DNA minor groove alkylating agents structurally related to distamycin A

Analogues of naturally occurring antitumour agents, such us distamycin A, which bind in the minor groove of DNA, represent a new class of antineoplastic compounds currently under investigation. Distamycin A has attracted researchers' attention not only for its biological activity, but also for its non-intercalative 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 AT base pairs. Distamycin has also been used as a DNA sequence-selective vehicle for the delivery of alkylating functions to DNA targets, leading to a sharp increase in cytotoxicity, in comparison to that of distamycin alone. In the last few years, several hybrid compounds, in which known antitumour derivatives or simple active moieties of known antitumour agents have been tethered to distamycin frames, have been designed, synthesised and tested. Several efforts have been made to modify the DNA sequence selectivity and stability of distamycin; structural modifications have been based on replacement of pyrrole by other heterocycles and/or benzoheterocycles resulting in a novel class of minor groove binding molecules called lexitropsins. The role of the amidino moiety has also been studied by substitution with various groups, including ionisable, acid or basic and non-ionisable groups. The synthesis of a hybrid derived from combining distamycin A and a naturally occurring alkylating agent structurally related to pyrrolo [2,1-c][1,4] benzodiazepine group, such as anthramycin and DC-81, has been also reported. Several classes of distamycin derivatives that have been reported in the published literature and in recent patent fillings have been described in this review article.