title: E-ring-modified 7-oxyiminomethyl camptothecins: Synthesis and preliminary in vitro and in vivo biological evaluation.
abstract: In contrast to five-membered E-ring analogues, 7-oxyiminomethyl derivatives of homocamptothecins showed ability to form stable ternary complexes with DNA and topoisomerase I. The 7-oxyiminomethyl derivatives of homocamptothecins were evaluated as a racemic mixture. Following the isolation of the two enantiomers, the 20 (R)-hydroxy isomer confirms the best activity. By using a panel of human tumor cells, all tested homocamptothecins showed a potent antiproliferative activity, correlating to the persistence of the cleavable complex. No significant difference was observed between the natural scaffold and the corresponding homocamptothecin homologue. A selected compound of this series exhibited an excellent antitumor activity against human gastrointestinal tumor xenografts.
authors.affiliation: Sigma-Tau Research & Development, Via Pontina Km 30.400, I-00040 Pomezia, Rome, Italy. giuseppe.giannini@sigma-tau.it
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Giannini
authors.forename: Mauro
authors.initials: M
authors.lastname: Marzi
authors.forename: Walter
authors.initials: W
authors.lastname: Cabri
authors.forename: Elena
authors.initials: E
authors.lastname: Marastoni
authors.forename: Gianfranco
authors.initials: G
authors.lastname: Battistuzzi
authors.forename: Loredana
authors.initials: L
authors.lastname: Vesci
authors.forename: Claudio
authors.initials: C
authors.lastname: Pisano
authors.forename: Giovanni Luca
authors.initials: GL
authors.lastname: Beretta
authors.forename: Michelandrea
authors.initials: M
authors.lastname: De Cesare
authors.forename: Franco
authors.initials: F
authors.lastname: Zunino
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000494:pharmacology*; D002166:Camptothecin / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D004264:DNA Topoisomerases, Type I / Q000737:chemistry / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology*; D006801:Humans; D020128:Inhibitory Concentration 50; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D023041:Xenograft Model Antitumor Assays
chemical_list: C437308:7-tert-butoxyiminomethylcamptothecin; D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; C120029:homocamptothecin; D004264:DNA Topoisomerases, Type I; D002166:Camptothecin