Asymmetrical Diaromatic Guanidinium/2-Aminoimidazolinium Derivatives: Synthesis and DNA Affinity

Abstract

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);

Antiprotozoal activity and DNA binding of N-substituted N-phenylbenzamide and 1,3-diphenylurea bisguanidines

“…Since N-phenylbenzamide and 1,3-diphenylurea guanidine and imidazoline derivatives are strong DNA minor groove binders [11,[26][27][28], we were interested in quantitatively evaluating the binding affinity of the new compounds with DNA. Binding to DNA and resultant inhibition of transcription and activity of other DNA-dependent enzymes is thought to contribute to the antiprotozoal activity of dicationic compounds [29].…”

On the protonated state of amidinium-like diaromatic derivatives: X-ray and UV studies

“…Compounds containing amidine-like groups (guanidines, 2-aminoimidazolines, isoureas) have shown to be active in different biological systems from binding to DNA [1][2][3] to inhibiting adrenergic receptors in the brain [4][5][6]. The protonation state of these amidine-like groups at physiological level plays a fundamental role in the interactions established with the target (hydrogen bonds, ionic contacts) and for this reason, information about this protonation state is crucial for the design of new biologically active derivatives.…”

“…We have previously reported the synthesis of different amidine-like series of diaromatic compounds [2,9] containing, guanidinium, 2-aminoimidazolinium or isouronium cations. However, their crystal structures were not known and now we have been able to resolve the crystal structures of two of these compounds [with ammonium and guanidinium (1) and with two isouronium (2) cations].…”

Synthesis, molecular modeling and biological evaluation of guanidine derivatives as novel antitubulin agents

“…[5][6][7] Guanidine derivatives have been intensively reported to possess potent antiviral and anticancer activites. [8][9][10] Guanidine derivatives have attracted considerable attention as they have been shown a tendency to inhibit S-adenosylmethionine decarboxylase (SAMDC), 11 ribonucleotide reductase (RR), 12 and can accumulate in the mitochondria to damage mitochondrial and inhibit respiratory chain, 13 and other can bind DNA minor groove, 14 leading to cell proliferation inhibition and apoptosis induction in the human tumor cells. For example, Methyl-GAG (methylglyoxal-bisguanylhydrazone, MAGA) as a single agent has been used in clinical for malignant lymphoma, carcinoma of the head, neck, and esophageal and non-small-cell lung cancer.…”