35418-07-6Relevant academic research and scientific papers
A convenient method for the synthesis of Troger's base analogues
Gopal Bag,Maitra
, p. 1849 - 1856 (1995)
Para substituted anilines have been converted to Troger's base analogues by refluxing with a mixture of methylal and methanesulfonic acid.
NMDA RECEPTOR ANTAGONISTS FOR NEUROPROTECTION
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Paragraph 0183, (2021/03/18)
Provided are compounds, pharmaceutical compositions and methods of treatment or prophylaxis of disorders associated with NMDA receptor activity, including neuropathic pain, stroke, traumatic brain injury, epilepsy, and related neurologic events or neurode
IN VITRO METHOD FOR DETECTION OF INFECTIONS CAUSED BY PSEUDOMONAS AERUGINOSA
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Page/Page column 12-14, (2021/10/11)
In vitro method for detection of infections caused by pseudomonas aeruginosa. The present invention relates to compounds of general Formula (I) and to their use as haptens. Moreover, the present invention also refers to conjugates comprising the haptens of the invention and to their use for obtaining antibodies. Finally, the invention also relates to an in vitro method for the detection of infections caused by Pseudomonas aeruginosa by means of the identification and/or quantification of the main signaling molecules from the pqs quorum sensing system.
Chemical Genetics Reveals a Role of Squalene Synthase in TGFβ Signaling and Cardiomyogenesis
Takemoto, Yasushi,Kadota, Shin,Minami, Itsunari,Otsuka, Shinya,Okuda, Satoshi,Abo, Masahiro,Punzalan, Louvy Lynn,Shen, Yan,Shiba, Yuji,Uesugi, Motonari
supporting information, p. 21824 - 21831 (2021/08/30)
KY02111 is a widely used small molecule that boosts cardiomyogenesis of the mesoderm cells derived from pluripotent stem cells, yet its molecular mechanism of action remains elusive. The present study resolves the initially perplexing effects of KY02111 on Wnt signaling and subsequently identifies squalene synthase (SQS) as a molecular target of KY02111 and its optimized version, KY-I. By disrupting the interaction of SQS with cardiac ER-membrane protein TMEM43, KY02111 impairs TGFβ signaling, but not Wnt signaling, and thereby recapitulates the clinical mutation of TMEM43 that causes arrhythmogenic right ventricular cardiomyopathy (ARVC), an inherited heart disease that involves a substitution of myocardium with fatty tissue. These findings reveal a heretofore undescribed role of SQS in TGFβ signaling and cardiomyogenesis. KY02111 may find its use in ARVC modeling as well as serve as a chemical tool for studying TGFβ/SMAD signaling.
(PYRIDIN-2-YL)AMINE DERIVATIVES AS TGF-BETA R1 (ALK5) INHIBITORS FOR THE TREATMENT OF CANCER
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Paragraph 00287-00288; 00295, (2020/07/15)
The present invention relates to pharmaceutical compounds, compositions and methods, especially as they are related to compositions and methods for the treatment and/or prevention of a proliferation disorder associated with ΤGFβR1 activity, such as a cancer or fibrosis. The invention provides compounds of Formula (I) and Formula (II) as further described herein having an acidic moiety that enhances tissue specificity for targeted tissues and organs. The invention includes pharmaceutical compositions, pharmaceutical combinations, and methods of use of these compounds for treating conditions including cancer or fibrosis.
Design, synthesis and biological evaluation of curcumin analogues as novel LSD1 inhibitors
Wang, Jiming,Zhang, Xiangyu,Yan, Jiangkun,Li, Wei,Jiang, Qinwen,Wang, Xinran,Zhao, Dongmei,Cheng, Maosheng
supporting information, (2019/10/22)
Histone lysine-specific demethylase 1 (LSD1) was the first discovered histone demethylase. Inactivating LSD1 or downregulating its expression inhibits cancer-cell development, and thus, it is an attractive molecular target for the development of novel cancer therapeutics. In this study, we worked on the structural optimization of natural products and identified 30 novel LSD1 inhibitors. Utilizing a structure-based drug design strategy, we designed and synthesized a series of curcumin analogues that were shown to be potent LSD1 inhibitors in the enzyme assay. Compound WB07 displayed the most potent LSD1 inhibitory activity, with an IC50 value of 0.8 μM. Moreover, WA20 showed an anticlonogenic effect on A549 cells with an IC50 value of 4.4 μM. Molecular docking simulations were also carried out, and the results indicated that the inhibitors bound to the protein active site located around the key residues of Asp555 and Asp556. These findings suggested that compounds WA20 and WB07 are the first curcumin analogue-based LSD1 inhibitors with remarkable A549 suppressive activity, providing a novel scaffold for the development of LSD1 inhibitors.
