@article{9312bd2abfee4075a24891b875cf3478,
title = "Design, synthesis, and pharmacological evaluations of pyrrolo[1,2-a]quinoxaline-based derivatives as potent and selective sirt6 activators",
abstract = "Sirt6 activation has emerged as a promising drug target for the treatment of various human diseases, while only limited Sirt6 activators have been reported. Herein, a series of novel pyrrolo[1,2-a]quinoxaline-based derivatives have been identified as potent and selective Sirt6 activators with low cytotoxicity. Sirt6-knockdown findings have validated the on-target effects of this class of Sirt6 activators. Docking studies indicate the protonated nitrogen on the side chain of 38 forms π-cation interactions with Trp188, further stabilizing it into this extended binding pocket. New compounds 35, 36, 38, 46, 47, and 50 strongly repressed LPS-induced proinflammatory cytokine/chemokine production, while 38 also significantly suppressed SARS-CoV-2 infection with an EC50 value of 9.3 μM. Moreover, compound 36 significantly inhibited the colony formation of cancer cells. These new molecules may serve as useful pharmacological tools or potential therapeutics against cancer, inflammation, and infectious diseases.",
keywords = "Anti-inflammation, Anti-SARS-CoV-2, Deacetylation, Drug discovery, Sirt6 activator",
author = "Jimin Xu and Shuizhen Shi and Gang Liu and Xuping Xie and Jun Li and Bolinger, {Andrew A.} and Haiying Chen and Wenbo Zhang and Shi, {Pei Yong} and Hua Liu and Jia Zhou",
note = "Funding Information: This work was supported in part by the National Institutes of Health (NIH) grant EY031054 (to H.L.). Jia Zhou was partly supported by the John D. Stobo, M.D. Distinguished Chair Endowment Fund. W.Z. was supported by NIH grants EY022694 and EY026629 , and UT System Faculty STARs Award. P.-Y.S. was supported by NIH grants U19AI171413 and U01AI151801 , and awards from the Sealy & Smith Foundation , the Kleberg Foundation , the John S. Dunn Foundation , the Amon G. Carter Foundation , the Gilson Longenbaugh Foundation , and the Summerfield Robert Foundation . The BV2 microglial cells were kindly provided by Prof. Linda J. Van Eldik (University of Kentucky, USA) and Prof. Elisabetta Blasi (University of Modena and Reggio Emilia, Italy). We thank Drs. Lawrence C. Sowers and Jason Herring at the Department of Pharmacology as well as Dr. Tianzhi Wang at the NMR core facility of UTMB for the NMR spectroscopy assistance, and Dr. William Russell at the UTMB mass spectrometry core with funding support from UT system proteomics network for the HRMS analysis. Funding Information: This work was supported in part by the National Institutes of Health (NIH) grant EY031054 (to H.L.). Jia Zhou was partly supported by the John D. Stobo, M.D. Distinguished Chair Endowment Fund. W.Z. was supported by NIH grants EY022694 and EY026629, and UT System Faculty STARs Award. P.-Y.S. was supported by NIH grants U19AI171413 and U01AI151801, and awards from the Sealy & Smith Foundation, the Kleberg Foundation, the John S. Dunn Foundation, the Amon G. Carter Foundation, the Gilson Longenbaugh Foundation, and the Summerfield Robert Foundation. The BV2 microglial cells were kindly provided by Prof. Linda J. Van Eldik (University of Kentucky, USA) and Prof. Elisabetta Blasi (University of Modena and Reggio Emilia, Italy). We thank Drs. Lawrence C. Sowers and Jason Herring at the Department of Pharmacology as well as Dr. Tianzhi Wang at the NMR core facility of UTMB for the NMR spectroscopy assistance, and Dr. William Russell at the UTMB mass spectrometry core with funding support from UT system proteomics network for the HRMS analysis. Publisher Copyright: {\textcopyright} 2022 Elsevier Masson SAS",
year = "2023",
month = jan,
day = "15",
doi = "10.1016/j.ejmech.2022.114998",
language = "English (US)",
volume = "246",
journal = "CHIM.THER.",
issn = "0223-5234",
publisher = "Elsevier Masson SAS",
}