European Journal of Medicinal Chemistry 61(2013)95-103 Contents lists available at sciverse ScienceDirect European Journal of Medicinal Chemistry ELSEVIER journalhomepagehttp://www.elsevier.com/locate/ejmech Original article Design, synthesis and biological evaluation of benzothiazepinones (btzs )as nov non-AtP competitive inhibitors of glycogen synthase kinase-3B(GSK-3 Peng Zhang a, Hai-Rong Hu, Shi-Hui Bian Zhao-Hui Huang a, Yong Chua, De-Yong Ye a.* Key Laboratory of State Genetics Engineering, School of life Sciences, Fudan University, 220 Handan Rd, Shanghai 200433, china A INFO ABSTRACT Glycogen synthase kinase-3B(GSK-3B)plays a key role in type ll diabetes and Alzheimers diseases, to eceived 1 March 2012 hich non-ATP competitive inhibitors represent an effectively therapeutical approach due to their good Received in revised form pecificity. Herein, a series of small molecules benzothiazepinones(Btzs)as novel non-ATP competitive 31July2012 Accepted 13 September 2012 inhibitors of GSK-3B have been designed and synthesized. The in vitro evaluation performed by lumi- vailable online 21 September 2012 ent assay showed most biz derivatives have inhibitory effects in micromolar scale. Among them ounds 61, 6t and 6v have the ICso values of 25.0 HM, 27.8 uM and 23.0 uM, respectively. Moreover 6v oid of any inhibitory activity in the assays to other thirteen protein kinases. Besides, SAR is analyzed hypothetical enzymatic binding mode is proposed by molecular docking study, which would be for new candidates design. e 2012 Elsevier Masson SAS. All rights reserved. nzothiazepinone Docking 1. Introduction effects. Normally these inhibitors would be inherently more pecific and usually show a far better true efficacy in cell or in vivo Glycogen synthase kinase-3B(GSK-3B) plays a key role in the assays than in vitro assays 9]. Thus, developing non-ATP compet egulation of many physiological responses in mammalian cells as itive GSK-3B inhibitors with high selectivity has already been a new a multifunctional serine/threonine protein kinase [1]. Its phos- hot spot for medicinal chemists in recent years. phorylation process controls a multitude of cellular processes, To our best knowledge, five kinds of chemical families of GSK-3B including gene transcription, metabolic pathways, cell growth and inhibitor with non-ATP competitive mechanism are already re- differentiation, as well as apoptosis [2,3]. Thus, inhibition of GSK-3B ported(see Fig. 1). It is worth noting that all of their Icso values are may represent a novel approach for the therapy of several human in micromolar level, suggesting poor activity in vitro of such type of diseases, such as type ll diabetes, Alzheimers diseases(AD), chronic inhibitors. The first ones are the thiadiazolidinones(tzds)[10]. inflammatory diseases, bipolar disorders and cancer [4-6] Among them, one compound called tideglusib(NP-12)is currently The search for GSK-3B inhibitors has spanned more than undergoing Phase llb clinical trials both on AD and orphan tauop a decade, and a number of structural diverse molecules that inhibit athy, and it is also the only gsK-3B inhibitor under clinical phase GSK-3B have already been reported in literature [7. However, the far [11. Halomethylketones(HMKs)are the second ones and have great majority of them might offer unfavorable off-target effects recently been viewed as the first irreversible GSK-3B inhibitors nsidering they are almost ATP competitors. Such inhibitors bind [12, 13. The irreversible inhibition is due to the formation of an competitively at the atp binding site of GSK-3B and are likely to act irreversible covalent sulfur-carbon bond between the hMK moiety on other undesirable protein kinases because of the highly and the amino acid residue Cys 199. This key amino acid residue conservation of aTP binding domain among more than 500 protein plays the role as 'gatekeeper' of GSK-3B [14 The small peptide kinases of human kinome [8 Nowadays non-ATP competitive L803-mts acts as substrate competitive inhibitor effectively in vi inhibitors are expected to be promising drugs for reducing adverse for neurological diseases and type ll diabetes [15 Lately, two marine natural products of alkaloid manzamine A and ses- rresponding authors. mailaddresses:cy110@fudan.edu.cn(YChu).dyye@shmueducn(D-YYe). ylation as cell permeable non-ATP competitive inhibitors 5, 16]. 