title: Antitumor agents. 7. Synthesis and antitumor activity of novel hexacyclic camptothecin analogues.
abstract: Eleven novel hexacyclic and three 7,9-disubstituted pentacyclic derivatives of camptothecin were synthesized and evaluated for in vitro cytotoxic activity against P388, HOC-21, and QG-56 and in vivo antileukemic activity against P388 in mice. Hexacyclic compounds which have an additional 5-, 6-, or 7-membered ring cyclized at positions 7 and 9 of camptothecin were prepared by intramolecular cyclization of pentacyclic camptothecin derivatives or Friedländer condensation of the appropriate bicyclic amino ketone and tricyclic ketone. All of the hexacyclic compounds exhibited compatible or superior activity of 7-ethyl-10-hydroxycamptothecin (SN-38) in in vitro assays without regard to the size or type of the additional ring, and three of six compounds showed more than 300% T/C on in vivo assay. These results suggest that the potency of the hexacyclic ring system is higher than that of the original pentacyclic ring system of camptothecin and that the conformational rigidity of substituents at positions 7 and 9 is favorable for antitumor activity.
authors.affiliation: Exploratory Research Laboratories I, Daiichi Pharmaceutical Company, Ltd., Tokyo, Japan.
authors.forename: M
authors.initials: M
authors.lastname: Sugimori
authors.forename: A
authors.initials: A
authors.lastname: Ejima
authors.forename: S
authors.initials: S
authors.lastname: Ohsuki
authors.forename: K
authors.initials: K
authors.lastname: Uoto
authors.forename: I
authors.initials: I
authors.lastname: Mitsui
authors.forename: K
authors.initials: K
authors.lastname: Matsumoto
authors.forename: Y
authors.initials: Y
authors.lastname: Kawato
authors.forename: M
authors.initials: M
authors.lastname: Yasuoka
authors.forename: K
authors.initials: K
authors.lastname: Sato
authors.forename: H
authors.initials: H
authors.lastname: Tagawa
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000494:pharmacology*; D002166:Camptothecin / Q000031:analogs & derivatives* / Q000494:pharmacology; D004354:Drug Screening Assays, Antitumor; D007941:Leukemia P388 / Q000188:drug therapy; D051379:Mice; D009374:Neoplasms, Experimental / Q000188:drug therapy; D011083:Polycyclic Compounds / Q000138:chemical synthesis / Q000494:pharmacology; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured
chemical_list: D000970:Antineoplastic Agents; D011083:Polycyclic Compounds; D002166:Camptothecin