83948-54-3Relevant academic research and scientific papers
Molecular Basis for the Selective Inhibition of Histone Deacetylase 6 by a Mercaptoacetamide Inhibitor
Porter, Nicholas J.,Shen, Sida,Barinka, Cyril,Kozikowski, Alan P.,Christianson, David W.
, p. 1301 - 1305 (2018)
Mercaptoacetamide histone deacetylase inhibitors are neuroprotective agents that do not exhibit the genotoxicity associated with more commonly used hydroxamate inhibitors. Here, we present the crystal structure of a selective mercaptoacetamide complexed w
QUINOLYL-CONTAINING COMPOUND AND PHARMACEUTICAL COMPOSITION, AND USE THEREOF
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, (2022/02/19)
Provided is a quinolyl-containing compound as shown in general formula (I) or (II) or a pharmaceutically acceptable salt, a solvate, an active metabolite, a polymorph, an isotopic label, or an isomer thereof, and further provided are a pharmaceutical composition comprising the compound and use of the compound and the pharmaceutical composition. The provided compound has a dual molecule function, can serve as multi -target inhibitors of novel tyrosine kinase/histone deacetylase, can simultaneously achieve the effect of two inhibitors, has excellent biological activity and pharmacokinetic properties, and has the application potential particularly in the field of treatment of tumors.
Thiol- And Disulfide-Containing Vancomycin Derivatives against Bacterial Resistance and Biofilm Formation
Gademann, Karl,Shchelik, Inga S.
supporting information, p. 1898 - 1904 (2021/11/16)
Antibiotic-resistant and biofilm-associated infections constitute a rapidly growing issue. Use of the last-resort antibiotic vancomycin is under threat due to the increasing appearance of vancomycin-resistant bacteria as well as the formation of biofilms. Herein, we report a series of novel vancomycin derivatives carrying thiol- and disulfide-containing moieties. The new compounds exhibited enhanced antibacterial activity against a broad range of bacterial strains, including vancomycin-resistant microbes and Gram-negative bacteria. Moreover, all obtained derivatives demonstrated improved antibiofilm formation activity against VanB-resistant Enterococcus compared to vancomycin. This work establishes a promising strategy for combating drug-resistant bacterial infections or disrupting biofilm formation and advances the knowledge on the structural optimization of antibiotics with sulfur-containing modifications.
Dual nicotinamide phosphoribosyltransferase and epidermal growth factor receptor inhibitors for the treatment of cancer
Zhang, Wanheng,Zhang, Kuojun,Yao, Yiwu,Liu, Yunyao,Ni, Yong,Liao, Chenzhong,Tu, Zhengchao,Qiu, Yatao,Wang, Dexiang,Chen, Dong,Qiang, Lei,Li, Zheng,Jiang, Sheng
, (2020/11/27)
Multitarget drugs have emerged as a promising treatment modality in modern anticancer therapy. Taking advantage of the synergy of NAMPT and EGFR inhibition, we have developed the first compounds that serve as dual inhibitors of NAMPT and EGFR. On the basis of CHS828 and erlotinib, a series of hybrid molecules were successfully designed and synthesized by merging of the pharmacophores. Among the compounds that were synthesized, compound 28 showed good NAMPT and EGFR inhibition, and excellent in vitro anti-proliferative activity. Compound 28, which is a new chemotype devoid of a Michael receptor, strongly inhibited the proliferation of several cancer cell lines, including H1975 non-small cell lung cancer cells harboring the EGFRL858R/T790M mutation. More importantly, it imparted significant in vivo antitumor efficacy in a human NSCLC (H1975) xenograft nude mouse model. This study provides promising leads for the development of novel antitumor agents and valuable pharmacological probes for the assessment of dual inhibition in NAMPT and EGFR pathway with a single inhibitor.
ISOINDOLINE DERIVATIVES WHICH BIND TO AN ATP BINDING SITE
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, (2021/07/31)
The present invention relates to novel probe compounds of formulae I and II defined herein. The present invention also relates to methods of synthesising these novel probe compounds and to their use in assays and screens for determining the binding of a test molecule to the ATP-binding site of a target protein, such as, for example, the Mismatch Repair (MMR) component proteins PMS2 and MLH1, or for determining the location and/or quantity of such target proteins in a biological sample.
