Novel iron complexes bearing N6-substituted adenosine derivatives: Synthesis, magnetic, 57Fe Mössbauer, DFT, and in vitro cytotoxicity studies

• Published in: Bioorganic & medicinal chemistry 2008-09, Vol.16 (18), p.8719-8728
• Main Authors: Trávníček, Zdeněk, Mikulík, Jiří, Čajan, Michal, Zbořil, Radek, Popa, Igor
• Format: Article
• Language: English
• Subjects: 57Fe Mössbauer spectroscopy; Adenosine - analogs & derivatives; Adenosine - chemical synthesis; Adenosine - pharmacology; Adenosine derivatives; Algorithms; Antineoplastic agents; Biological and medical sciences; Cell Line, Tumor; Cytotoxicity; DFT calculations; General aspects; Humans; Inhibitory Concentration 50; Iron - chemistry; Iron complexes; Magnetic Resonance Spectroscopy; Magnetics; Medical sciences; Organometallic Compounds - chemical synthesis; Organometallic Compounds - pharmacology; Pharmacology. Drug treatments; Spectrometry, Mass, Electrospray Ionization; Spectrophotometry, Infrared; Spectroscopy, Mossbauer
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/j.bmc.2008.07.082

The prepared iron complexes showed notable in vitro cytotoxicity against HOS, K-562 and MCF-7 human cancer cell lines in some cases. Spectral, Mössbauer and magnetic studies revealed the presence of four different spin and/or valency states of iron cations in the complexes. Geometries of all possible structures were optimized on the DFT level. Iron complexes ( 1– 7) involving N6-benzyladenosine derivatives of the predominant composition [Fe( L n )Cl 3] · H 2O {where L 1 = N6-(2-fluorobenzyl)adenosine ( 1), L 2 = N6-(4-fluorobenzyl)adenosine ( 2), L 3 = N6-(2-trifluoromethylbenzyl)adenosine ( 3), L 4 = N6-(3-trifluoromethylbenzyl)adenosine ( 4), L 5 = N6-(4-trifluoromethylbenzyl)adenosine ( 5), L 6 = N6-(4-trifluoromethoxybenzyl)adenosine ( 6), and L 7 = N6-(4-chlorobenzyl)adenosine ( 7)} have been synthesized. The compounds have been characterized by elemental analysis, variable-temperature and in-field 57Fe Mössbauer, ES+ MS, FTIR, 1H and 13C NMR spectroscopies, magnetochemical and conductivity measurements, thermal (TGA/DSC/DTA) analyses, and DFT calculations. It has been found that the organic molecule is coordinated to iron via N7 atom of the appropriate adenosine derivative and the products are represented by mixtures of complexes with various iron oxidation (Fe III/Fe II) and spin states ( S = 5/2, 4/2, 3/2, 2/2) and geometries (tetrahedral or trigonal bipyramidal). It is caused by the fact that partial redox processes proceed during the reactions due to the presence of a ribose moiety, which is oxidized to the corresponding 5′-ribotic acid, and simultaneously, a portion of Fe III cations is reduced to Fe II ones. Moreover, a significant effect of crystal water molecules on stereochemistry, and hence, on magnetic and spectral properties of the prepared complexes has been found. The compounds have been tested for their in vitro cytotoxicity against the following human cancer cell lines: malignant melanoma ( G-361), osteogenic sarcoma ( HOS), chronic myelogenous leukemia ( K-562), and breast adenocarcinoma ( MCF-7). The most important results have been obtained for complex 2 with IC 50 values 8–16 μM against HOS, K-562, and MCF-7 cell lines, and for complex 6 with IC 50 value 4 μM against MCF-7 cell line.