title: Novel 7-oxyiminomethyl derivatives of camptothecin with potent in vitro and in vivo antitumor activity.
abstract: In an attempt to synthesize potential anticancer agents acting by inhibition of topoisomerase I (Topo I) a new series of oxyiminomethyl derivatives in position 7 of camptothecin (CPT) was prepared. The synthesis relied on the condensation of 20S-CPT-7-aldehyde or 20S-CPT-7-ketones with alkyl, aryl, heteroaryl, arylalkyl, and heteroarylalkyl O-substituted hydroxylamines. The compounds were tested for their cytotoxic activity in vitro against H460 non-small lung carcinoma cell line, the activity being for 24 out of 37 compounds in the 0.01-0.3 microM range. A QSAR analysis indicated that lipophilicity is the main parameter correlated with cytotoxicity. Investigation of the DNA-Topo I-drug cleavable complex showed a rough parallelism between cytotoxicity and inhibition of Topo I. Persistence of the DNA cleavage after NaCl-mediated disruption of the ternary complex suggests that for the most potent compounds, e.g., 15, the cytotoxicity was at least in part related to stabilization of the complex, as also supported by the persistence of the DNA-enzyme complex in drug-treated cells. The in vivo antitumor efficacy of the most potent analogue (15) was evaluated in direct comparison with topotecan using human lung tumor xenograft models. In the range of optimal doses (2-3 mg/kg), the improved efficacy of 15 was documented in terms of inhibition of tumor growth and rate of complete response.
authors.affiliation: Dipartimento di Scienze Molecolari Agroalimentari, Sezione di Chimica, Università di Milano, Via Celoria 2, 20133 Milan, Italy.
authors.forename: S
authors.initials: S
authors.lastname: Dallavalle
authors.forename: A
authors.initials: A
authors.lastname: Ferrari
authors.forename: B
authors.initials: B
authors.lastname: Biasotti
authors.forename: L
authors.initials: L
authors.lastname: Merlini
authors.forename: S
authors.initials: S
authors.lastname: Penco
authors.forename: G
authors.initials: G
authors.lastname: Gallo
authors.forename: M
authors.initials: M
authors.lastname: Marzi
authors.forename: M O
authors.initials: MO
authors.lastname: Tinti
authors.forename: R
authors.initials: R
authors.lastname: Martinelli
authors.forename: C
authors.initials: C
authors.lastname: Pisano
authors.forename: P
authors.initials: P
authors.lastname: Carminati
authors.forename: N
authors.initials: N
authors.lastname: Carenini
authors.forename: G
authors.initials: G
authors.lastname: Beretta
authors.forename: P
authors.initials: P
authors.lastname: Perego
authors.forename: M
authors.initials: M
authors.lastname: De Cesare
authors.forename: G
authors.initials: G
authors.lastname: Pratesi
authors.forename: F
authors.initials: F
authors.lastname: Zunino
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002166:Camptothecin / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D004247:DNA / Q000737:chemistry / Q000378:metabolism; D004264:DNA Topoisomerases, Type I / Q000737:chemistry / Q000378:metabolism; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D007097:Imines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D015151:Immunoblotting; D020128:Inhibitory Concentration 50; D051379:Mice; D008819:Mice, Nude; D021281:Quantitative Structure-Activity Relationship; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured
chemical_list: C437308:7-tert-butoxyiminomethylcamptothecin; D000970:Antineoplastic Agents; D007097:Imines; D004247:DNA; D004264:DNA Topoisomerases, Type I; D002166:Camptothecin