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Bioorganic & Medicinal Chemistry

Yan-Ru Li, Guo-Hui Li, Ming-Xing Zhou, Lan Xiang, Dong-Mei Ren, Hong-Xiang Lou, Xiao-Ning Wang, Tao Shen
Continuous overproduction of reactive oxygen species (ROS), termed as oxidative stress, plays a crucial role in the onset and progression of many human diseases. Activation of nuclear transcription factor erythroid 2-related factor (Nrf2) by small molecules could eliminate ROS, and thus block the pathogenesis of oxidative stress-induced diseases. In this study, a natural flavonoid library was established and tested for their potential Nrf2 inducing effects. Based on QR inducing effect of flavonoids, their structure-activity relationship (SAR) on Nrf2 induction was summarized, and twenty flavonoids were firstly identified to be potential activators of Nrf2-mediated defensive response...
September 11, 2018: Bioorganic & Medicinal Chemistry
Tsuyoshi Shinozuka, Tomoharu Tsukada, Kunihiko Fujii, Eri Tokumaru, Kousei Shimada, Yoshiyuki Onishi, Yumi Matsui, Satoko Wakimoto, Masanori Kuroha, Tsuneaki Ogata, Kazushi Araki, Jun Ohsumi, Ryoko Sawamura, Nobuaki Watanabe, Hideki Yamamoto, Kazunori Fujimoto, Yoshiro Tani, Makoto Mori, Jun Tanaka
The lead identification of a novel potent selective PPARγ agonist, DS-6930 is reported. To avoid PPARγ-related adverse effects, a partial agonist was designed to prevent the direct interaction with helix 12 of PPARγ-LBD. Because the TZD group is known to interact with helix 12, the TZD in efatutazone (CS-7017) was replaced to discover novel PPARγ intermediate partial agonist 8i. The optimization of 8i yielded 13ac with high potency in vitro. Compound 13ac exhibited robust plasma glucose lowering effects comparable to those of rosiglitazone (3 mg/kg) in Zucker diabetic fatty rats...
September 8, 2018: Bioorganic & Medicinal Chemistry
Tsuyoshi Shinozuka, Tomoharu Tsukada, Kunihiko Fujii, Eri Tokumaru, Kousei Shimada, Yoshiyuki Onishi, Yumi Matsui, Satoko Wakimoto, Masanori Kuroha, Tsuneaki Ogata, Kazushi Araki, Jun Ohsumi, Ryoko Sawamura, Nobuaki Watanabe, Hideki Yamamoto, Kazunori Fujimoto, Yoshiro Tani, Makoto Mori, Jun Tanaka
Attempts were made to reduce the lipophilicity of previously synthesized compound (II) for the avoidance of hepatotoxicity. The replacement of the left-hand side benzene with 2-pyridine resulted in the substantial loss of potency. Because poor membrane permeability was responsible for poor potency in vitro, the adjustment of lipophilicity was examined, which resulted in the discovery of dimethyl pyridine derivative (I, DS-6930). In preclinical studies, DS-6930 demonstrated high PPARγ agonist potency with robust plasma glucose reduction...
September 8, 2018: Bioorganic & Medicinal Chemistry
Yuko Kazui, Shinya Fujii, Ayumi Yamada, Mari Ishigami-Yuasa, Hiroyuki Kagechika, Aya Tanatani
The androgen receptor (AR) is a ligand-inducible transcription factor belonging to the nuclear receptor superfamily, and is a target molecule for development of drugs to treat prostate cancer. However, AR antagonists in clinical use, such as flutamide (3a) and bicalutamide (4), encounter resistance after several years of hormone therapy, predominantly due to mutations of AR. Thus, although some new-generation AR antagonists have been developed, novel types of AR antagonists are still required to treat drug-resistant prostate cancer...
