Biological Properties of New Viologen-Phosphorus Dendrimers Karol Ciepluch, † Nadia Katir, ‡,§ Abdelkrim El Kadib,* ,§ Aleksandra Felczak, ∥ Katarzyna Zawadzka, ∥ Monika Weber, † Barbara Klajnert, † Katarzyna Lisowska, ∥ Anne-Marie Caminade, ‡ Mostapha Bousmina, ⊥ Maria Bryszewska,* ,† and Jean Pierre Majoral* ,‡ † Department of General Biophysics, University of Lodz, 141/143 Pomorska Street, 90-236 Lodz, Poland ‡ Laboratoire de Chimie de Coordination du CNRS, 205 route de Narbonne, F-31077 Toulouse cedex 4, France § Institute of Nanomaterials and NanotechnologyMAScIR (Moroccan Foundation for Advanced Science, Innovation and Research), ENSET, Avenue de l’Arme ́ e Royale, Madinat El Irfane, 10100 Rabat, Morocco ∥ Department of Industrial Microbiology and Biotechnology, University of Lodz, 12/16 Banacha Street, 90-237 Lodz, Poland ⊥ Hassan II Academy of Science and Technology, Rabat, Morocco * S Supporting Information ABSTRACT: Some biological properties of eight dendrimers incorporating both phosphorus linkages and viologen units within their cascade structure or at the periphery were investigated for the first time. In particular cytotoxicity, hemotoxicity, and anti- microbial and antifungal activity of these new macromolecules were examined. Even if for example all these species exhibited good antimicrobial properties, it was demonstrated that their behavior strongly depends on several parameters as their size and molecular weight, the number of viologen units and the nature of the terminal groups. KEYWORDS: viologen dendrimers, hemolysis, cytotoxicity, antibacterial activity, membrane fluidity ■ INTRODUCTION 4,4′-Bipyridinium salts better known under the name of viologen derivatives are showing an increasing number of applications in addition to their former use as herbicides. 1 This is mainly due to their properties as photoactive and electroactive compounds, and to their ability to give strong donor−acceptor complexes with electron donating species. However viologens by themselves can present risks for human health. As an example 1,1′-4,4′-bipyridinium dichloride is known to induce formation of superoxide (O 2 − ) and to cause damage to multiple organs. 2−4 A therapeutic protocol for the treatment of viologen poisoning based on host−guest chemistry and involving the effective inhibition of viologen toxicity by complexation of p-sulfonatocalix[n]arenes was reported. 5 In marked contrast to this isolated “dark image” of viologen monomer behavior, their introduction as building blocks for the design of polycationic dendrimers allowed De Clercq et al. 6 to point out the activity of various viologen dendrimers against human immunodeficiency virus (HIV-1, strain III b replication in MT-4 cells), as well as to a lesser extent against herpes simplex virus (HSV), vesicular stomatitis, Punta Toro virus, Sindbis virus, Reovirus and respiratory syncytial viruses. Indeed it was demonstrated that their behavior strongly depends on the number and distance of the positive charges. Surprisingly and to the best of our knowledge no study on other biological properties of viologen dendrimers was reported. Having these observations in mind we decided to open the field of such investigations, our first goal being to design other types of dendrimers in order to have a more precise idea on their biological activities. For such a purpose we designed new viologen monomers, dendrons, and dendrimers bearing phosphorus groups as additional units incorporated either at the focal point or at the periphery or both of these key structural positions of the dendritic backbone. This choice of strategy was aimed by the fact that we already demonstrated the key role played by phosphorus dendrimers in biology and for bio- medical applications due to several specificities. 7 Briefly they have a remarkable influence on cell growth, in particular for neuronal cells, 8 and for human immune blood cells such as monocytes and Natural Killer cells, 9−12 the latter playing a key role for fight- ing against viral infections and cancers. The uselfulness of phosphorus dendrimers was also pointed out for elaboration of highly sensitive biosensors 13−16 and for in vitro drug delivery, for instance as transfecting agents 17−19 or against HIV-1 20 and the scrapie form of prions. 21 In vivo biological properties of phosphorus dendrimers as anti- prion agents, for ocular drug delivery, 22 and for imaging rat brain blood vessels 23,24 were Special Issue: Biological Applications of Dendrimers Received: October 28, 2011 Revised: January 3, 2012 Accepted: January 3, 2012 Published: January 3, 2012 Article pubs.acs.org/molecularpharmaceutics © 2012 American Chemical Society 448 dx.doi.org/10.1021/mp200549c | Mol. Pharmaceutics 2012, 9, 448−457