0223-5234s-see front matter o 2012 1 p: //dx. doiorg /10.1016 j. ejmech 2012.0Original article Design, synthesis and biological evaluation of benzothiazepinones (BTZs) as novel non-ATP competitive inhibitors of glycogen synthase kinase-3b (GSK-3b) Peng Zhang a , Hai-Rong Hu b , Shi-Hui Bian a , Zhao-Hui Huang a , Yong Chu a,*, De-Yong Ye a,* aDepartment of Medicinal Chemistry, School of Pharmacy, Fudan University, 826 Zhangheng Rd, Shanghai 201203, China b Key Laboratory of State Genetics Engineering, School of Life Sciences, Fudan University, 220 Handan Rd, Shanghai 200433, China article info Article history: Received 1 March 2012 Received in revised form 31 July 2012 Accepted 13 September 2012 Available online 21 September 2012 Keywords: GSK-3b Kinase inhibitor Non-ATP competitive Benzothiazepinones Selectivity Docking abstract Glycogen synthase kinase-3b (GSK-3b) plays a key role in type II diabetes and Alzheimer’s diseases, to which non-ATP competitive inhibitors represent an effectively therapeutical approach due to their good specificity. Herein, a series of small molecules benzothiazepinones (BTZs) as novel non-ATP competitive inhibitors of GSK-3b have been designed and synthesized. The in vitro evaluation performed by lumi￾nescent assay showed most BTZ derivatives have inhibitory effects in micromolar scale. Among them compounds 6l, 6t and 6v have the IC50 values of 25.0 mM, 27.8 mM and 23.0 mM, respectively. Moreover 6v is devoid of any inhibitory activity in the assays to other thirteen protein kinases. Besides, SAR is analyzed and a hypothetical enzymatic binding mode is proposed by molecular docking study, which would be useful for new candidates design.
2012 Elsevier Masson SAS. All rights reserved. 1. Introduction Glycogen synthase kinase-3b (GSK-3b) plays a key role in the regulation of many physiological responses in mammalian cells as a multifunctional serine/threonine protein kinase [1]. Its phos￾phorylation process controls a multitude of cellular processes, including gene transcription, metabolic pathways, cell growth and differentiation, as well as apoptosis [2,3]. Thus, inhibition of GSK-3b may represent a novel approach for the therapy of several human diseases, such as type II diabetes, Alzheimer’s diseases (AD), chronic inflammatory diseases, bipolar disorders and cancer [4e6]. The search for GSK-3b inhibitors has spanned more than a decade, and a number of structural diverse molecules that inhibit GSK-3b have already been reported in literature [7]. However, the great majority of them might offer unfavorable off-target effects considering they are almost ATP competitors. Such inhibitors bind competitively at the ATP binding site of GSK-3b and are likely to act on other undesirable protein kinases because of the highly conservation of ATP binding domain among more than 500 protein kinases of human kinome [8]. Nowadays non-ATP competitive inhibitors are expected to be promising drugs for reducing adverse effects. Normally these inhibitors would be inherently more specific and usually show a far better true efficacy in cell or in vivo assays than in vitro assays [9]. Thus, developing non-ATP compet￾itive GSK-3b inhibitors with high selectivity has already been a new hot spot for medicinal chemists in recent years. To our best knowledge, five kinds of chemical families of GSK-3b inhibitor with non-ATP competitive mechanism are already re￾ported (see Fig. 1). It is worth noting that all of their IC50 values are in micromolar level, suggesting poor activity in vitro of such type of inhibitors. The first ones are the thiadiazolidinones (TDZDs) [10]. Among them, one compound called tideglusib (NP-12) is currently undergoing Phase IIb clinical trials both on AD and orphan tauop￾athy, and it is also the only GSK-3b inhibitor under clinical phase so far [11]. Halomethylketones (HMKs) are the second ones and have recently been viewed as the first irreversible GSK-3b inhibitors [12,13]. The irreversible inhibition is due to the formation of an irreversible covalent sulfurecarbon bond between the HMK moiety and the amino acid residue Cys199. This key amino acid residue plays the role as ‘gatekeeper’ of GSK-3b [14]. The small peptide L803-mts acts as substrate competitive inhibitor effectively in vivo for neurological diseases and type II diabetes [15]. Lately, two marine natural products of alkaloid manzamine A and ses￾terterpene palinurin are reported to well decrease tau phosphor￾ylation as cell permeable non-ATP competitive inhibitors [5,16]. * Corresponding authors. E-mail addresses: cy110@fudan.edu.cn (Y. Chu), dyye@shmu.edu.cn (D.-Y. Ye). Contents lists available at SciVerse ScienceDirect European Journal of Medicinal Chemistry journal homepage: http://www.elsevier.com/locate/ejmech 0223-5234/$ e see front matter
2012 Elsevier Masson SAS. All rights reserved. http://dx.doi.org/10.1016/j.ejmech.2012.09.021 European Journal of Medicinal Chemistry 61 (2013) 95e103