September 6, 2018: Bioorganic & Medicinal Chemistry
Ahmed H E Hassan, Min Chang Cho, Hye In Kim, Ji Seul Yang, Kyung Tae Park, Ji Young Hwang, Choon-Gon Jang, Ki Duk Park, Yong Sup Lee
CRA13; a peripheral dual CB1 R/CB2 R agonist with clinically proven analgesic properties, infiltrates into CNS producing adverse effects due to central CB1 R agonism. Such adverse effects might be circumvented by less lipophilic compounds with attenuated CB1 R affinity. Metabolism produces less lipophilic metabolites that might be active metabolites. Some CRA13 oxidative metabolites and their analogues were synthesized as less lipophilic CRA13 analogues. Probing their CB1 R and CB2 R activity revealed the alcohol metabolite 8c as a more potent and more effective CB2 R ligand with attenuated CB1 R affinity relative to CRA13...
September 6, 2018: Bioorganic & Medicinal Chemistry
Jürgen Vahter, Kaido Viht, Asko Uri, Ganesh Babu Manoharan, Erki Enkvist
A previously disclosed protein kinase (PK) CK2-selective inhibitor 4-(2-amino-1,3-thiazol-5-yl)benzoic acid (ATB) and its selenium-containing counterpart (ASB) revealed remarkable room temperature phosphorescence when bound to the ATP pocket of the protein kinase CK2. Conjugation of these fragments with a mimic of CK2 substrate peptide resulted in bisubstrate inhibitors with increased affinity towards the kinase. Attachment of the fluorescent acceptor dye 5-TAMRA to the conjugates led to significant enhancement of intensity of long-lifetime (microsecond-scale) photoluminescence of both sulfur- and selenium-containing compounds...
September 5, 2018: Bioorganic & Medicinal Chemistry
Shao-Ru Chen, Feng Li, Mo-Yu Ding, Decai Wang, Qi Zhao, Yitao Wang, Guo-Chun Zhou, Ying Wang
Sustained activation of the Janus kinase-signal transducers and activators of transcription (JAK-STAT) pathway contributed to the progression of cancer and liver diseases. STAT3 signaling inhibitor has been extensively investigated for pharmacological use. We synthesized a series of andrographolide derivatives, and characterized their activity against STAT3 signaling pathway both in vitro and in the CCl4 -induced acute liver damage mice model. Among these derivatives, compound 24 effectively inhibited phosphorylation and dimerization of STAT3 but not its DNA binding activity...
September 4, 2018: Bioorganic & Medicinal Chemistry
Atziri Corin Chavez Alvarez, Mitra Zarifi Khosroshahi, Marie-France Côté, Mathieu Gagné-Boulet, Sébastien Fortin
The role and the importance of the sulfonate moiety in phenyl 4-(2-oxo-3-alkylimidazolidin-1-yl)benzenesulfonates (PAIB-SOs) were assessed using its bioisosteric sulfonamide equivalent leading to new cytochrome P450 1A1 (CYP1A1)-activated prodrugs designated as 4-(3-alkyl-2-oxoimidazolidin-1-yl)-N-phenylbenzenesulfonamides (PAIB-SAs). PAIB-SAs are active in the submicromolar to low micromolar range showing selectivity toward CYP1A1-expressing MCF7 cells as compared to cells devoid of CYP1A1 activity such as MDA-MB-231 and HaCaT cells...
September 4, 2018: Bioorganic & Medicinal Chemistry
Giacomo Mari, Simona Catalani, Elena Antonini, Lucia De Crescentini, Fabio Mantellini, Stefania Santeusanio, Paolo Lombardi, Antonella Amicucci, Serafina Battistelli, Serena Benedetti, Francesco Palma
Tetrahydroberberine (THB), otherwise known as canadine, is a natural alkaloid showing significant pharmacological properties and antioxidant protection against oxidative damage. Herein, we synthetized structurally complex THB analogues, namely pyrrolino-tetrahydroberberines (PTHBs) 4a-g, containing the pyrrolino[2,3-b]pyridine system, by means of the reactions of 1,2-diaza-1,3-dienes and 7,8-dihydroberberine. Aim of the study was to explore the in vitro antioxidant properties of PTHBs in comparison to THB thus to identify the most effective against free radical-induced oxidative injury, by using three different antioxidant tests: the ORAC method, the DNA nicking assay, and the DCFH-DA cellular assay...
