Structure-activity relationships of cyclic enediynes related to dynemicin A. II. Synthesis and antitumor activity of 9- and 12-substituted enediynes equipped with aryl carbamate moieties.
Novel enediyne compounds 4-8, simple analogues of dynemicin A (1) equipped with the phenyl or 4-chlorophenyl carbamate moiety, were synthesized and evaluated for DNA-cleaving ability, in vitro cytotoxicity, and in vivo antitumor activity. As a result of the SAR study, it was revealed that the size and character of the substituents (R1 and R2) at the C9 position critically influenced both the stability and antitumor activity of the enediyne compounds. We found that the 9-deoxy compound 6a, a stable and less bulky enediyne having a hydrogen as the R1 and R2 substituents, showed a significant in vivo activity with a T/C of 215% at a daily dosage of 2.0 mg/kg for 4 days. The incorporation of an oxygen-containing functional group as the R3 substituent on a benzene ring resulted in considerable abolishing of both the in vitro and in vivo potencies. In a series of 9-acyloxy compounds, incorporation of the basic aromatic moiety such as 8e was effective for the in vitro activity, but it was ineffective for the in vivo activity. Furthermore, for the stereochemistry-activity relationships at the C9 position, the (9R*)-isomers of 8c, 8e, and 8f were found to show higher both in vitro and in vivo than the corresponding (9S*)-isomers. For the mechanistic studies, compound 6a underwent Bergman cycloaromatization via a diradical pathway under acidic conditions, whereas it scarcely showed DNA-cleaving activity due to the chemical stability of the aryl carbamate moiety under neutral conditions.
Unno
R
R
Drug Discovery Research Department, Sanwa Kagaku Kenkyusho Co., Ltd., Mie, Japan.
Michishita
H
H
Inagaki
H
H
Suzuki
Y
Y
Baba
Y
Y
Jomori
T
T
Moku
M
M
Nishikawa
T
T
Isobe
M
M
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; D007941:Leukemia P388 / Q000188:drug therapy; D051379:Mice; D013329:Structure-Activity Relationship
D000880:Anthraquinones; D000903:Antibiotics, Antineoplastic; D053281:Enediynes; D004247:DNA; C061229:dynemicin A