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Bioorganic & Medicinal Chemistry Letters

Rui-Xue Rong, Shan-Shan Wang, Xuan Liu, Ren-Feng Li, Ke-Rang Wang, Zhi-Ran Cao, Xiao-Liu Li
A series of novel N,N-bis(3-aminopropyl)methylamine bridged bis-naphthalimide derivatives NI1-NI8 containing saturated nitrogenous heterocycles were designed and synthesized, their cytotoxic activities against Hela, MCF-7, A549 and MGC-803 cells were investigated, Compounds NI1-NI4 modified with piperidine and piperazine exhibited good and selective cytotoxic activity, for instance, compounds NI1 and NI4 showed potent cytotoxic activity against Hela cells and MGC-803 cells with the IC50 values of 2.89, 060, 2...
January 9, 2018: Bioorganic & Medicinal Chemistry Letters
Jeffrey J Letourneau, Ilana L Stroke, David W Hilbert, Laurie J Sturzenbecker, Brett A Marinelli, Jorge G Quintero, Joan Sabalski, Linh Ma, David J Diller, Philip D Stein, Maria L Webb
The discovery, synthesis and preliminary structure-activity relationship (SAR) of a novel class of inhibitors of Clostridium difficile (C. difficile) toxin B (TcdB) is described. A high throughput screening (HTS) campaign resulted in the identification of moderately active screening hits 1-5 the most potent of which was compound 1 (IC50 = 0.77 µM). In silico docking of an early analog offered suggestions for structural modification which resulted in the design and synthesis of highly potent analogs 13j(IC50 = 1 nM) and 13 l(IC50 = 7 nM) which were chosen as leads for further optimization...
January 5, 2018: Bioorganic & Medicinal Chemistry Letters
Folkert Reck, Alun Bermingham, Johanne Blais, Vladimir Capka, Taryn Cariaga, Anthony Casarez, Richard Colvin, Charles R Dean, Alex Fekete, Wanben Gong, Ellie Growcott, Hongqiu Guo, Adriana K Jones, Cindy Li, Fengxia Li, Xiaodong Lin, Mika Lindvall, Sara Lopez, David McKenney, Louis Metzger, Heinz E Moser, Ramadevi Prathapam, Dita Rasper, Patrick Rudewicz, Vijay Sethuraman, Xiaoyu Shen, Jacob Shaul, Robert L Simmons, Kyuto Tashiro, Dazhi Tang, Meiliana Tjandra, Nancy Turner, Tsuyoshi Uehara, Charles Vitt, Steven Whitebread, Aregahegn Yifru, Xu Zang, Qingming Zhu
Metallo-β-lactamases (MBLs), such as New Delhi metallo-β-lactamase (NDM-1) have spread world-wide and present a serious threat. Expression of MBLs confers resistance in Gram-negative bacteria to all classes of β-lactam antibiotics, with the exception of monobactams, which are intrinsically stable to MBLs. However, existing first generation monobactam drugs like aztreonam have limited clinical utility against MBL-expressing strains because they are impacted by serine β-lactamases (SBLs), which are often co-expressed in clinical isolates...
January 4, 2018: Bioorganic & Medicinal Chemistry Letters
Zsófia Czudor, Mária Balogh, Péter Bánhegyi, Sándor Boros, Nóra Breza, Judit Dobos, Márk Fábián, Zoltán Horváth, Eszter Illyés, Péter Markó, Anna Sipos, Csaba Szántai-Kis, Bálint Szokol, László Őrfi
Cyclin-dependent kinases (CDKs) and Polo-like kinases (PLKs) play key role in the regulation of the cell cycle. The aim of our study was originally the further development of our recently discovered polo-like kinase 1 (PLK1) inhibitors. A series of new 2,4-disubstituted pyrimidine derivatives were synthesized around the original hit, but their PLK1 inhibitory activity was very poor. However the novel compounds showed nanomolar CDK9 inhibitory activity and very good antiproliferative effect on multiple myeloma cell lines (RPMI-8226)...
January 2, 2018: Bioorganic & Medicinal Chemistry Letters
Jumpei Morimoto, Yuki Hosono, Shinsuke Sando
α-Helix-mediated protein-protein interactions (PPIs) are important targets in biological research and drug development. Peptides containing d-amino acid residues are attractive molecules for inhibiting α-helix-mediated PPIs because of their wide surface area and high protease resistance. In this study, a peptide library was constructed using a one-bead one-compound format designed to isolate left-handed α-helical peptides, which are promising molecules as inhibitors of α-helix-mediated PPIs. Screening of the library against an α-helix-mediated PPI between MDM2 and p53 yielded an inhibitor of the PPI...
