Synthesis of Two New Thiazole-containing Oligopeptides as Potential DNA Minor Groove Binding Analogs of Netropsin

On the basis of previous studies on synthetic models related to the antibiotic agents Netropsin and Distamycin-A, the design and synthesis of two potential DNA minor groove ligands are described.Methia-Nt and lsothia-Nt were prepared by liquid-phase peptidic synthesis from the key compounds ethyl 2-amino-5-methyithiazoie-4-carboxylate (1) and ethyl 2-aminothiazole-Scarboxylate (8) respectively.Most of antitumor agents used in clinic are thought to exert their cytotoxic activity by modifying the DNA metabolism.1 Beside drugs which covalently bind DNA,z other compounds are known to induce DNA breakage or inhibit the nucieic acids synthesis by intercaiative3 or non intercalative4 processes.Among this last class, two natural compounds, the antibiotics Netropsin (Nt) and Distamycin-A (Dst) form highly ordered complexes in the minor groove of DNA and recognize particular nucieotide sequences of double-stranded DNA4.5 with a high Adenine-Thymine (AT) specificity.These DNA binders could constitute adequate models for the design of synthetic pseudopeptides, referenced as sequence-reading oligopeptides.6 in order to modify the biological processes of replication and transcription: as such, they can constitute adequate candidates for antiviral and antineoplastic activities.Because of current interest in the control of gene expression, increasing works aim at developing DNA sequence specific agents.For these reasons, it seems particularly interesting to apply the concept of molecules possessing at once strong affinity and specific binding properties to definite nucieotidic sequences.Such molecules would be of great utility when such a recognition is essential on predetermined oligonucieotidic sequence of oncogenes for example.Thus, in order to delineate the structural, conformational and chemical basis of DNA binding, systematic modifications on Nt and Dst have been fulfilled, implying the different factors responsible for the processes of molecular recognition.in this context, analogs of Nt have been built via replacement of one or two pyrroie units by other heterocyles such as imidazoie,73 oxazoieg or thiazole.lo-14The consequences of such substitutions in terms of AT specificity alteration and GC acceptance enhancement have been analyzed and, in addition, the influence of the nature and length of the cationic side chain on the specificity of interaction has been proposed.s.ls