title: Modification of the hydroxy lactone ring of camptothecin: inhibition of mammalian topoisomerase I and biological activity.
abstract: Several camptothecin derivatives containing a modified hydroxy lactone ring have been synthesized and evaluated for inhibition of topoisomerase I and cytotoxicity to mammalian cells. Each of the groups of the hydroxy lactone moiety, the carbonyl oxygen, the ring lactone oxygen, and the 20-hydroxy group, were shown to be critical for enzyme inhibition. For example the lactol, lactam, thiolactone, and 20-deoxy derivatives did not stabilize the covalent DNA-topoisomerase I complex. With a few exceptions, those compounds that did not inhibit topoisomerase I were not cytotoxic to mammalian cells. Two cytotoxic derivatives that did not inhibit topoisomerase I were shown to produce non-protein-associated DNA single-strand breaks and are likely to have a different mechanism of action. One of these compounds was tested for antitumor activity and was found to be inactive. The present findings, as well as other reports that the hydroxy lactone ring of camptothecin is critical for antitumor activity in vivo, correlate with the structure-activity relationships at the level of topoisomerase I and support the hypothesis that antitumor activity is related to inhibition of this target enzyme.
authors.affiliation: Department of Medical Chemistry, Smith Kline and French Laboratories, Kind of Prussia, Pennsylvania 19406.
authors.forename: R P
authors.initials: RP
authors.lastname: Hertzberg
authors.forename: M J
authors.initials: MJ
authors.lastname: Caranfa
authors.forename: K G
authors.initials: KG
authors.lastname: Holden
authors.forename: D R
authors.initials: DR
authors.lastname: Jakas
authors.forename: G
authors.initials: G
authors.lastname: Gallagher
authors.forename: M R
authors.initials: MR
authors.lastname: Mattern
authors.forename: S M
authors.initials: SM
authors.lastname: Mong
authors.forename: J O
authors.initials: JO
authors.lastname: Bartus
authors.forename: R K
authors.initials: RK
authors.lastname: Johnson
authors.forename: W D
authors.initials: WD
authors.lastname: Kingsbury
mesh_terms: D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000138:chemical synthesis* / Q000494:pharmacology; D002166:Camptothecin / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology; D055598:Chemical Phenomena; D002621:Chemistry; D004354:Drug Screening Assays, Antitumor; D007939:Leukemia L1210 / Q000188:drug therapy; D051379:Mice; D013329:Structure-Activity Relationship; D059004:Topoisomerase I Inhibitors
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D059004:Topoisomerase I Inhibitors; D002166:Camptothecin