January 2, 2018: Bioorganic & Medicinal Chemistry Letters
Meral Tuncbilek, Aslıgul Kucukdumlu, Ebru Bilget Guven, Duygu Altiparmak, Rengul Cetin-Atalay
New nucleoside derivatives with nitrogen substitution at the C-6 position were prepared and screened initially for their in vitro anticancer bioactivity against human epithelial cancer cells (liver Huh7, colon HCT116, breast MCF7) by the NCI-sulforhodamine B assay. N6-(4-trifluoromethylphenyl)piperazine analog (27) exhibited promising cytotoxic activity. The compound 27 was more cytotoxic (IC50 = 1-4 μM) than 5-FU, fludarabine on Huh7, HCT116 and MCF7 cell lines. The most potent nucleosides (11, 13, 16, 18, 19, 21, 27, 28) were further screened for their cytotoxicity in hepatocellular cancer cell lines...
January 2, 2018: Bioorganic & Medicinal Chemistry Letters
Sayaka Ohrui, Naoshi Yamamoto, Tsuyoshi Saitoh, Noriki Kutsumura, Yasuyuki Nagumo, Yoko Irukayama-Tomobe, Yasuhiro Ogawa, Yukiko Ishikawa, Yurie Watanabe, Daichi Hayakawa, Hiroaki Gouda, Masashi Yanagisawa, Hiroshi Nagase
The 14-dehydration- and 14-H derivatives of the orexin 1 receptor (OX1R) antagonist YNT-707 (2) were synthesized. The obtained derivatives showed higher affinities for OX1R than the corresponding 14-hydroxy derivatives. The conformational analysis suggested that the 17-sulfonamide groups in the derivatives without the 14-hydroxy group have a greater tendency to be oriented toward the upper side of the D-ring compared with the 14-hydroxy derivatives. Additionally, the 14-dehydration-derivative with 6α-amide side chain showed significantly higher affinity than the 14-hydroxy derivative, while the corresponding 14-H derivative showed only slightly higher affinity...
December 30, 2017: Bioorganic & Medicinal Chemistry Letters
Xiu-Wei Yang, Li-Yuan Ma, Qi-Le Zhou, Wei Xu, You-Bo Zhang
Panax ginseng as a traditional Chinese medicine has been extensively used for the treatment of many diseases, especially in prolonging life and anti-tumor. Dammarane-type triterpenoids from P. ginseng have diverse beneficial effects and their chemical structures can be modified in the gastrointestinal tract after oral administration. In this paper, the dammarane-type triterpenoids were isolated from artificial gastric juice incubate of total saponins in the stems and leaves of P. ginseng through column chromatographic methods and their chemical structures were determined based on spectral data...
December 30, 2017: Bioorganic & Medicinal Chemistry Letters
Simone Tasca Cargnin, Andressa Finkler Staudt, Patrícia Medeiros, Daniel de Medeiros Sol Sol, Ana Paula de Azevedo Dos Santos, Fernando Berton Zanchi, Grace Gosmann, Antonio Puyet, Carolina Bioni Garcia Teles, Simone Baggio Gnoatto
In this report, we describe the semisynthesis of two series of ursolic and betulinic acid derivatives through designed by modifications at the C-3 and C-28 positions and demonstrate their antimalarial activity against chloroquine-resistant P. falciparum (W2 strain). Structural modifications at C-3 were more advantageous to antimalarial activity than simultaneous modifications at C-3 and C-28 positions. The ester derivative, 3β-butanoyl betulinic acid (7b), was the most active compound (IC50 = 3.4 µM) and it did not exhibit cytotoxicity against VERO nor HepG2 cells (CC50 > 400 µM), showing selectivity towards parasites (selectivity index > 117...
December 29, 2017: Bioorganic & Medicinal Chemistry Letters
Ji Hoon Song, Myoung-Sook Shin, Gwi Seo Hwang, Seong Taek Oh, Jung Jin Hwang, Ki Sung Kang
Glutamate-induced excitotoxicity and oxidative stress is a major causative factor in neuronal cell death in acute brain injuries and chronic neurodegenerative diseases. The prevention of oxidative stress is a potential therapeutic strategy. Therefore, in the present study, we aimed to examine a potential therapeutic agent and its protective mechanism against glutamate-mediated cell death. We first found that chebulinic acid isolated from extracts of the fruit of Terminalia chebula prevented glutamate-induced HT22 cell death...
