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Nucleic Acids Research, Vol 24, Issue 2 311-315, Copyright © 1996 by Oxford University Press

ARTICLES

Backbone and benzoyl mustard carrying moiety modifies DNA interactions of distamycin analogues

A Ciucci, S Manzini, P Lombardi and F Arcamone
Menarine Ricerche Sud, Pomezia, Italy.

Alkylating distamycin derivative FCE-24517 (l) is the prototype of a novel class of alkylating agents. In the present study we have investigated the effect of further chemical modifications introduced in the alkylating distamycin-derived molecule with the aim of improving their ability to bind DNA. The new compound, MEN 10710 (II), has a four pyrrolecarboxamide backbone linked at its N-terminus and through a butanamido residue to a 4-[bis(chloroethyl)amino]phenyl moiety. We have demonstrated 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 II (being 200-fold more efficient than melphalan) but not with I. Similar results were obtained with a related compound of II containing a three 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 induce DNA breaks at bases closely located to AT-rich tracts, however II was more potent than I in producing greater amount of covalent adducts. These data suggest that the new compound shows a different and peculiar mechanism of interaction with DNA.
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