Nitro-imidazoles in ferrocenyl alkylation reaction. Synthesis, enantiomeric resolution and in vitro and in vivo bioeffects Lubov V. Snegur a, * , Maria V. Lyapunova b , Daria D. Verina c , Vadim V. Kachala d , Alexander A. Korlyukov a, e , Mikhail M. Ilyin Jr. a , Vadim A. Davankov a , Larissa A. Ostrovskaya f , Natalia V. Bluchterova f , Margarita M. Fomina f , Victor S. Malkov b , Kseniya V. Nevskaya g , Alexandra G. Pershina g , Alexander A. Simenel a, h a A.N. Nesmeyanov Institute of OrganoElement Compounds, Russian Academy of Sciences, 28 Vavilov St,119991 Moscow, Russian Federation b National Research Tomsk State University, 36 Lenin Ave, 634050 Tomsk, Russian Federation c D.I. Mendeleev University of Chemical Technology of Russia, 9 Miusskaya sq,125047 Moscow, Russian Federation d N.D. Zelynski Institute of Organic Chemistry RAS, 47 Leninsky Ave.,119991 Moscow, Russian Federation e N.I. Pirogov Russian National Research Medical University,1 Ostrovityanov St., 117997 Moscow, Russian Federation f N.M. Emanuel Institute of Biochemical Physics, Russian Academy of Sciences, 4 Kosigin St,119991 Moscow, Russian Federation g Siberian State Medical University, 2 Moskovsky trakt, 634055 Tomsk, Russian Federation h National University of Science and Technology "MISIS", Chemistry Department, 4 Leninskiy Ave.,119049 Moscow, Russian Federation article info Article history: Received 19 February 2018 Received in revised form 18 June 2018 Accepted 24 June 2018 Available online 28 June 2018 Keywords: Ferrocene compounds Nitro-imidazoles Enantiomeric resolution X-ray crystal structure Toxicity in vitro Bioactivity in vivo abstract Ferrocenylalkyl nitro-imidazoles (4a-h, 5a-h) were prepared via the regiospecific reaction of the a- (hydroxy)alkyl ferrocenes, FcCHR (OH) (1aeh; Fc ¼ ferrocenyl; R ¼ H, Me, Et, Pr, i-Pr, Ph, ortho-Cl-Ph, ortho-I-Ph), with nitro-imidazoles in aqueous organic medium (H 2 O-CH 2 Cl 2 ) at room temperature in the presence of HBF 4 , within several minutes in good yields. X-ray structural data for racemic (R,S)-1-N- (benzyl ferrocenyl)-2-methyl-4-nitroimidazole (5f) were determined. The resulting enantiomers were resolved into enantiomers by analytical HPLC on modified amylose or cellulose chiral stationary phases. The viabilities of 4b, 4d, 5b, 5c in vitro, and in experiments in vivo antitumor effects of 1-N-ferroceny- lethyl-4-nitroimidazole (4b) against murine solid tumor system Ca755 carcinoma were evaluated. © 2018 Elsevier B.V. All rights reserved. 1. Introduction The conjugation of nitrogen-containing hetero cycles with ferrocene represents perspective directions for design and syn- thesis of bioactive compounds with different types of activities including antianemic, tuberculostatic, antimalarial, antimicrobic and antiproliferative [1e 10]. The antiproliferative activity has been especially investigated by numerous research groups [10e15]. Among heterocycles, azoles and especially imidazole cause a high interest because represent essential components of DNA, RNA, histidine amino acid or drugs [10e14, 16e20]. On the other hand, such nitrogen-heterocycleferrocene ensembles possess positive enthalpies of formation to give highly energetic structures [21]. Well known, that both ferrocenes and nitro-compounds were applied for solid rocket propellant in the early 1970s [10]. More- over, nitro groups being in the structures of nitro-glycerin and trinitro-toluene make these compounds high explosive. To our knowledge, there are no systematic studies on synthesis of com- pounds combining both nitro-imidazole and ferrocene fragments excluding the data in the review article of Tverdohlebov with co- authors [21]. Ferrocene-modification of organic compounds was widely rep- resented in reviews [17 ,22,23] and special recent issue [24] The ferrocenylalkylation method for the introduction of ferrocenylalkyl groups into various nucleophilic substrates was based on the sub- stitution reactions of ferrocenylalkyl amines or a-(hydroxy)alkyl ferrocenes with nucleophiles [22]. The later one is extensively explored approach to ferrocene-based compounds [23,25,26]. * Corresponding author. E-mail address: snegur@ineos.ac.ru (L.V. Snegur). Contents lists available at ScienceDirect Journal of Organometallic Chemistry journal homepage: www.elsevier.com/locate/jorganchem https://doi.org/10.1016/j.jorganchem.2018.06.019 0022-328X/© 2018 Elsevier B.V. All rights reserved. Journal of Organometallic Chemistry 871 (2018) 10e20