Xiaoping Zheng, Hai Chen, Xiaojing Wang, Jun Liang
Despite tremendous progress made in the understanding of the ERα signaling pathway and the approval of many therapeutic agents, ER+ breast cancer continues to be a leading cause of cancer death in women. We set out to discover compounds with a dual mechanism of action in which they not only compete with estradiol for binding with ERα, but also can induce the degradation of the ERα protein itself. We were attracted to the constrained chromenes containing a tetracyclic benzopyranobenzoxepine scaffold, which were reported as potent selective estrogen receptor modulators (SERMs)...
February 1, 2019: Bioorganic & Medicinal Chemistry Letters
Junjie Liu, Xiaozhong Cheng, Xiaobo Tian, Dongliang Guan, Jiwei Ao, Zhimeng Wu, Wei Huang, Zhiping Le
The specific binding of RGD cyclic peptide with integrin αv β3 attracts great research interest for tumor-targeting drug delivery. Herein, we designed and synthesized a series of dual-ring RGD-peptide derivatives as a drug carrier for αv β3 targeting. Three novel peptides showed excellent cell adhesion inhibition effect, in which, P3 exhibited 7-fold enhancement in IC50 compared with cyclo(RGDfK). Drug-loaded cytotoxicity experiment and imaging experiment indicated that such dual-cyclic RGD peptides have good tumor targeting effects...
February 1, 2019: Bioorganic & Medicinal Chemistry Letters
Hiroyuki Tobinaga, Takayuki Kameyama, Kentarou Asahi, Tohru Horiguchi, Miho Oohara, Yukio Tada, Kouki Fuchino, Sae Jikihara, Takeshi Endoh, Naoko Kurihara, Yasuhiko Kanda, Masayoshi Ogawa, Naomi Tamura, Shigenori Yagi, Emiko Taniguchi, Yukio Takahara, Shinji Shimada, Chie Takeyama, Shoichi Yamamoto, Shunji Shinohara, Hiroyuki Kai
Some P2X3 receptor antagonists have been developed as new therapeutic drugs for pain. We discovered a novel chemotype of P2X3 receptor antagonists with a pyrrolinone skeleton. Because of SAR studies to improve bioavailability of lead compound 2, compound (R)-24 was identified, which showed an analgesic effect against neuropathic pain by oral administration. We constructed a human P2X3 homology model as a template for the zebrafish P2X4 receptor, which agreed with SAR studies of pyrrolinone derivatives.
February 1, 2019: Bioorganic & Medicinal Chemistry Letters
Wei-Guang Shan, Han-Guang Wang, Rui Wu, Zha-Jun Zhan, Lie-Feng Ma
To improve the drug-ability of celastrol, a series of PEGylation celastrol (PEGC) were designed and synthesized by conjugation with different kinds of polyethylene glycols (PEGs) with celastrol. Most of PEGCs could easily dissolve in water. In particular, one of them (DC1000) could be dispersed in water to form nanoparticles by self-assembly. The cytotoxic evaluation of PEGCs revealed that some of PEGCs showed more potent cytotoxicity than celastrol, and the molecular weight of PEG parts in PEGCs had apparent influence on their cytotoxic activity...
February 1, 2019: Bioorganic & Medicinal Chemistry Letters
Vivek K Vyas, Gulamnizami Qureshi, Drashti Oza, Hardik Patel, Krupali Parmar, Palak Patel, Manjunath D Ghate
Following our research for human dihydroorotate dehydrogenase (hDHODH) inhibitors as anticancer agents, herein we describe 3D QSAR-based design, synthesis and in vitro screening of 2-,4,-6-, and/or 7-substituted quinoline derivatives as hDHODH inhibitors and anticancer agents. We have designed 2-,4,-6-, and/or 7-substituted quinoline derivatives and predicted their hDHODH inhibitory activity based on 3D QSAR study on 45 substituted quinoline derivatives as hDHODH inhibitors, and also predicted toxicity. Designed compounds were docked into the binding site of hDHODH...
January 31, 2019: Bioorganic & Medicinal Chemistry Letters
Dominique Lesuisse, André Malanda, Jean-François Peyronel, Yannick Evanno, Patrick Lardenois, Danielle De-Peretti, Pierre-Yves Abécassis, Pascal Barnéoud, Pascale Brunel, Marie-Claude Burgevin, Céline Cegarra, Florian Auger, Amélie Dommergue, Corinne Lafon, Luc Even, Joanna Tsi, Thy Phuong Hieu Luc, Antonio Almario, Anne Olivier, Marie-Noëlle Castel, Véronique Taupin, Thomas Rooney, Xavier Vigé
In the course of a programme aimed at identifying Nurr1/NOT agonists for potential treatment of Parkinson's disease, a few hits from high throughput screening were identified and characterized. A combined optimization pointed to a very narrow and stringent structure activity relationship. A comprehensive program of optimization led to a potent and safe candidate drug displaying neuroprotective and anti-inflammatory activity in several in vitro and in vivo models.
