Original article Novel N-(phosphonomethyl) glycine derivatives: Design, characterization and biological activity Emilia D. Naydenova a , Petar T. Todorov a , Margarita N. Topashka-Ancheva b , Georgi Ts. Momekov c , Tsvetelina Z. Yordanova b , Spiro M. Konstantinov c , Kolio D. Troev d, * a University of Chemical Technology and Metallurgy, Department of Organic Chemistry, Sofia 1756, Bulgaria b Institute of Zoology, Bulgarian Academy of Sciences, ‘‘Tzar Osvoboditel’’ 1000, Sofia 1000, Bulgaria c Laboratory of Experimental Chemotherapy, Department of Pharmacology, Pharmacotherapy and Toxicology, Faculty of Pharmacy, Medical University e Sofia, Sofia 1000, Bulgaria d Institute of Polymers, Bulgarian Academy of Sciences, Sofia 1113, Bulgaria Received 10 May 2007; received in revised form 17 July 2007; accepted 9 August 2007 Available online 11 September 2007 Abstract A series of Ca,a-disubstituted cyclic derivatives of N-(phosphonomethyl) glycine have been synthesized and characterized. They exhibited moderate clastogenicity, low antiproliferative activity on mice bone marrow cells and well expressed cytotoxicity against human tumor cell lines. The 8- and 12-membered cyclic analogs proved superior to the remaining compounds and were found to trigger apoptotic cell death in DOHH-2 cells. The latter compound caused 50% inhibition of the viability of hemobastose-derived cell lines at concentrations ranging from 20 to 67 mM. Ó 2007 Elsevier Masson SAS. All rights reserved. Keywords: Aminophosphonic acids; N-(Phosphonomethyl) glycine derivatives; Chromosome aberrations; Cell proliferation; Clastogenic effects; Cytotoxic activity 1. Introduction Aminophosphonic acids are considered to be an important class of amino acid mimetics. They have reached a position of eminence in the field of, or in the research works aimed at discovery, understanding, and modification of physiological processes in living organisms [1e3]. a-Aminophosphonic acids are found to compete effectively with their amino acid counterparts for binding to enzyme active centers or other cel- lular targets [4]. This, together with their low mammalian tox- icity makes the a-aminophosphonic acids an important class of antimetabolites and a potential source of medicinal lead compounds [5]. The most important a-aminophosphonic acids are N-(phosphonomethyl) glycine and its derivatives, which have been found to exert prominent antineoplastic, antiviral and antibacterial effects [6e11]. Kabachnik and Medved [12], and Fields [13] have discovered the first method for the prep- aration of a-aminophosphonic acids. The impressive array of applications has recently stimulated considerable effort towards the synthesis of a-aminophosphonic acids and many methods are now available [14e20]. Novel a-aminophosphonic acids with moderate clastogenic effect were synthesized reacting 1,3-oxazolidin-2-one derivatives with formaldehyde and phos- phorus trichloride [21]. One-pot reaction is used to prepare a- aminoalkylphosphonic acid in good yield via ethyl carbamate, aldehyde and dichlorophosphites [22]. Optically active amino- phosphonic acids have found widespread application in medic- inal chemistry and pharmaceutical science [23]. Highly effective solvent-free and catalyst-free microwave-assisted synthesis of a-aminophosphonates was shown [24,25]. The recent advance * Corresponding author. Tel.: þ359 2 979 2203; fax: þ359 2 870 0309. E-mail addresses: e_naydenova@abv.bg (E.D. Naydenova), pepi_37@abv. bg (P.T. Todorov), topashka.mn@lycos.com (M.N. Topashka-Ancheva), gmomekov@gmail.com (G.Ts. Momekov), ktroev@polymer.bas.bg (K.D. Troev). 0223-5234/$ - see front matter Ó 2007 Elsevier Masson SAS. All rights reserved. doi:10.1016/j.ejmech.2007.08.010 Available online at www.sciencedirect.com European Journal of Medicinal Chemistry 43 (2008) 1199e1205 http://www.elsevier.com/locate/ejmech