December 29, 2017: Bioorganic & Medicinal Chemistry Letters
Yongli Duan, Shan Xu, Hehua Xiong, Linxiao Wang, Bingbing Zhao, Ping Wang, Caolin Wang, Yiqing Peng, Shifan Cai, Rong Luo, Pengwu Zheng, Qidong Tang
A series of 2-substituted-4-phenoxypyridine derivatives were designed, synthesized, and evaluated for their antiproliferative activity against 4 cancer cell lines (A549, HT-29, H460, and U87MG) in vitro. Most compounds showed moderate to excellent potency. Nine tyrosine kinases (c-Met, Flt-3, ALK, VEGFR-2, VEGFR-3, PDGFR-α, PDGFR-β, c-Kit, and EGFR) were used to evaluate the inhibitory activities with the most promising analogue 39, which showed the Flt-3/c-Met IC50 values of 2.18/2.61 nM. Structure-activity relationship studies indicated that n-Pr served as R1 group showed a higher preference, and stronger mono-EWGs on the phenyl ring (such as R2 = 4-F) was benefited to the potency...
December 29, 2017: Bioorganic & Medicinal Chemistry Letters
Jianbo Wu, Chunkai Wang, Derek Leas, Mireille Vargas, Karen L White, David M Shackleford, Gong Chen, Austin G Sanford, Ryan M Hemsley, Paul H Davis, Yuxiang Dong, Susan A Charman, Jennifer Keiser, Jonathan L Vennerstrom
N,N'-Diaryl ureas have recently emerged as a new antischistosomal chemotype. We now describe physicochemical profiling, in vitro ADME, plasma exposure, and ex vivo and in vivo activities against Schistosoma mansoni for twenty new N,N'-diaryl ureas designed primarily to increase aqueous solubility, but also to maximize structural diversity. Replacement of one of the 4-fluoro-3-trifluoromethylphenyl substructures of lead N,N'-diaryl urea 1 with azaheterocycles and benzoic acids, benzamides, or benzonitriles decreased lipophilicity, and in most cases, increased aqueous solubility...
December 29, 2017: Bioorganic & Medicinal Chemistry Letters
Manohar Salla, Mark S Butler, Nicholas L Massey, Janet C Reid, Matthew A Cooper, Avril A B Robertson
This study describes the syntheses of di, tetra and hexa deuterated analogues of the NOD-like receptor pyrin domain-containing protein 3 (NLRP3) inflammasome inhibitor MCC950. In di and tetra deuterated analogues, deuteriums were incorporated into the 1,2,3,5,6,7-hexahydro-s-indacene moiety, whereas in the hexa deuterated MCC950 deuteriums were incorporated into the 2-(furan-3-yl)propan-2-ol moiety. The di deuterated MCC950 analogue was synthesised from 4-amino-3,5,6,7-tetrahydro-s-indacen-1(2H)-one 5. Tetra deuterated analogues were synthesised in 10 chemical steps starting with 5-bromo-2,3-dihydro-1H-inden-1-one 9, whereas the hexa deuterated analogue was synthesised in four chemical steps starting with ethyl-3-furoate 24...
December 26, 2017: Bioorganic & Medicinal Chemistry Letters
Christo de Lange, Dina Coertzen, Frans J Smit, Johannes F Wentzel, Ho Ning Wong, Lyn-Marie Birkholtz, Richard K Haynes, David D N'Da
Novel derivatives bearing a ferrocene attached via a piperazine linker to C-10 of the artemisinin nucleus were prepared from dihydroartemisinin and screened against chloroquine (CQ) sensitive NF54 and CQ resistant K1 and W2 strains of Plasmodium falciparum (Pf) parasites. The overall aim is to imprint oxidant (from the artemisinin) and redox (from the ferrocene) activities. In a preliminary assessment, these compounds were shown to possess activities in the low nM range with the most active being compound 6 with IC50 values of 2...
December 26, 2017: Bioorganic & Medicinal Chemistry Letters
Tomoaki Anabuki, Miu Tsukahara, Masanori Okamoto, Hideyuki Matsuura, Kosaku Takahashi
We synthesized a novel linker (1) with biotin, alkyne and amino groups for the identification of target proteins using a small molecule that contains an azide group (azide probe). The alkyne in the linker bound the azide probe via an azide-alkyne Huisgen cycloaddition. A protein cross-linker effectively bound the conjugate of the linker and an azide probe with a target protein. The covalently bound complex was detected by western blotting. Linker 1 was applied to a model system using an abscisic acid receptor, RCAR/PYR/PYL (PYL)...
