2. Academic Validation
  3. Hit-to-lead optimization of phenylsulfonyl hydrazides for a potent suppressor of PGE2 production: Synthesis, biological activity, and molecular docking study

Hit-to-lead optimization of phenylsulfonyl hydrazides for a potent suppressor of PGE2 production: Synthesis, biological activity, and molecular docking study

  • Bioorg Med Chem Lett. 2016 Jan 1;26(1):94-9. doi: 10.1016/j.bmcl.2015.11.024.
Minju Kim 1,  Sunhoe Lee 1,  Eun Beul Park 1,  Kwang Jong Kim 1,  Hwi Ho Lee 2,  Ji-Sun Shin 3,  Katrin Fischer 4,  Andreas Koeberle 4,  Oliver Werz 5,  Kyung-Tae Lee 6,  Jae Yeol Lee 7
Affiliations

Affiliations

  • 1 Research Institute for Basic Sciences and Department of Chemistry, College of Sciences, Kyung Hee University, 26 Kyungheedae-ro, Dongdaemun-gu, Seoul 02447, Republic of Korea.
  • 2 Department of Life and Nanopharmaceutical Science, Kyung Hee University, 26 Kyungheedae-ro, Dongdaemun-gu, Seoul 02447, Republic of Korea.
  • 3 Reactive Oxygen Species Medical Research Center, School of Medicine, Kyung Hee University, 26 Kyungheedae-ro, Dongdaemun-gu, Seoul 02447, Republic of Korea.
  • 4 Department of Pharmaceutical/Medicinal Chemistry, Institute of Pharmacy, Friedrich-Schiller-University Jena, Philosophenweg 14, 07743 Jena, Germany.
  • 5 Department of Pharmaceutical/Medicinal Chemistry, Institute of Pharmacy, Friedrich-Schiller-University Jena, Philosophenweg 14, 07743 Jena, Germany. Electronic address: oliver.werz@uni-jena.de.
  • 6 Department of Life and Nanopharmaceutical Science, Kyung Hee University, 26 Kyungheedae-ro, Dongdaemun-gu, Seoul 02447, Republic of Korea. Electronic address: ktlee@khu.ac.kr.
  • 7 Research Institute for Basic Sciences and Department of Chemistry, College of Sciences, Kyung Hee University, 26 Kyungheedae-ro, Dongdaemun-gu, Seoul 02447, Republic of Korea. Electronic address: ljy@khu.ac.kr.
PMID: 26602278 DOI: 10.1016/j.bmcl.2015.11.024
Abstract

Preliminary hit-to-lead optimization of a novel series of phenylsulfonyl hydrazide derivatives, which were derived from the high throughput screening hit compound 1 (IC50=5700nM against PGE2 production), for a potent suppressor of PGE2 production is described. Subsequent optimization led to the identification of the potent lead compound 8n with IC50 values of 4.5 and 6.9nM, respectively, against LPS-induced PGE2 production and NO production in RAW 264.7 macrophage cells. In addition, 8n was about 30- and >150-fold more potent against mPGES-1 Enzyme in a cell-free assay (IC50=70nM) than MK-886 and hit compound 1, respectively. Molecular docking suggests that compound 8n could inhibit PGE2 production by blocking the PGH2 binding site of human mPGES-1 Enzyme.

Keywords

Inflammation; Molecular docking study; Phenylsulfonyl hydrazide; Prostaglandin E(2); mPGES-1.

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