Hisashi Michishita

Structure-activity relationships of cyclic enediynes related to dynemicin A. I. Synthesis and antitumor activity of 9-acetoxy enediynes equipped with aryl carbamate moieties.

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.

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.