December 26, 2017: Bioorganic & Medicinal Chemistry Letters
Kun Li, Baitao Wang, Lifang Zheng, Kun Yang, Yuanyuan Li, Minmin Hu, Dian He
The 1,4-naphthoquinone derivatives bearing 5,7-dimethoxyl moiety were designed, synthesized, and tested as the antitumor agents against five human cancer cell lines (A549, Hela, HepG2, NCI-H460 and HL-60). All the compounds are described herein for the first time. The structure-activity relationships indicated that the presence of chlorine atom at the 2-position was crucial for the antiproliferative activity. Further, the electrochemical properties of the representative compounds (7e, 8e and 9e) were evaluated and a definite correlation between the redox potential and the antiproliferative activity...
December 26, 2017: Bioorganic & Medicinal Chemistry Letters
Tatyana V Popova, Hamda Khan, Alexey S Chubarov, Vladimir A Lisitskiy, Natalya M Antonova, Andrey E Akulov, Oleg B Shevelev, Evgenii L Zavjalov, Vladimir N Silnikov, Saheem Ahmad, Tatyana S Godovikova
Human serum albumin is playing an increasing role as a drug carrier in clinical settings. Biotin molecules are often used as suitable tags in targeted anti-tumor drug delivery systems. We report on the synthesis and properties of a new multimodal theranostic conjugate based on an anti-cancer fluorinated nucleotide conjugated with a biotinylated dual-labeled albumin. Interestingly, in vitro and in vivo study revealed stronger anti-tumor activity of the non-tagged theranostic conjugate than that of the biotin-tagged conjugate, which can be explained by decreased binding of the biotin-tagged conjugate to cellular receptors...
December 26, 2017: Bioorganic & Medicinal Chemistry Letters
Hang Zhou, Juanhong Gao, Zhaohang Chen, Shan Duan, Chao Li, Renzhong Qiao
Phenazine and its derivatives have been widely applied as nucleic acid cleavage agents due to active oxygen activating the C-H bond of the substrate. However, diffusion of oxygen radicals limits their potential applications in the DNA-targeted metal-free drug. Introduction of groove binder moiety such as polyamide enhanced the regional stability of radical molecules and reduced cytotoxicity of the drugs. In this work, we described the design and synthesis of a polyamide-modified phenazine-di-N-oxide as a DNA double-strand cleavage agent...
December 26, 2017: Bioorganic & Medicinal Chemistry Letters
Rosanna Maccari, Roberta Ettari, Ilenia Adornato, Alexandra Naß, Gerhard Wolber, Alessandra Bitto, Federica Mannino, Federica Aliquò, Giuseppe Bruno, Francesco Nicolò, Santo Previti, Silvana Grasso, Maria Zappalà, Rosaria Ottanà
This paper describes the design, synthesis, and biological evaluation of 2-thioxoimidazolidin-4-one derivatives as inhibitors of proteasome and immunoproteasome, potential targets for the treatment of hematological malignancies. In particular, we focused our efforts on the design of noncovalent inhibitors, which might be a promising therapeutic option potentially devoid of drawbacks and side-effects related to irreversible inhibition. Among all the synthesized compounds, we identified a panel of active inhibitors with Ki values towards one or two chymotrypsin-like activities of proteasome (β5c) and immunoproteasome (β5i and β1i subunits) in the low micromolar range...
December 26, 2017: Bioorganic & Medicinal Chemistry Letters
Florian Guibbal, Sébastien Bénard, Jessica Patché, Vincent Meneyrol, Joël Couprie, Jennyfer Yong-Sang, Olivier Meilhac, Emmanuelle Jestin
Darapladib is one of the most potent Lp-PLA2 (Lipoprotein-associated phospholipase A2) inhibitor with an IC50 of 0.25 nM. We demonstrate that a crucial step of Darapladib synthesis was not correctly described in the literature, leading to the production of wrong regioisomers. Moreover we show that the inhibitory activity is directly linked to the position on N1 since compounds bearing alkylation on different sites have potentially less interaction within the active site of Lp-PLA2.
December 24, 2017: Bioorganic & Medicinal Chemistry Letters
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