title: Design, modeling, synthesis and biological activity evaluation of camptothecin-linked platinum anticancer agents.
abstract: The design, modeling, synthesis and biological activity evaluation of two hybrid agents formed by 7-oxyiminomethylcamptothecin derivatives and diaminedichloro-platinum (II) complex are reported. The compounds showed growth inhibitory activity against a panel of human tumor cell lines, including sublines resistant to topotecan and platinum compounds. The derivatives were active in all the tested cell lines, and compound 1b, the most active one, was able to overcome cisplatin resistance in the osteosarcoma U2OS/Pt cell line. Platinum-containing camptothecins produced platinum-DNA adducts and topoisomerase I-mediated DNA damage with cleavage pattern and persistence similar to SN38, the active principle of irinotecan. Compound 1b exhibited an appreciable antitumor activity in vivo against human H460 tumor xenograft, comparable to that of irinotecan at lower well-tolerated dose levels and superior to cisplatin. The results support the interpretation that the diaminedichloro-platinum (II) complex conjugated via an oxyiminomethyl linker at the 7-position of the camptothecin resulted in a new class of effective antitumor compounds.
authors.affiliation: Department of Food, Environmental and Nutritional Sciences, Division of Chemistry and Molecular Biology, Università di Milano, Via Celoria 2, 20133 Milano, Italy.
authors.forename: Raffaella
authors.initials: R
authors.lastname: Cincinelli
authors.forename: Loana
authors.initials: L
authors.lastname: Musso
authors.forename: Sabrina
authors.initials: S
authors.lastname: Dallavalle
authors.forename: Roberto
authors.initials: R
authors.lastname: Artali
authors.forename: Stella
authors.initials: S
authors.lastname: Tinelli
authors.forename: Donato
authors.initials: D
authors.lastname: Colangelo
authors.forename: Franco
authors.initials: F
authors.lastname: Zunino
authors.forename: Michelandrea
authors.initials: M
authors.lastname: De Cesare
authors.forename: Giovanni Luca
authors.initials: GL
authors.lastname: Beretta
authors.forename: Nadia
authors.initials: N
authors.lastname: Zaffaroni
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology; D002166:Camptothecin / Q000737:chemistry*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004264:DNA Topoisomerases, Type I / Q000737:chemistry / Q000378:metabolism; D015195:Drug Design; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D004354:Drug Screening Assays, Antitumor; D005260:Female; D006801:Humans; D020128:Inhibitory Concentration 50; D051379:Mice; D008819:Mice, Nude; D008956:Models, Chemical; D008958:Models, Molecular; D008968:Molecular Conformation; D015394:Molecular Structure; D009944:Organoplatinum Compounds / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology; D010984:Platinum / Q000737:chemistry*; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D009944:Organoplatinum Compounds; D010984:Platinum; D004264:DNA Topoisomerases, Type I; D002166:Camptothecin