摘要：
Indole represents one of the most important privileged scaffolds in drug discovery. Indole derivatives have the unique property of mimicking the structure of peptides and to bind reversibly to enzymes, which provide tremendous opportunities to discover novel drugs with different modes of action. There are seven indole-containing commercial drugs in the Top-200 Best Selling Drugs by US Retail Sales in 2012. There are also an amazing number of approved indole-containing drugs in the market as well as compounds currently going through different clinical phases or registration statuses. This review focused on the recent development of indole derivatives as antiviral agents with the following objectives: 1) To present one of the most comprehensive listings of indole antiviral agents, drugs on market or compounds in clinical trials; 2) To focus on recent developments of indole compounds (including natural products) and their antiviral activities, summarize the structure property, hoping to inspire new and even more creative approaches; 3) To offer perspectives on how indole scaffolds as a privileged structure might be exploited in the future. (C) 2014 Elsevier Masson SAS. All rights reserved.
期刊：
Journal of Medicinal Chemistry,2016年59(21):9575-9598 ISSN：0022-2623
通讯作者：
Miao, ZH;Zhang, A
作者机构：
[Miao, Ze-Hong; Wang, Ying-Qing; Wang, Yu-Ting] Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Div Antitumor Pharmacol, Shanghai 201203, Peoples R China.;[Zhang, Ao; Wang, Ping-Yuan] Chinese Acad Sci, Shanghai Inst Mat Med, CAS Key Lab Receptor Res, 555 Zuchongzhi Lu,Bldg 3,Room 426, Shanghai 201203, Peoples R China.;[Zhang, Ao; Wang, Ping-Yuan] Chinese Acad Sci, Shanghai Inst Mat Med, Synthet Organ & Med Chem Lab, 555 Zuchongzhi Lu,Bldg 3,Room 426, Shanghai 201203, Peoples R China.;[Yang, Guang-Fu; Wang, Ping-Yuan] Cent China Normal Univ, Coll Chem, Key Lab Pesticide & Chem Biol, Minist Educ, Wuhan 430079, Peoples R China.
通讯机构：
CAS Key Laboratory of Receptor Research, Synthetic Organic and Medicinal Chemistry Laboratory, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Building 3, 555 Zuchongzhi Lu, Pudong, Shanghai, China
摘要：
Poly(ADP-ribose)polymerase-1 (PARP-1) is a critical DNA repair enzyme in the base excision repair pathway. Inhibitors of this enzyme comprise a new type of anticancer drug that selectively kills cancer cells by targeting homologous recombination repair defects. Since 2010, important advances have been achieved in PARP-1 inhibitors. Specifically, the approval of olaparib in 2014 for the treatment of ovarian cancer with BRCA mutations validated PARP-1 as an anticancer target and established its clinical importance in cancer therapy. Here, we provide an update on PARP-1 inhibitors, focusing on breakthroughs in their clinical applications and investigations into relevant mechanisms of action, biomarkers, and drug resistance. We also provide an update on the design strategies and the structural types of PARP-1 inhibitors. Opportunities and challenges in PARP-1 inhibitors for cancer therapy will be discussed based on the above advances.
摘要：
On the basis of the principle of combination of active structural moieties, a modified and efficient synthetic method for three series of novel indole-based 1,3,4-oxadiazoles is described. Bioassays conducted at Syngenta showed that several of the synthesized compounds exhibit higher antifungal activity than pimprinine, the natural product which inspired this synthesis. Two main structural-alterations were found to broaden the spectrum of biological activity in most cases. Compounds 3g, 6c, 6e, 6h, 9d, 9e, 9h and 9m (Fig. 1) were identified as the most active on the biological assays, and will be studied further. (c) 2013 Elsevier Masson SAS. All rights reserved.
