title: Synthesis and preliminary biological evaluation of a new pyridocarbazole derivative covalently linked to a thymidine nucleoside as a potential targeted antitumoral agent. I.
abstract: The therapy of human cancer is one of the more pursued goals by medicinal chemistry research. Most of the compounds clinically used as a treatment owe their efficacy to their cytotoxic interaction (direct or indirect) with nuclear DNA. This interaction results in the inhibition of DNA synthesis and the degradation of nucleic strands. Ellipticine is a naturally occurring 6H-pyrido[4,3-b]carbazole alkaloid endowed with antitumor activity, and several ellipticine derivatives have been used in clinical trials. We previously reported some 1,4-dimethyl-9H-carbazole derivatives structurally related to ellipticine. The purpose of our research was to transform the pyridocarbazole in a prodrug so that it would have more penetration in the tumor cells and block their replication. Our prodrug is slowly hydrolyzed in human plasma in the corresponding acid. From these preliminary results, we deduce that our compound can block cellular replication. Our hypothesis is that the antitumoral activity is probably related to the induction of damage to DNA, without cellular lysis in the short term.
authors.affiliation: Dipartimento di Scienze Farmaceutiche, Università degli Studi di Salerno, Salerno, Italy.
authors.forename: Carmela
authors.initials: C
authors.lastname: Saturnino
authors.forename: Mariafrancesca
authors.initials: M
authors.lastname: Buonerba
authors.forename: Gianpiero
authors.initials: G
authors.lastname: Boatto
authors.forename: Maria
authors.initials: M
authors.lastname: Pascale
authors.forename: Ornella
authors.initials: O
authors.lastname: Moltedo
authors.forename: Lorenzo
authors.initials: L
authors.lastname: de Napoli
authors.forename: Daniela
authors.initials: D
authors.lastname: Montesarchio
authors.forename: Jean-Charles
authors.initials: JC
authors.lastname: Lancelot
authors.forename: Paolo
authors.initials: P
authors.lastname: de Caprariis
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D002227:Carbazoles / Q000138:chemical synthesis* / Q000494:pharmacology; D045744:Cell Line, Tumor; D016503:Drug Delivery Systems / Q000379:methods*; D004353:Drug Evaluation, Preclinical / Q000379:methods; D006801:Humans; D011728:Pyridones / Q000138:chemical synthesis* / Q000494:pharmacology; D011741:Pyrimidine Nucleosides / Q000138:chemical synthesis / Q000494:pharmacology; D013936:Thymidine / Q000138:chemical synthesis* / Q000494:pharmacology
chemical_list: D000970:Antineoplastic Agents; D002227:Carbazoles; D011728:Pyridones; D011741:Pyrimidine Nucleosides; D013936:Thymidine