A bicyclic pentapeptide-based highly potent and selective pan-SIRT1/2/3 inhibitor harboring Nε-thioacetyl-lysine
Li, Renwu,Sun, Xun,Yan, Lingling,Zheng, Weiping
, (2020/02/22)
Past few years have seen an active pursuit of the inhibitors for the deacylation catalyzed by the seven human sirtuins (i.e. SIRT1-7) as valuable chemical biological/pharmacological probes of this enzymatic deacylation and lead compounds for developing novel therapeutics for human diseases. In the current study, we prepared eight monocyclic and one bicyclic analogs of a linear pentapeptide-based potent (sub-μM IC50’s) pan-SIRT1/2/3 inhibitor Zheng laboratory discovered recently that harbors the catalytic mechanism-based SIRT1/2/3 inhibitory warhead Nε-thioacetyl-lysine at its central position. We found that the bicyclic analog exhibited largely comparable SIRT1/2/3 inhibitory potencies to those of the parent linear pentapeptide, however, the former is proteolytically much more stable than the latter. Moreover, the bicyclic analog displayed very weak inhibition against SIRT5/6/7, was cell permeable, and exhibited an anti-proliferative effect on the human SK-MEL-2 melanoma cells. This bicyclic analog could be a lead for the future development of more potent and still selective pan-SIRT1/2/3 inhibitors whose use in studies on human sirtuin biology, pharmacology, and medicinal chemistry could complement with the use of the potent inhibitors selective for a single human sirtuin.
Membrane Phospholipid Analogues as Molecular Rulers to Probe the Position of the Hydrophobic Contact Point of Lysophospholipid Ligands on the Surface of G-Protein-Coupled Receptor during Membrane Approach
Aoki, Junken,Inoue, Asuka,Ohwada, Tomohiko,Otani, Yuko,Sayama, Misa,Sekijima, Masakazu,Uwamizu, Akiharu
, p. 1173 - 1201 (2020/04/10)
When lipid mediators bind to G-protein-coupled receptors (GPCRs), the ligand first enters the lipid bilayer, then diffuses laterally in the cell membrane to make hydrophobic contact with the receptor protein, and finally enters the receptor's binding pock
Preparation of bivalent agonists for targeting the mu opioid and cannabinoid receptors
Dvorácskó, Szabolcs,Keresztes, Attila,Mollica, Adriano,Stefanucci, Azzurra,Macedonio, Giorgia,Pieretti, Stefano,Zádor, Ferenc,Walter, Fruzsina R.,Deli, Mária A.,Kékesi, Gabriella,Bánki, László,Tuboly, Gábor,Horváth, Gy?ngyi,T?mb?ly, Csaba
, p. 571 - 588 (2019/06/19)
In order to obtain novel pharmacological tools and to investigate a multitargeting analgesic strategy, the CB1 and CB2 cannabinoid receptor agonist JWH-018 was conjugated with the opiate analgesic oxycodone or with an enkephalin related tetrapeptide. The opioid and cannabinoid pharmacophores were coupled via spacers of different length and chemical structure. In vitro radioligand binding experiments confirmed that the resulting bivalent compounds bound both to the opioid and to the cannabinoid receptors with moderate to high affinity. The highest affinity bivalent derivatives 11 and 19 exhibited agonist properties in [35S]GTPγS binding assays. These compounds activated MOR and CB (11 mainly CB2, whereas 19 mainly CB1) receptor-mediated signaling, as it was revealed by experiments using receptor specific antagonists. In rats both 11 and 19 exhibited antiallodynic effect similar to the parent drugs in 20 μg dose at spinal level. These results support the strategy of multitargeting G-protein coupled receptors to develop lead compounds with antinociceptive properties.
SYNTHETIC RECEPTORS FOR IONOPHORIC COMPOUNDS
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, (2019/09/18)
The present invention relates to synthetic receptors for ionophoric compounds, such as ionophoric toxins. Hence, the invention provides synthetic molecules capable of binding different ionophoric compounds, thereby being suitable for use in the detection,
An Affinity-Based Probe for the Human Adenosine A2A Receptor
Yang, Xue,Michiels, Thomas J. M.,De Jong, Coen,Soethoudt, Marjolein,Dekker, Niek,Gordon, Euan,Van Der Stelt, Mario,Heitman, Laura H.,Van Der Es, Daan,Ijzerman, Adriaan P.
, p. 7892 - 7901 (2018/09/06)
Using activity-based protein profiling (ABPP), functional proteins can be interrogated in their native environment. Despite their pharmaceutical relevance, G protein-coupled receptors (GPCRs) have been difficult to address through ABPP. In the current study, we took the prototypical human adenosine A2A receptor (hA2AR) as the starting point for the construction of a chemical toolbox allowing two-step affinity-based labeling of GPCRs. First, we equipped an irreversibly binding hA2AR ligand with a terminal alkyne to serve as probe. We showed that our probe irreversibly and concentration-dependently labeled purified hA2AR. Click-ligation with a sulfonated cyanine-3 fluorophore allowed us to visualize the receptor on SDS-PAGE. We further demonstrated that labeling of the purified hA2AR by our probe could be inhibited by selective antagonists. Lastly, we showed successful labeling of the receptor in cell membranes overexpressing hA2AR, making our probe a promising affinity-based tool compound that sets the stage for the further development of probes for GPCRs.
