Synthesis and antitumor activity of water-soluble enediyne compounds related to dynemicin A.
The enediyne compounds 9-14, simple dynemicin A (1) analogues equipped with aryl carbamate moieties with various aliphatic amino or hydroxy groups at the C9 position, were synthesized and evaluated for DNA-cleaving ability, in vitro cytotoxicity, and in vivo antitumor activity. We found that the water-soluble compounds, in which the tert-amines such as the 2-(dimethylamino)ethyl (10b, 14b), 2-(pyrrolidino)ethyl (10c), or 1-azabicyclo[3.3.0]oct-5-ylmethyl (10d, 12d, 14d) group were attached, showed not only the enhanced in vivo antitumor activity but also the decreased toxicity compared to the corresponding 9-acetoxy enediyne compounds 6-8. In particular, compound 10c showed the most enhanced in vivo antitumor activity (T/C = 222% at a daily dose of 1.25 mg/kg for 4 days) at about half of the dose of 6. These results suggest that both the enhanced antitumor activity and the reduced toxicity might be due to the improved bioavailability or disposition of compounds 6-8 by their water-solubilization.
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
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; D004354:Drug Screening Assays, Antitumor; D053281:Enediynes; D006801:Humans; D007941:Leukemia P388 / Q000188:drug therapy; D051379:Mice; D012995:Solubility; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured; D014867:Water
D000880:Anthraquinones; D000903:Antibiotics, Antineoplastic; D053281:Enediynes; D014867:Water; D004247:DNA; C061229:dynemicin A