September 1, 2018: Bioorganic & Medicinal Chemistry
Deboshikha Bhattacharjee, Sanjoy Kumar Sheet, Snehadrinarayan Khatua, Koel Biswas, Santaram Joshi, Bekington Myrboh
A library of biologically important heterocycles, viz. pyrazolyl pyrimidine-triones, bis(heterocyclyl)methanes were successfully synthesised by the condensation of barbituric acid, pyrazolone with an aldehyde and dimedone/4-hydoxy coumarin with various substituted aldehydes in aqueous medium at room temperature catalysed by nickel nanoparticles which proved to be an efficient magnetically recyclable catalyst. The method is simple, eco-friendly and gave excellent yields of the products without taking recourse to column chromatographic separation procedures...
August 28, 2018: Bioorganic & Medicinal Chemistry
Manda Sathish, Sabanis Chetan Dushantrao, Shalini Nekkanti, Ramya Tokala, Soujanya Thatikonda, Yellaiah Tangella, Gunda Srinivas, Shirisha Cherukommu, Namballa Hari Krishna, Nagula Shankaraiah, Narayana Nagesh, Ahmed Kamal
A series of new C3-trans-cinnamide linked β-carboline conjugates has been synthesized by coupling between various β-carboline amines and substituted cinnamic acids. Evaluation of their anti-proliferative activity against a panel of selected human cancer cell lines such as A549 (lung cancer), MCF-7 (breast cancer), B16 (melanoma), HeLa (cervical cancer) and a normal cell line NIH3T3 (mouse embryonic fibroblast cell line), suggested that the newly designed conjugates are considerably active against all the tested cancer cell lines with IC50 values 13-45 nM...
August 25, 2018: Bioorganic & Medicinal Chemistry
Binh Huy Le, Thuy-Van Thi Nguyen, Han Na Joo, Young Jun Seo
Large-Stokes-shift based simple folded DNA probing system (LSFP) had a simple folded DNA structure and exhibited a large Stokes-shifted (194 nm) fluorescence signal upon excitation at a single wavelength (386 nm). This Stokes shift was achieved through a simple combination of donor and acceptor fluorophores and employing multi-FRET systematically. This unique large Stokes-shifted fluorescence signal was used to detect target DNA with large increases in the fluorescence signal (9.7-14.2 fold). This LSFP exhibited enough selectivity, distinguishing a perfectly matched sequence from the probe itself and mismatched sequences...
August 25, 2018: Bioorganic & Medicinal Chemistry
Renshuai Liu, Lulu Liu, Tingting Liu, Xinying Yang, Yichao Wan, Hao Fang
Anti-apoptotic Bcl-2 family proteins are vital for cancer cells to escape apoptosis, which make them attractive targets for cancer therapy. Recently, a lead compound 1 was found to modestly inhibit the binding of BH3 peptide to Bcl-2 protein with a Ki value of 5.2 µM. Based on this, a series of substituted tyrosine derivatives were developed and tested for their binding affinities to Bcl-2 protein. Results indicated that these compounds exhibited potent binding affinities to Bcl-2 and Mcl-1 protein but not to Bcl-XL protein...
August 24, 2018: Bioorganic & Medicinal Chemistry
Rui Yang, Yu Chen, Liangkun Pan, Yanyan Yang, Qiang Zheng, Yue Hu, Yuxi Wang, Liangren Zhang, Yang Sun, Zhongjun Li, Xiangbao Meng
Indoleamine 2,3-dioxygenase 1 (IDO1) is regarded as a promising target for cancer immunotherapy. Many naphthoquinone derivatives have been reported as IDO1 inhibitors so far. Herein, two series of naphthoquinone derivatives, naphthoindolizine and indolizinoquinoline-5,12-dione derivatives, were synthesized and evaluated for their IDO1 inhibitory activity. Most of the target compounds showed significant inhibition potency and high selectivity for IDO1 over tryptophan 2,3-dioxygenase (TDO). The structure-activity relationship was also summarized...
August 24, 2018: Bioorganic & Medicinal Chemistry
Tania Luthra, K Naga Lalitha, A Uma, Subhabrata Sen
Diabetes a non-communicable disease occurs either due to the lack of insulin or the inability of the human body to recognize it. The recent data indicated an increase in the trend of people diagnosed with type 2 diabetes mainly due to unhealthy life style. Here in we report a new class of oxindole derivatives 6a-kvia scaffold hopping of known α-glucosidase inhibitors 1-4. When molecular docking was performed against a homology model of α-glucosidase the resulting compound 6d revealed binding interactions comparable to 1-4...
