title: Novel 7-substituted camptothecins with potent antitumor activity.
abstract: The natural alkaloid camptothecin is the lead compound of a new class of antitumor agents with a unique mechanism of action (i.e. inhibition of DNA topoisomerase I). The pharmacological interest of these agents has generated a large number of derivatives and analogues endowed with potent cytotoxic activity, two of them being in clinical use as antitumor drugs. We have synthesized a new series of camptothecins substituted in position 7 with an alkyl or alkenyl chain bearing cyano and/or carbethoxy groups. These compounds showed potent cytotoxic activity in vitro against the human non-small-cell lung carcinoma H460 cell line, most of them exhibiting IC(50) values in the 0.05-1 microM range, more active than topotecan used as a reference compound. In particular 7-cyano-20S-camptothecin (5a) showed high in vitro cytotoxicity against a topotecan-resistant H460 cell subline (H460/TPT) and a cisplatin-resistant ovarian carcinoma subline (IGROV-1/Pt 1). In an in vivo evaluation of the antitumor activity, 5a appeared significantly more effective than topotecan in the H460 tumor model and comparable with topotecan in a small-cell lung carcinoma model and a colon carcinoma model. The efficacy and good tolerability of this compound increase interest for further preclinical development.
authors.affiliation: Dipartimento di Scienze Molecolari Agroalimentari, Sezione di Chimica, Università di Milano, Via Celoria 2, 20133 Milano, Italy.
authors.forename: S
authors.initials: S
authors.lastname: Dallavalle
authors.forename: T
authors.initials: T
authors.lastname: Delsoldato
authors.forename: A
authors.initials: A
authors.lastname: Ferrari
authors.forename: L
authors.initials: L
authors.lastname: Merlini
authors.forename: S
authors.initials: S
authors.lastname: Penco
authors.forename: N
authors.initials: N
authors.lastname: Carenini
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; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured
chemical_list: C415573:7-cyanocamptothecin; D000970:Antineoplastic Agents; D002166:Camptothecin