摘要：
Exploring small-molecule acetylcholinesterase (AChE) inhibitors to slow the breakdown of acetylcholine (Ach) represents the mainstream direction for Alzheimer's disease (AD) therapy. As the first acetylcholinesterase inhibitor approved for the clinical treatment of AD, tacrine has been widely used as a pharmacophore to design hybrid compounds in order to combine its potent AChE inhibition with other multi-target profiles. In present study, a series of novel tacrine-coumarin hybrids were designed, synthesized and evaluated as potent dual-site AChE inhibitors. Moreover, compound 1g was identified as the most potent candidate with about 2-fold higher potency (K-i = 16.7 nM) against human AChE and about 2-fold lower potency (K-i = 16.1 nM) against BChE than tacrine (K-i = 35.7 nM for AChE, K-i = 8.7 nM for BChE), respectively. In addition, some of the tacrine-coumarin hybrids showed simultaneous inhibitory effects against both A beta aggregation and beta-secretase. We therefore conclude that tacrine-coumarin hybrid is an interesting multifunctional lead for the AD drug discovery. (C) 2014 Elsevier Ltd. All rights reserved.
通讯机构：
Key Laboratory of Pesticide and Chemical Biology of Ministry of Education, College of Chemistry, Central China Normal University, Wuhan, China
关键词：
herbicide;4-hydroxyphenylpyruvate dioxygenase;quinazoline-2;4-dione;structure-activity relationship;weed control
摘要：
BACKGROUND4-Hydroxyphenylpyruvate dioxygenase (HPPD) (EC 1.13.11.27) has been identified as one of the most promising target sites for herbicide discovery. To discover novel HPPD inhibitors with high herbicidal activity and improved crop selectivity, a series of novel triketone-containing quinazoline-2,4-dione derivatives possessing a variety of substituents at the N-1 position of the quinazoline-2,4-dione ring were designed and synthesised. RESULTSThe results of in vitro tests and greenhouse experiments indicated that some analogues showed good HPPD inhibitory activity, with promising broad-spectrum herbicidal activity at a rate of 150g AI ha(-1). Most surprisingly, compound 11h, 1-ethyl-6-(2-hydroxy-6-oxocyclohex-1-enecarbonyl)-3-(o-tolyl)quinazoline-2,4(1H,3H)-dione, showed the highest HPPD inhibition activity, with a K-i value of 0.005 M, about 2 times more potent than mesotrione (K-i=0.013 M). Further greenhouse experiments indicated that compounds 11d and 11h displayed strong and broad-spectrum post-emergent herbicidal activity even at a dosage as low as 37.5g AI ha(-1), which was superior to mesotrione. More importantly, compounds 11d and 11h were safe for maize at a rate of 150g AI ha(-1), and compound 11d was safe for wheat as well. CONCLUSIONThe present work indicated that the triketone-containing quinazoline-2,4-dione motif could be a potential lead structure for further development of novel herbicides. (c) 2014 Society of Chemical Industry
作者机构：
[Yang, Guang-Fu; Yang, Wen-Chao; Sun, Qi; Yang, Shu-Hou; Wu, Lei] Cent China Normal Univ, Coll Chem, Key Lab Pesticide & Chem Biol, Minist Educ, Wuhan 430079, Peoples R China.;[Dong, Qing-Jian] Huazhong Univ Sci & Technol, Tongji Hosp, Dept Nucl Med, Tongji Med Coll, Wuhan 430030, Peoples R China.
通讯机构：
Key Laboratory of Pesticide and Chemical Biology, Ministry of Education, College of Chemistry, Central China Normal University, Wuhan, China
摘要：
Selenocysteine (Sec), encoded as the 21st amino acid, is the predominant chemical form of selenium that is closely related to various human diseases. Thus, it is of high importance to identify novel probes for sensitive and selective recognition of Sec and Sec-containing proteins. Although a few probes have been reported to detect artificially introduced selenols in cells or tissues, none of them has been shown to be sensitive enough to detect endogenous selenols. We report the characterization and application of a new fluorogenic molecular probe for the detection of intracellular selenols. This probe exhibits near-zero background fluorescence but produces remarkable fluorescence enhancement upon reacting with selenols in a fast chemical reaction. It is highly specific and sensitive for intracellular selenium-containing molecules such as Sec and selenoproteins. When combined with flow cytometry, this probe is able to detect endogenous selenols in various human cancer cells. It is also able to image endogenous selenol-containing molecules in zebrafish under a fluorescence microscope. These results demonstrate that this molecular probe can function as a useful molecular tool for intracellular selenol sensing, which is valuable in the clinical diagnosis for human diseases associated with Sec-deficiency or overdose.
