BACKBONE AND BENZOYL MUSTARD CARRYING MOIETY MODIFIES DNA INTERACTIONS OF DISTAMYCIN ANALOGS

Alkylating distamycin derivative FCE 24517 (I) is the prototype of a n ovel class of alkylating agents, In the present study we have investig ated the effect of further chemical modifications introduced in the al kylating distamycin-derived molecule with the aim of improving their a bility to bind DNA, The new compound, MEN 10710 (II), has a four pyrro lecarboxamide backbone linked at its N-terminus and through a butanami do residue to a 4-[bis(2-chloroethyl)amino]phenyl moiety. We have demo nstrated that the presence of the flexible trimethylene chain confers to the novel distamycin derivative a peculiar mode of interaction with DNA as compared with I or melphalan. In fact, interstrand cross-links are detected in DNA samples treated even with low concentrations of I I (being 200-fold more efficient than melphalan) but not with I. Simil ar results were obtained with a related compound of II containing a th ree pyrrole ring backbone. Compound II induces a conformational change in the DNA structure as deduced from the inhibition of T4 DNA ligase activity. In alkylation experiments, unlike melphalan, both I and II i nduce DNA breaks at bases closely located to AT-rich tracts, however I I was more potent than I in producing greater amount of covalent adduc ts. These data suggest that the new compound shows a different and pec uliar mechanism of interaction with DNA.