In this paper we report the synthesis of three families of new amidine-based aromatic derivatives as potential DNA minor groove binding agents for the treatment of cancer. The preparation of mono-guanidine, mono-2-aminoimidazoline and asymmetric diphenyl guanidine/2-aminoimidazoline derivatives (compounds 1a,b,c to 8a,b,c) is presented. The affinity of these substrates and of a family of mono-and bis-isoureas (previously prepared in Rozas' laboratory) for DNA was evaluated by means of DNA thermal denaturation measurements. In particular, compounds 2c, 5c, 6c, 7c, and 8c were found to bind strongly both to natural DNA and to Adenine-Thymine oligonucleotides, showing a preference for the Adenine-Thymine base pairs sequences.Abbreviations: HB, hydrogen bond; ΔT m , increment in DNA denaturation temperature; AT, Adenine-Thymine pairs; MES, 2-(N-morpholino)ethanesulfonic acid; P/D, ratio between base pairs and ligand (drug);

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We present the crystal structures of the chloride salts of the mono-guanidinium 1 (-CH 2 CH 2 -linker) and the bis-isouronium 2 (-O-linker) that have been resolved by us indicating that these compounds are diprotonated in the solid state as informed by the counterions positions. To determine the pK a values of these compounds as well as those of their analogues 3 (mono-2-aminoimidazolinium with a -CH 2 CH 2 -linker) and 4 (mono-guanidinium with a -O-linker), the corresponding UV-Vis titrations were carried out. Thus, in aqueous solution compounds 1, 3 and 4 were present as mono-cationic species while derivative 2 was a bis-cation.

In this paper we report the synthesis of a new family of hydroxyguanidinium aromatic derivatives (4a-g) as potential minor groove binders and cytotoxic agents. Their DNA affinity was evaluated by thermal denaturation experiments using salmon sperm DNA. The antiproliferative effects of derivatives 4a, 4d, and 4f were evaluated in human promyelocytic HL-60, breast carcinoma MCF-7, and neuroblastoma Kelly cell lines using the AlamarBlue viability assay, and IC(50) values were obtained. All three compounds were active in the HL-60 cell line. In particular, 4b exhibits antiproliferative effects in all three cell lines while 4d reduced HL-60 and Kelly viability. Both 4b and 4d produced considerable antiproliferative activity in the Kelly cell line. Derivative 4d was chosen for further cell cycle and apoptosis studies using flow cytometric analysis of cellular DNA content.