期刊：
Drug Discovery Today,2012年17(19-20):1121-1126 ISSN：1359-6446
通讯作者：
Yang, G.-F.
作者机构：
[Guang-Fu Yang; Ge-Fei Hao] Cent China Normal Univ, Coll Chem, Minist Educ, Key Lab Pesticide & Chem Biol, Wuhan 430079, Peoples R China.;[Chang-Guo Zhan] Univ Kentucky, Coll Pharm, Dept Pharmaceut Sci, Lexington, KY 40536 USA.
通讯机构：
Key Laboratory of Pesticide and Chemical Biology of Ministry of Education, College of Chemistry, Central China Normal University, China
摘要：
Drug resistance has become one of the biggest challenges in drug discovery and/or development and has attracted great research interests worldwide. During the past decade, computational strategies have been developed to predict target mutation-induced drug resistance. Meanwhile, various molecular design strategies, including targeting protein backbone, targeting highly conserved residues and dual/multiple targeting, have been used to design novel inhibitors for combating the drug resistance. In this article we review recent advances in development of computational methods for target mutation-induced drug resistance prediction and strategies for rational design of novel inhibitors that could be effective against the possible drug-resistant mutants of the target.
期刊：
The FASEB Journal,2011年25(2):653-664 ISSN：0892-6638
通讯作者：
Xi, Z.
作者机构：
[Qin, Xiaohong; Shen, Yuequan; Wang, Lele] Nankai Univ, Coll Life Sci, Tianjin 300071, Peoples R China.;[Wang, Baifan; Xi, Zhen; Wen, Xin; Tan, Ying; Wang, Zhifang] Nankai Univ, State Key Lab Elementoorgan Chem, Dept Biol Chem, Coll Chem, Tianjin 300071, Peoples R China.;[Yang, Guangfu; Tan, Ying] Cent China Normal Univ, Key Lab Pesticide & Chem Biol, Minist Educ, Coll Chem, Wuhan, Peoples R China.
通讯机构：
Department of Chemical Biology, College of Chemistry, Nankai University, China
关键词：
protoporphyrinogen IX oxidase;mitochondrial inner membrane protein;VP‐causing mutations;FAD‐containing enzyme
摘要：
Human protoporphyrinogen IX oxidase (hPPO), a mitochondrial inner membrane protein, converts protoporphyrinogen IX to protoporphyrin IX in the heme biosynthetic pathway. Mutations in the hPPO gene cause the inherited human disease variegate porphyria (VP). In this study, we report the crystal structure of hPPO in complex with the coenzyme flavin adenine dinucleotide (FAD) and the inhibitor acifluorfen at a resolution of 1.9 angstrom. The structural and biochemical analyses revealed the molecular details of FAD and acifluorfen binding to hPPO as well as the interactions of the substrate with hPPO. Structural analysis and gel chromatography indicated that hPPO is a monomer rather than a homodimer in vitro. The founder-effect mutation R59W in VP patients is most likely caused by a severe electrostatic hindrance in the hydrophilic binding pocket involving the bulky, hydrophobic indolyl ring of the tryptophan. Forty-seven VP-causing mutations were purified by chromatography and kinetically characterized in vitro. The effect of each mutation was demonstrated in the high-resolution crystal structure.-Qin, X., Tan, Y., Wang, L., Wang, Z., Wang, B., Wen, X., Yang, G., Xi, Z., Shen, Y. Structural insight into human variegate porphyria disease. FASEB J. 25, 653-664 (2011). www.fasebj.org
