16807-37-7Relevant articles and documents
Benzisothiazolinone Derivatives as Potent Allosteric Monoacylglycerol Lipase Inhibitors That Functionally Mimic Sulfenylation of Regulatory Cysteines
Castelli, Riccardo,Scalvini, Laura,Vacondio, Federica,Lodola, Alessio,Anselmi, Mattia,Vezzosi, Stefano,Carmi, Caterina,Bassi, Michele,Ferlenghi, Francesca,Rivara, Silvia,M?ller, Ingvar R.,Rand, Kasper D.,Daglian, Jennifer,Wei, Don,Dotsey, Emmanuel Y.,Ahmed, Faizy,Jung, Kwang-Mook,Stella, Nephi,Singh, Simar,Mor, Marco,Piomelli, Daniele
, p. 1261 - 1280 (2019/12/25)
We describe a set of benzisothiazolinone (BTZ) derivatives that are potent inhibitors of monoacylglycerol lipase (MGL), the primary degrading enzyme for the endocannabinoid 2-arachidonoyl-sn-glycerol (2-AG). Structure-activity relationship studies evaluated various substitutions on the nitrogen atom and the benzene ring of the BTZ nucleus. Optimized derivatives with nanomolar potency allowed us to investigate the mechanism of MGL inhibition. Site-directed mutagenesis and mass spectrometry experiments showed that BTZs interact in a covalent reversible manner with regulatory cysteines, Cys201 and Cys208, causing a reversible sulfenylation known to modulate MGL activity. Metadynamics simulations revealed that BTZ adducts favor a closed conformation of MGL that occludes substrate recruitment. The BTZ derivative 13 protected neuronal cells from oxidative stimuli and increased 2-AG levels in the mouse brain. The results identify Cys201 and Cys208 as key regulators of MGL function and point to the BTZ scaffold as a useful starting point for the discovery of allosteric MGL inhibitors.
Rational design of triplet sensitizers for the transfer of excited state photochemistry from UV to visible
Booker-Milburn, Kevin,Elliott, Luke D.,George, Michael W.,Kayal, Surajit
, p. 14947 - 14956 (2020/10/13)
Time Dependent Density Functional Theory has been used to assist the design and synthesis of a series thioxanthone triplet sensitizers. Calculated energies of the triplet excited state (ET) informed both the type and position of auxochromes placed on the thioxanthone core, enabling fine-tuning of the UV-vis absorptions and associated triplet energies. The calculated results were highly consistent with experimental observation in both the order of the λmax and ET values. The synthesized compounds were then evaluated for their efficacies as triplet sensitizers in a variety of UV and visible light preparative photochemical reactions. The results of this study exceeded expectations; in particular [2 + 2] cycloaddition chemistry that had previously been sensitized in the UV was found to undergo cycloaddition at 455 nm (blue) with a 2- to 9-fold increase in productivity (g/h) relative to input power. This study demonstrates the ability of powerful modern computational methods to aid in the design of successful and productive triplet sensitized photochemical reactions.
Discovery of Ziresovir as a Potent, Selective, and Orally Bioavailable Respiratory Syncytial Virus Fusion Protein Inhibitor
Zheng, Xiufang,Gao, Lu,Wang, Lisha,Liang, Chungen,Wang, Baoxia,Liu, Yongfu,Feng, Song,Zhang, Bo,Zhou, Mingwei,Yu, Xin,Xiang, Kunlun,Chen, Li,Guo, Tao,Shen, Hong C.,Zou, Gang,Wu, Jim Zhen,Yun, Hongying
, p. 6315 - 6329 (2019/07/09)
Ziresovir (RO-0529, AK0529) is reported here for the first time as a promising respiratory syncytial virus (RSV) fusion (F) protein inhibitor that currently is in phase 2 clinical trials. This article describes the process of RO-0529 as a potent, selective, and orally bioavailable RSV F protein inhibitor and highlights the in vitro and in vivo anti-RSV activities and pharmacokinetics in animal species. RO-0529 demonstrates single-digit nM EC50 potency against laboratory strains, as well as clinical isolates of RSV in cellular assays, and more than one log viral load reduction in BALB/c mouse model of RSV viral infection. RO-0529 was proven to be a specific RSV F protein inhibitor by identification of drug resistant mutations of D486N, D489V, and D489Y in RSV F protein and the inhibition of RSV F protein-induced cell-cell fusion in cellular assays.
Scaffold Diversity Inspired by the Natural Product Evodiamine: Discovery of Highly Potent and Multitargeting Antitumor Agents
Wang, Shengzheng,Fang, Kun,Dong, Guoqiang,Chen, Shuqiang,Liu, Na,Miao, Zhenyuan,Yao, Jianzhong,Li, Jian,Zhang, Wannian,Sheng, Chunquan
, p. 6678 - 6696 (2015/09/07)
A critical question in natural product-based drug discovery is how to translate the product into drug-like molecules with optimal pharmacological properties. The generation of natural product-inspired scaffold diversity is an effective but challenging strategy to investigate the broader chemical space and identify promising drug leads. Extending our efforts to the natural product evodiamine, a diverse library containing 11 evodiamine-inspired novel scaffolds and their derivatives were designed and synthesized. Most of them showed good to excellent antitumor activity against various human cancer cell lines. In particular, 3-chloro-10-hydroxyl thio-evodiamine (66c) showed excellent in vitro and in vivo antitumor efficacy with good tolerability and low toxicity. Antitumor mechanism and target profiling studies indicate that compound 66c is the first-in-class triple topoisomerase I/topoisomerase II/tubulin inhibitor. Overall, this study provided an effective strategy for natural product-based drug discovery. (Figure Presented).
