Facile fabrication of promising protein tyrosine phosphatase (PTP) inhibitor entities based on ‘clicked’ serine/threonine–monosaccharide hybrids Xiao-Peng He a,c , Qiong Deng a , Li-Xin Gao b , Cui Li a , Wei Zhang b , Yu-Bo Zhou b , Yun Tang a , Xiao-Xin Shi a , Juan Xie c,⇑ , Jia Li b,⇑ , Guo-Rong Chen a,⇑ , Kaixian Chen a,b a Key Laboratory for Advanced Materials & Institute of Fine Chemicals and School of Pharmacy, East China University of Science and Technology, Shanghai 200237, PR China b National Center for Drug Screening, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 201203, PR China c PPSM, Institut d’Alembert, ENS de Cachan, CNRS UMR 8531, F-94235 Cachan, France article info Article history: Received 8 April 2011 Revised 21 May 2011 Accepted 23 May 2011 Available online 27 May 2011 Keywords: Sugar template Click chemistry Amino acid PTP inhibitor MTT assay abstract Protein tyrosine phosphatases (PTPs) are well-validated therapeutic targets for many human major dis- eases. The development of their potent inhibitors has therefore become a main focus of both academia and the pharmaceutical industry. We report herein a facile strategy toward the fabrication of new and competent PTP inhibitor entities by simply ’clicking’ alkynyl amino acids onto diverse azido sugar tem- plates. Triazolyl glucosyl, galactosyl, and mannosyl serine and threonine derivatives were efficiently syn- thesized via click reaction, which were then identified as potent CDC25B and PTP1B inhibitors selective over a panel of homologous PTPs tested. Their inhibitory activity and selectivity were found to largely lie on the structurally and configurationally diversified monosaccharide moieties whereon serinyl and thre- oninyl residues were introduced. In addition, MTT assay revealed the triazole-connected sugar-amino acid hybrids may also inhibit the growth of several human cancer cell lines including A549, Hela, and especially HCT-116. On the basis of such compelling evidence, we consider that this compound series could furnish promising chemical entities serving as new CDC25B and PTP1B inhibitors with potential cellular activity. Furthermore, the ‘click’ strategy starting from easily accessible and biocompatible amino acids and sugar templates would allow the modular fabrication of a rich library of new PTP inhibitors effi- caciously and productively. Ó 2011 Elsevier Ltd. All rights reserved. 1. Introduction The protein tyrosine phosphatases (PTPs) constitute a large class of functional enzymes governing the pivotal tyrosine phos- phorylation processes on cellular level. 1 A myriad of biochemical studies indicated that the suppression of certain overexpressed PTPs with dysfunctions in vivo may lead to the treatment of many human major diseases. For instance, the PTP1B-knockout mice model displayed in- creased insulin sensitivity and enhanced glycemic control, and was resistant to diet-induced obesity. 2,3 Meanwhile, several recent investigations suggest that PTP1B may qualify as a new therapeutic target for breast cancer. 4 The cell division cycle 25 (CDC25) phos- phatases A, B, and C regulate cyclin-dependent kinases, the crucial component of the eukaryotic cell division cycle. 5a Among the three isoforms, CDC25A and B have been identified to be overexpressed in a wide range of human cancers including breast, colon, cervix, lung, etc. 5b This suggests that the inhibition of CDC25A and/or B may become a promising strategy in oncology. Consequently, numerous programs have been initiated en route to the fabrication of potent and bioavailable small-molecule PTP inhibitors via both academia and the pharmaceutical industry. 6,7 The majority of these bioactive compounds are phosphotyrosine (pTyr) mimetics that competitively inhibit the targeted PTP. For example, the difluoromethylene phosphonate (DFMP), carboxylic acid and heterocyclic pTyr surrogates generally constitute the competitive inhibitor category of PTP1B. 8 Furthermore, noncom- petitive inhibitors that induce the open conformation of WPD loop have furnished alternative insight for gaining its inhibition. 9 On the other hand, CDC25 phosphatase inhibitors discovered till date fall principally into quinoids whereas relatively fewer other bioactive compound sorts were identified. 5 Nevertheless, most of the currently characterized PTPs inhibi- tors encounter limitations such as the unsatisfactory cellular activ- ity and low bioavailability. In addition, several special compound series such as the quinonyl derivatives could release reactive oxy- gen species (ROS) which may uncertainly bring on toxicity to nor- mal tissues. As a consequence, the discovery of new chemical 0968-0896/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved. doi:10.1016/j.bmc.2011.05.049 ⇑ Corresponding authors. Tel.: +86 21 64253016; fax: +86 21 64252758. E-mail addresses: joanne.xie@ens-cachan.fr (J. Xie), jli@mail.shcnc.ac.cn (J. Li), mrs_guorongchen@ecust.edu.cn (G.-R. Chen). Bioorganic & Medicinal Chemistry 19 (2011) 3892–3900 Contents lists available at ScienceDirect Bioorganic & Medicinal Chemistry journal homepage: www.elsevier.com/locate/bmc