January 30, 2019: Bioorganic & Medicinal Chemistry Letters
Stuart Francis, Daniel Croft, Alexander W Schüttelkopf, Charles Parry, Angelo Pugliese, Ken Cameron, Sophie Claydon, Martin Drysdale, Claire Gardner, Andrea Gohlke, Gillian Goodwin, Christopher H Gray, Jennifer Konczal, Laura McDonald, Mokdad Mezna, Andrew Pannifer, Nikki R Paul, Laura Machesky, Heather McKinnon, Justin Bower
Fascin is an actin binding and bundling protein that is not expressed in normal epithelial tissues but overexpressed in a variety of invasive epithelial tumors. It has a critical role in cancer cell metastasis by promoting cell migration and invasion. Here we report the crystal structures of fascin in complex with a series of novel and potent inhibitors. Structure-based elaboration of these compounds enabled the development of a series with nanomolar affinities for fascin, good physicochemical properties and the ability to inhibit fascin-mediated bundling of filamentous actin...
January 30, 2019: Bioorganic & Medicinal Chemistry Letters
You-Zhen Ma, Zhen-Bo Tang, Chun-Yan Sang, Zhi-Yuan Qi, Ling Hui, Shi-Wu Chen
To find novel effective Aurora kinases inhibitors, a series of structurally interesting nitroxide labeled pyrimidines were synthesized and evaluated their anti-proliferative and Aurora kinases inhibitory activities. Among them, butyl 2-(3-((5-fluoro-2-((4-((1-oxyl-2,2,6,6-tetramethylpiperidin-4-yl)carbamoyl) phenyl) amino)pyrimidin-4-yl)amino)-1H-pyrazol-5-yl)acetate (22) possessed the most potent anti-proliferative effects against four carcinoma cell lines with IC50 values in range of 0.89-11.41 μM, and kinases inhibition against Aurora A and B with the IC50 values were 9...
January 30, 2019: Bioorganic & Medicinal Chemistry Letters
Kazuki Kunieda, Mitsuyasu Kawaguchi, Naoya Ieda, Hidehiko Nakagawa
Peptidyl arginine deiminases (PADs) catalyze the post-translational deimination of arginine residues to citrulline residues. Aberrant levels of PAD activity are associated with various diseases, such as rheumatoid arthritis, Alzheimer's disease, and multiple sclerosis, so there is a need for simple and convenient high-throughput screening systems to discover PAD inhibitors as candidate therapeutic agents. Here, we report a highly sensitive off/on-type fluorescence probe for PAD activity based on the donor-excited photoinduced electron transfer (d-PeT) mechanism, utilizing the specific cycloaddition reaction between the benzil group of the probe and the ureido group of the PAD product, citrulline, under acidic conditions...
January 25, 2019: Bioorganic & Medicinal Chemistry Letters
Chowdhury Raihan Bikash, Yftah Tal-Gan
Quorum sensing (QS) controls the pathogenic behavior of Streptococcus mutans, a primary cause of dental caries. S. mutans uses the competence stimulating peptide (CSP) to control mutacin production, a bacteriocin utilized by S. mutans to outcompete different commensal bacteria in mixed biofilm environments. In this study, we performed an N-methyl scan of an 18-CSP-based scaffold lacking the first two amino acid residues that were shown to be dispensable, to gain important mechanistic insight as to the role of backbone amide protons in the interaction between CSP and the ComD receptor...
January 25, 2019: Bioorganic & Medicinal Chemistry Letters
Junxing Niu, Hui Huang, Fei Wang, Xianjing Zhang, Yi Liu, Qiang Yu, Lihong Hu
2-Desoxy-4-epi-puchellin (PCL) is a sesquiterpene-lactone, which naturally occurs in many traditional Chinese medicinal plants, and has antitumor and anti-inflammatory activities. In this work, a series of 13-amino derivatives of PCL were synthesized through Michael addition reaction. Inhibition of IL-6-induced STAT3 signaling pathway and in vitro cytotoxicity of these compounds were evaluated, and their effect on the cell cycle was also studied. The methyl hydroxyethylamine derivatives showed higher potency than PCL, which could induce significant mitotic arrest via G2/M arrest in HCT116 cancer cells, indicating that these derivatives have the potential to be developed into anti-colon cancer drugs...
January 25, 2019: Bioorganic & Medicinal Chemistry Letters
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