3507-37-7Relevant academic research and scientific papers
IRAK DEGRADERS AND USES THEREOF
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Paragraph 00803; 00268-00270, (2021/06/26)
The present invention provides compounds, compositions thereof, and methods of using the same.
Exploration of Benzothiazole Rhodacyanines as Allosteric Inhibitors of Protein-Protein Interactions with Heat Shock Protein 70 (Hsp70)
Shao, Hao,Li, Xiaokai,Moses, Michael A.,Gilbert, Luke A.,Kalyanaraman, Chakrapani,Young, Zapporah T.,Chernova, Margarita,Journey, Sara N.,Weissman, Jonathan S.,Hann, Byron,Jacobson, Matthew P.,Neckers, Len,Gestwicki, Jason E.
, p. 6163 - 6177 (2018/07/09)
Cancer cells rely on the chaperone heat shock protein 70 (Hsp70) for survival and proliferation. Recently, benzothiazole rhodacyanines have been shown to bind an allosteric site on Hsp70, interrupting its binding to nucleotide-exchange factors (NEFs) and promoting cell death in breast cancer cell lines. However, proof-of-concept molecules, such as JG-98, have relatively modest potency (EC50 ≈ 0.7-0.4 μM) and are rapidly metabolized in animals. Here, we explored this chemical series through structure- and property-based design of ～300 analogs, showing that the most potent had >10-fold improved EC50 values (～0.05 to 0.03 μM) against two breast cancer cells. Biomarkers and whole genome CRISPRi screens confirmed members of the Hsp70 family as cellular targets. On the basis of these results, JG-231 was found to reduce tumor burden in an MDA-MB-231 xenograft model (4 mg/kg, ip). Together, these studies support the hypothesis that Hsp70 may be a promising target for anticancer therapeutics.
Design, synthesis and biological evaluation of novel unsymmetrical azines as quorum sensing inhibitors
Chourasiya, Sumit S.,Kathuria, Deepika,Singh, Shaminder,Sonawane, Vijay C.,Chakraborti, Asit K.,Bharatam, Prasad V.
, p. 80027 - 80038 (2015/10/05)
Targeting quorum sensing signals using quorum sensing inhibitors has opened new avenues for the application of known antibiotics. In this context, twenty five unsymmetrical azines were synthesised and evaluated as quorum sensing inhibitors. An efficient one-pot procedure was adopted that directly links 3-methyl-2-(methylthio)benzo[d]thiazol-3-ium salt, hydrazine hydrate and substituted aldehyde to give the designed compounds. The synthesized compounds were preliminarily tested for their potential to inhibit CviR receptor based QS signals in Chromobacterium violaceum. The bioassay screening results suggested that two compounds exhibited potent QS inhibition activity against CviR receptor, showing violacein inhibition (>50%) at 200 μM. Further, the putative positive hits were checked for their potential to inhibit LasR receptor-based QS using the PlasB-gfp(ASV) biomonitor strain of Pseudomonas aeruginosa. These compounds were found to inhibit the QS-mediated GFP signals in a dose dependant manner. Two active compounds also exhibited biofilm clearance at 50 μM concentration. Docking studies were performed to examine their potential to bind to the LasR protein of Pseudomonas aeruginosa.
Analogues of the allosteric heat shock protein 70 (Hsp70) inhibitor, MKT-077, as anti-cancer agents
Li, Xiaokai,Srinivasan, Sharan R.,Connarn, Jamie,Ahmad, Atta,Young, Zapporah T.,Kabza, Adam M.,Zuiderweg, Erik. R. P.,Sun, Duxin,Gestwicki, Jason E.
supporting information, p. 1042 - 1047 (2013/12/04)
The rhodacyanine, MKT-077, has antiproliferative activity against cancer cell lines through its ability to inhibit members of the heat shock protein 70 (Hsp70) family of molecular chaperones. However, MKT-077 is rapidly metabolized, which limits its use as either a chemical probe or potential therapeutic. We report the synthesis and characterization of MKT-077 analogues designed for greater stability. The most potent molecules, such as 30 (JG-98), were at least 3-fold more active than MKT-077 against the breast cancer cell lines MDA-MB-231 and MCF-7 (EC50 values of 0.4 ± 0.03 and 0.7 ± 0.2 μM, respectively). The analogues modestly destabilized the chaperone clients, Akt1 and Raf1, and induced apoptosis in these cells. Further, the microsomal half-life of JG-98 was improved at least 7-fold (t1/2 = 37 min) compared to MKT-077 (t1/2 5 min). Finally, NMR titration experiments suggested that these analogues bind an allosteric site that is known to accommodate MKT-077. These studies advance MKT-077 analogues as chemical probes for studying Hsp70s roles in cancer.
2-[3H-THIAZOL-2-YLIDINEMETHYL]PYRIDINES AND RELATED COMPOUNDS AND THEIR USE
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Page/Page column 37, (2009/10/06)
The present invention pertains to certain 2-[3H-thiazol-2-ylidinemethyl]pyridine compounds and analogs thereof, which, inter alia, inhibit cell proliferation, treat cancer, etc., and more specifically to compounds of the following formula, wherein RA1, RA2, RA3, RA4, RB1, RB2, RNA, RNB, and X? are as defined herein: The present invention also pertains to pharmaceutical compositions comprising such compounds, and the use of such compounds and compositions, both in vitro and in vivo, to inhibit cell proliferation, and in the treatment of proliferative conditions such as cancer, etc.
Cycloaddition reactions of thiazolium azomethine ylides: Application to pyrrolo[2,1-b]thiazoles
Berry, Craig R.,Zificsak, Craig A.,Gibbs, Alan C.,Hlasta, Dennis J.
, p. 4099 - 4102 (2008/03/11)
Thiazolium azomethine ylides, equipped with a C-2 methanethiol group, participate in an efficient [3 + 2] cycloaddition reaction with acetylene derivatives to yield unique pyrrolo[2,1-b]thiazoles. The elimination of the methanethiol leaving group from the cycloadduct has replaced the need for a separate oxidation step and suppresses ring-opening side reactions. Products were obtained in short synthetic sequences to demonstrate their use as a scaffold for compound libraries.
