Sulfur, selenium and tellurium pseudopeptides: Synthesis and biological evaluation Saad Shaaban a,b,c , Florenz Sasse b,⇑ , Torsten Burkholz c , Claus Jacob c,⇑ a Department of Chemistry, Faculty of Science, Mansoura University, El-Gomhoria Street, Mansoura 35516, Egypt b Department of Chemical Biology, Helmholtz Centre for Infection Research, Inhoffenstraße 7, D-38124 Braunschweig, Germany c Division of Bioorganic Chemistry, School of Pharmacy, Saarland University, D-66123 Saarbruecken, Germany article info Article history: Received 18 March 2014 Revised 9 May 2014 Accepted 12 May 2014 Available online 21 May 2014 Keywords: Isonitrile based multicomponent reactions (IMCR) Tellurium Redox-modulation Anticancer activity Antimicrobial activity Lipinski’s Rule of Five abstract A new series of sulfur, selenium and tellurium peptidomimetic compounds was prepared employing the Passerini and Ugi isocyanide based multicomponent reactions (IMCRs). These reactions were clearly superior to conventional methods traditionally used for organoselenium and organotellurium synthesis, such as classical nucleophilic substitution and coupling methods. From the biological point of view, these compounds are of considerable interest because of suspected anticancer and antimicrobial activities. While the sulfur and selenium containing compounds generally did not show either anticancer or anti- microbial activities, their tellurium based counterparts frequently exhibited antimicrobial activity and were also cytotoxic. Some of the compounds synthesized even showed selective activity against certain cancer cells in cell culture. These compounds induced a cell cycle delay in the G0/G1 phase. At closer inspection, the ER and the actin cytoskeleton appeared to be the primary cellular targets of these tellu- rium compounds, in line with some of our previous studies. As most of these peptidomimetic compounds also comply with Lipinski’s Rule of Five, they promise good bioavailability, which needs to be studied as part of future investigations. Ó 2014 Elsevier Ltd. All rights reserved. 1. Introduction The efficient synthesis of drug-like molecules is a major theme in the field of pharmaceutical chemistry. In this context, multicom- ponent reactions (MCRs) offer an interesting approach to achieve structural diversity and molecular complexity through comparably straight-forward chemical transformations. Indeed, the easy access to a wide variety of starting materials, comparably mild reaction conditions and the wide spectrum of attainable products place such reactions at the heart of many combinatorial approaches and also form the bedrock for the generation of small product libraries. 1,2 In pharmaceutical chemistry, isocyanide-based MCRs (IMCRs), such as the Ugi and Passerini reactions, are of particular interest as they allow the synthesis of peptidomimetic compounds, that is, compounds which ‘resemble’ natural, peptide-like substances. Many peptides possess signaling and regulatory functions, and therefore the potential applications of such peptide-like structures are legion and become immediately apparent. 3 Furthermore, many of these compounds exhibit good solubility, permeability—and hence bioavailability—and are also rather stable chemically and metabolically. In fact, among the various MCRs, the Ugi and Passe- rini reactions can be considered a breakthrough as far as diversity of products, chemo-, regio- and stereoselectivity and ease of oper- ation are concerned. 4–7 At the same time, chalcogen containing peptoids often also exhibit pronounced—yet also selective—biological activities, 8–10 especially in the context of redox-modulation. Although, several preparative methods are nowadays available for the preparation of simple chalcogen-containing molecules, there have been only a few reports on the synthesis of more sophisticated compounds, such as larger, multifunctional selenium- or tellurium compounds or biologically ‘more amenable’ structures, such as redox-active seleno- and telluropeptoids. This may be due to the fact that orga- noselenium and organotellurium chemistry are not always straight forward. Furthermore, decomposition of the products and difficul- ties to generate compounds with sufficient purity are often observed. Recently, we have therefore applied the potential provided by IMCRs to the synthesis of biologically useful chalcogen-compounds, reporting the synthesis of selenium- and tellurium-containing http://dx.doi.org/10.1016/j.bmc.2014.05.019 0968-0896/Ó 2014 Elsevier Ltd. All rights reserved. ⇑ Corresponding authors. Tel.: +49 531 6181 3428; fax: +49 531 6181 3499 (F.S.); tel.: +49 681 302 3129; fax: +49 681 302 3464 (C.J.). E-mail addresses: florenz.sasse@helmholtz-hzi.de (F. Sasse), c.jacob@mx. uni-saarland.de (C. Jacob). Bioorganic & Medicinal Chemistry 22 (2014) 3610–3619 Contents lists available at ScienceDirect Bioorganic & Medicinal Chemistry journal homepage: www.elsevier.com/locate/bmc