De Novo Design of Bioactive Small Molecules by Artificial Intelligence
Merk, Daniel,Friedrich, Lukas,Grisoni, Francesca,Schneider, Gisbert
, (2018/02/21)
Generative artificial intelligence offers a fresh view on molecular design. We present the first-time prospective application of a deep learning model for designing new druglike compounds with desired activities. For this purpose, we trained a recurrent neural network to capture the constitution of a large set of known bioactive compounds represented as SMILES strings. By transfer learning, this general model was fine-tuned on recognizing retinoid X and peroxisome proliferator-activated receptor agonists. We synthesized five top-ranking compounds designed by the generative model. Four of the compounds revealed nanomolar to low-micromolar receptor modulatory activity in cell-based assays. Apparently, the computational model intrinsically captured relevant chemical and biological knowledge without the need for explicit rules. The results of this study advocate generative artificial intelligence for prospective de novo molecular design, and demonstrate the potential of these methods for future medicinal chemistry.
Design, synthesis and structure–activity relationship studies of novel free fatty acid receptor 1 agonists bearing amide linker
Yang, Jianyong,Li, Zheng,Li, Huilan,Liu, Chunxia,Wang, Nasi,Shi, Wei,Liao, Chen,Cai, Xingguang,Huang, Wenlong,Qian, Hai
supporting information, p. 2445 - 2450 (2017/04/03)
The free fatty acid receptor 1 (FFA1/GPR40) has attracted extensive attention as a novel antidiabetic target. Aiming to explore the chemical space of FFA1 agonists, a new series of lead compounds with amide linker were designed and synthesized by combining the scaffolds of NIH screened lead compound 1 and GW9508. Among them, the optimal lead compound 17 exhibited a considerable agonistic activity (45.78%) compared to the NIH screened compound 1 (15.32%). During OGTT in normal mice, the compound 17 revealed a significant glucose-lowering effect (?23.7%) at the dose of 50?mg/kg, proximity to the hypoglycemic effect (?27.8%) of Metformin (200?mg/kg). In addition, the compound 17 (100?mg/kg) also exhibited a significant improvement in glucose tolerance with a 29.1% reduction of glucose AUC0–2?h in type 2 diabetic mice. All of these results indicated that compound 17 was considered to be a promising lead structure suitable for further optimization.
Light-Controlled Histone Deacetylase (HDAC) Inhibitors: Towards Photopharmacological Chemotherapy
Szymanski, Wiktor,Ourailidou, Maria E.,Velema, Willem A.,Dekker, Frank J.,Feringa, Ben L.
supporting information, p. 16517 - 16524 (2015/11/09)
Cancer treatment suffers from limitations that have a major impact on the patient's quality of life and survival. In the case of chemotherapy, the systemic distribution of cytotoxic drugs reduces their efficacy and causes severe side effects due to nonselective toxicity. Photopharmacology allows a novel approach to address these problems because it employs external, local activation of chemotherapeutic agents by using light. The development of photoswitchable histone deacetylase (HDAC) inhibitors as potential antitumor agents is reported herein. Analogues of the clinically used chemotherapeutic agents vorinostat, panobinostat, and belinostat were designed with a photoswitchable azobenzene moiety incorporated into their structure. The most promising compound exhibits high inhibitory potency in the thermodynamically less stable cis form and a significantly lower activity for the trans form, both in terms of HDAC activity and proliferation of HeLa cells. This approach offers a clear prospect towards local photoactivation of HDAC inhibition to avoid severe side effects in chemotherapy.
Catechol-based substrates of chalcone synthase as a scaffold for novel inhibitors of PqsD
Allegretta, Giuseppe,Weidel, Elisabeth,Empting, Martin,Hartmann, Rolf W.
, p. 351 - 359 (2015/02/19)
A new strategy for treating Pseudomonas aeruginosa infections could be disrupting the Pseudomonas Quinolone Signal (PQS) quorum sensing (QS) system. The goal is to impair communication among the cells and, hence, reduce the expression of virulence factors and the formation of biofilms. PqsD is an essential enzyme for the synthesis of PQS and shares some features with chalcone synthase (CHS2), an enzyme expressed in Medicago sativa. Both proteins are quite similar concerning the size of the active site, the catalytic residues and the electrostatic surface potential at the entrance of the substrate tunnel. Hence, we evaluated selected substrates of the vegetable enzyme as potential inhibitors of the bacterial protein. This similarity-guided approach led to the identification of a new class of PqsD inhibitors having a catechol structure as an essential feature for activity, a saturated linker with two or more carbons and an ester moiety bearing bulky substituents. The developed compounds showed PqsD inhibition with IC50 values in the single-digit micromolar range. The binding mode of these compounds was investigated by Surface Plasmon Resonance (SPR) experiments revealing that their interaction with the protein is not influenced by the presence of the anthranilic acid bound to active site cysteine. Importantly, some compounds reduced the signal molecule production in cellulo.
