title: Structure-activity relationships of cyclic enediynes related to dynemicin A. I. Synthesis and antitumor activity of 9-acetoxy enediynes equipped with aryl carbamate moieties.
abstract: A series of the 9-acetoxy enediyne compounds, 6a-k which were simplified from natural dynemicin A, and designed to be equipped with various aryl carbamate moieties, was synthesized and evaluated for DNA-cleaving ability, in vitro cytotoxicity, and in vivo antitumor activity. As a result of this study of the structure-activity relationships (SAR) with regard to the Rt substituent, both compounds 6a and 6f with the phenyl carbamate and 4-chlorophenyl carbamate moiety, respectively, were found to exhibit significant activity (T/C > 200%) against murine P388 leukemia in mice, in spite of having IC50 values in the micromolar range. In particular, compound 6f showed the most potent activity with a maximum T/C of 256% at a daily dosage of 4.0 mg/kg for four days. Furthermore, both compounds 6a and 6f were effective against Meth A sarcoma in mice and inhibited 71 and 77% of the tumor growth at 2.0 and 3.0 mg/kg dosages, respectively. In contrast to 6f, compound 6i possessing the 2-nitrophenyl carbamate moiety showed only a slight in vivo activity, while it had about one order of magnitude higher in vitro cytotoxicity than 6f. For the stereochemistry-activity relationships at the C9 position, the (9R*)-isomers of 6c, 6g, and 6j were found to show higher in vitro and in vivo potencies than the corresponding (9S*)-isomers.
authors.affiliation: Drug Discovery Research Department, Sanwa Kagaku Kenkyusho Co. Ltd, Mie, Japan.
authors.forename: R
authors.initials: R
authors.lastname: Unno
authors.forename: H
authors.initials: H
authors.lastname: Michishita
authors.forename: H
authors.initials: H
authors.lastname: Inagaki
authors.forename: Y
authors.initials: Y
authors.lastname: Suzuki
authors.forename: Y
authors.initials: Y
authors.lastname: Baba
authors.forename: T
authors.initials: T
authors.lastname: Jomori
authors.forename: T
authors.initials: T
authors.lastname: Nishikawa
authors.forename: M
authors.initials: M
authors.lastname: Isobe
mesh_terms: D000818:Animals; D000880:Anthraquinones / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D000903:Antibiotics, Antineoplastic / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D016923:Cell Death / Q000187:drug effects; D002460:Cell Line; D004247:DNA / Q000187:drug effects; D015195:Drug Design; D004354:Drug Screening Assays, Antitumor; D053281:Enediynes; D006801:Humans; D007941:Leukemia P388 / Q000188:drug therapy; D051379:Mice; D012513:Sarcoma, Experimental / Q000188:drug therapy; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: D000880:Anthraquinones; D000903:Antibiotics, Antineoplastic; D053281:Enediynes; D004247:DNA; C061229:dynemicin A