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Pure Appl. Chem., 2003, Vol. 75, No. 2-3, pp. 187-194

DNA minor-groove binders. Design, synthesis and biological evaluation of ligands structurally related to CC-1065, distamycin, and anthramycin

P. G. Baraldi, M. A. Tabrizi, D. Preti, Francesca Fruttarolo, Barbara Avitabile, Andrea Bovero, G. Pavani, M. Carmen Nunez del Carretero and R. Romagnoli

University of Ferrara, Dipartimento di Scienze Farmaceutiche, Via Fossato di Mortara 17/19, 44100 Ferrara, Italy

Many natural and synthetic anticancer agents with the ability to interact with DNA have been discovered, but most have little sequence-specificity and often exhibit severe toxicity to normal tissues. Thus, there has been considerable interest in molecular biology and human medicine to find small molecules that can alkylate the DNA in a sequence-specific manner and modify the function of nucleic acids irreversibly. Analogs of naturally occurring antitumor agents, such as distamycin A, which bind in the minor groove of DNA, represent a new class of anticancer compounds currently under investigation. Distamycin A has driven researchers' attention not only for its biological activity, but also for its nonintercalative binding to the minor groove of double-stranded B-DNA, where it forms a strong reversible complex preferentially at the nucleotide sequences consisting of 4-5 adjacent adenine-thymine (AT) base pairs. The pyrrole-amide skeleton of distamycin A has been also used as DNA sequence-selective vehicles for the delivery of alkylating functions to DNA targets, leading to a sharp increase of its cytotoxicity, in comparison to that, very weak, of distamycin itself.
In the last few years, several hybrid compounds, in which derivatives of naturally occurring antitumor agents, such as anthramycin or the alkylating unit of the antibiotic CC-1065, have been tethered to distamycin frames. The DNA alkylating and cytotoxic activities against several tumor cell lines are reported and discussed in terms of their structural differences in relation to both the number of N-methyl pyrrole rings and the type of alkylating unit tethered to the oligopeptidic frame.