Backbone and benzoyl mustard carrying moiety modifies DNA interactions of distamycin analogues.
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.
Ciucci
A
A
Menarine Ricerche Sud, Pomezia, Italy.
Manzini
S
S
Lombardi
P
P
Arcamone
F
F
D000478:Alkylation; D001483:Base Sequence; D003432:Cross-Linking Reagents; D004247:DNA / Q000737:chemistry / Q000378:metabolism*; D018736:DNA Adducts / Q000737:chemistry; D011088:DNA Ligases / Q000037:antagonists & inhibitors; D004278:DNA, Superhelical / Q000737:chemistry; D004214:Distamycins / Q000138:chemical synthesis / Q000378:metabolism* / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D008558:Melphalan / Q000494:pharmacology; D008969:Molecular Sequence Data; D009588:Nitrogen Mustard Compounds / Q000138:chemical synthesis / Q000378:metabolism* / Q000494:pharmacology; D009690:Nucleic Acid Conformation / Q000187:drug effects
D003432:Cross-Linking Reagents; D018736:DNA Adducts; D004278:DNA, Superhelical; D004214:Distamycins; D004791:Enzyme Inhibitors; C098491:MEN 10710; D009588:Nitrogen Mustard Compounds; C066900:tallimustine; D004247:DNA; D011088:DNA Ligases; D008558:Melphalan