title: Novel isoxazole polycyclic aromatic hydrocarbons as DNA-intercalating agents.
abstract: The third generation of isoxazole polycyclic aromatic hydrocarbons, acting as DNA-intercalator agents and possessing the binding constants in the range 10(4)-10(5) M(-1), in order to easily diffuse targeting remotely implanted tumors, has been synthesized in good yields according to the 1,3-dipolar cycloaddition methodology. The structure of the obtained cycloadducts has been determined by NOE experiments and supported by computational studies at PM3 level. All the obtained compounds have been tested for their in vitro cytotoxic activity and the most potent of them, (3RS,5SR)-2-benzyl-N,N-dimethyl-3-(pyren-1-yl)isoxazolidine-5-carboxamide (7d), showed an IC(50) of 4 μM upon the human lung cancer (A-549) cells. Moreover, compound 7d showed binding constant for the intercalation with calf thymus DNA, poly-d(AT)(2) and poly-d(GC)(2) of 1.7 × 10(5) M(-1), 1.6 × 10(5) M(-1) and 0.3 × 10(5) M(-1), respectively. Biological and docking studies showed that, in vitro, these compounds complex by intercalation between base pairs, approaching the DNA from its minor groove with a preference for the AT nucleobases pairs.
authors.affiliation: Dipartimento di Scienze del Farmaco, Università di Catania, Viale Andrea Doria 6, Catania 95125, Italy. arescifina@unict.it
authors.forename: Antonio
authors.initials: A
authors.lastname: Rescifina
authors.forename: Maria Giulia
authors.initials: MG
authors.lastname: Varrica
authors.forename: Caterina
authors.initials: C
authors.lastname: Carnovale
authors.forename: Giovanni
authors.initials: G
authors.lastname: Romeo
authors.forename: Ugo
authors.initials: U
authors.lastname: Chiacchio
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D002417:Cattle; D045744:Cell Line, Tumor; D004247:DNA / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D007364:Intercalating Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D007555:Isoxazoles / Q000737:chemistry*; D008958:Models, Molecular; D009690:Nucleic Acid Conformation; D011084:Polycyclic Aromatic Hydrocarbons / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; D007364:Intercalating Agents; D007555:Isoxazoles; D011084:Polycyclic Aromatic Hydrocarbons; D004247:DNA