Synthesis of a phenolic precursor and its efficient O-[18F] fluoroethylation with purified no-carrier-added [18F]2-fluoroethyl brosylate as the labeling agent
Jarkas, Nashwa,Voll, Ronald J.,Goodman, Mark M.
, p. 539 - 543 (2013/11/06)
[18F]2-Fluoroethyl-p-toluenesulfonate also called [ 18F]2-fluoroethyl tosylate has been widely used for labeling radioligands for positron emission tomography (PET). [18F]2- Fluoroethyl-4-bromobenzenesulfonate, also called [18F]2-fluoroethyl brosylate ([18F]F(CH2)2OBs), was used as an alternative radiolabeling agent to prepare [18F]FEOHOMADAM, a fluoroethoxy derivative of HOMADAM, by O-fluoroethylating the phenolic precursor. Purified by reverse-phase HPLC, the no-carrier-added [ 18F]F(CH2)2OBs was obtained in an average radiochemical yield (RCY) of 35%. The reaction of the purified and dried [ 18F]F(CH2)2OBs with the phenolic precursor was performed by heating in DMF and successfully produced [18F] FEOHOMADAM, after HPLC purification, in RCY of 21%. Copyright
Synthesis and structure activity relationship studies of benzothieno[3,2-b]furan derivatives as a novel class of IKKβ inhibitors
Sugiyama, Hideyuki,Yoshida, Masato,Mori, Kouji,Kawamoto, Tomohiro,Sogabe, Satoshi,Takagi, Terufumi,Oki, Hideyuki,Tanaka, Toshimasa,Kimura, Hiroyuki,Ikeura, Yoshinori
, p. 613 - 624 (2008/02/13)
As a novel class of IKKβ inhibitors, a series of tricyclic furan derivatives was designed and synthesized based on the structure of known thiophene IKKβ inhibitors. Among the various fused furan derivatives synthesized, a benzothieno[3,2-b]furan derivative 13a displayed potent inhibitory activity towards IKKβ in enzymatic and cellular assays. The potent inhibitory activity originates from an intramolecular non-bonded S...O interaction which was confirmed by the X-ray structure of JNK3 with 16k. The introduction of further substituents on the core structure led to the discovery of the 6-alkoxy derivatives, which possessed a comparable IKKβ inhibitory activity to 13a and an improved metabolic stability. Among these, appropriately lipophilic compounds 16a, h, i, and 13g (logD>2) were found to possess good oral bioavailability.
2-(2′-((Dimethylamino)methyl)-4′-(fluoroalkoxy)-phenylthio) benzenamine derivatives as serotonin transporter imaging agents
Parhi, Ajit K.,Wang, Julie L.,Oya, Shunichi,Choi, Seok-Rye,Kung, Mei-Ping,Kung, Hank F.
, p. 6673 - 6684 (2008/09/17)
A novel series of ligands with substitutions at the 5-position on phenyl ring A and at the 4′-position on phenyl ring B of 2-(2′- ((dimethylamino)methyl)-4′-(fluoroalkoxy)phenylthio)benzenamine (4′-2-fluoroethoxy derivatives 28-31 and 4′-3-fluoropropoxy d
Substituent effects on the reactivity of benzo-1,2-dithiolan-3-one 1-oxides and their possible application to the synthesis of DNA-targeting drugs
Sawwan, Nahed,Brzostowska, Edyta M.,Greer, Alexander
, p. 6968 - 6971 (2007/10/03)
The efficiency of polysulfane product generation has been investigated for n-propyl thiol reactions with ortho- and para-substituted benzo-1,2-dithiolan-3- one 1-oxides in acetonitrile-water (7:3) mixtures. The reaction is facilitated by reducing the electron density at the para position or by placing substituents bearing lone pair electrons ortho to the dithiolanone-oxide (S1) reaction center. Through-space and through-bond effects both contribute to the conversion of polysulfane products.
Benzothiopyranoindazoles, a new class of chromophore modified anthracenedione anticancer agents. Synthesis and activity against murine leukemias
Hollis Showalter,Angelo,Berman,Kanter,Ortwine,Ross-Kesten,Sercel,Turner,Werbel,Worth,Elslager,Leopold,Shillis
, p. 1527 - 1539 (2007/10/02)
The synthesis of the benzothiopyranoindazoles (3), a new class of chromophore modified anthracenediones related to mitoxantrone (1), is described. In this structural class the quinone moiety, which is believed to be responsible for the cardiotoxicity of t
Analogues of hycanthone and lucanthone as antitumor agents
Archer,Zayed,Rej,Rugino
, p. 1240 - 1246 (2007/10/02)
Hycanthone analogues (5 and 6) containing 7-substituted hydroxyl groups were prepared and evaluated as antitumor agents. These compounds were significantly more active than the corresponding unsubtituted derivatives. The 7-hydroxylated-4-(hydroxymethyl)-9H-xanthen-9-ones, 11 and 12, were also active antitumor agents. However, the 7-hydroxy-9H-xanthen-9-one counterparts of the 7-hydroxylucanthones were totally devoid of antitumor activity. Results obtained thus far are consistent with the hypothesis that 4-hydroxymethyl substituents in the 9H-xanthen-9-one and 9H-thioxanthen-9-one series are required for antitumor activity.