August 22, 2018: Bioorganic & Medicinal Chemistry
Siyuan Xu, Chen Zhou, Rongfeng Liu, Qihua Zhu, Yungen Xu, Fei Lan, Xiaoming Zha
Histone lysine specific demethylase 1 (LSD1) is overexpressed in diverse hematologic disorders and recognized as a promising target for blood medicines. In this study, molecular docking-based virtual screening united with bioevaluation was utilized to identify novel skeleton of 5-arylidene barbiturate as small-molecule inhibitors of LSD1. Among the synthesized derivatives, 12a exhibited reversible and potent inhibition (IC50  = 0.41 μM) and high selectivity over the MAO-A and MAO-B. Notably, 12a strongly induced differentiation effect on acute promyelocytic leukemia NB4 cell line and distinctly escalated the methylation level on histone 3 lysine 4 (H3K4)...
August 22, 2018: Bioorganic & Medicinal Chemistry
Lara A Zimmermann, Milene H de Moraes, Rafael da Rosa, Eduardo B de Melo, Fávero R Paula, Eloir P Schenkel, Mario Steindel, Lílian S C Bernardes
Despite the impressive scientific and technological advances of recent decades, no effective treatment is currently available for Chagas disease. Our research group has been studying the design and synthesis of analogues of natural lignans aiming to identify compounds with antiparasitic activity. This article reports the synthesis of 42 novel bis-heterocyclic derivatives and the structure-activity relationship study conducted based on results of biological assays against Trypanosoma cruzi amastigotes. Thirty-seven compounds were active, and eight of them had GI50 values lower than 100 μM (GI50 88...
August 19, 2018: Bioorganic & Medicinal Chemistry
Shiyang Zhou, Guangying Chen, Gangliang Huang
In the studied a series novel of lazabemide derivatives were designed, synthesized and evaluated as inhibitors of monoamine oxidase (MAO-A or MAO-B). These compounds used lazabemide as the lead compound, and the chemistry structures were modified by used the bioisostere and modification of compound with alkyl principle. The two types of inhibitors (inhibition of MAO-A and inhibition of MAO-B) were screened by inhibition activity of MAO. In vitro experiments showed that compounds 3a, 3d and 3f had intensity inhibition the biological activity of MAO-A, while compounds 3i and 3m had intensity inhibition the biological activity of MAO-B...
August 19, 2018: Bioorganic & Medicinal Chemistry
Liming Chang, Mengwu Xiao, Linlin Yang, Shuai Wang, Sai-Qi Wang, Andreas Bender, Aixi Hu, Zhe-Sheng Chen, Bin Yu, Hong-Min Liu
Multidrug resistance (MDR) has been shown to reduce the effectiveness of chemotherapy. Strategies to overcoming MDR have been widely explored in the last decades, leading to a generation of numerous small molecules targeting ABC and MRP transporters. Among the ABC family, ABCB1 plays key roles in the development of drug resistance and is the most well studied. In this work, we report the discovery of a non-toxic [1,2,4]triazolo[1,5-a]pyrimidin-7-one (WS-10) from our structurally diverse in-house compound collection that selectively modulates ABCB1-mediated multidrug resistance...
August 18, 2018: Bioorganic & Medicinal Chemistry
Maddie R Lemieux, Shajila Siricilla, Katsuhiko Mitachi, Shakiba Eslamimehr, Yuehong Wang, Dong Yang, Jeffrey D Pressly, Ying Kong, Frank Park, Scott G Franzblau, Michio Kurosu
Pleuromutilin is a promising pharmacophore to design new antibacterial agents for Gram-positive bacteria. However, there are limited studies on the development of pleuromutilin analogues that inhibit growth of Mycobacterium tuberculosis (Mtb). In screening of our library of pleuromutilin derivatives, UT-800 (1) was identified to kill replicating- and non-replicating Mtb with the MIC values of 0.83 and 1.20 μg/mL, respectively. UT-800 also kills intracellular Mtb faster than rifampicin at 2× MIC concentrations...
August 18, 2018: Bioorganic & Medicinal Chemistry
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