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-clea ving ability, in vitro cytotoxicity, and in vivo antitumor activity. W e found that the water-soluble compounds, in which the tert-amines suc h 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 atta ched, showed not only the enhanced in vivo antitumor activity but also the decreased toxicity compared to the corresponding 9-acetoxy enediy ne 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 fo r 4 days) at about half of the dose of 6. These results suggest that b oth 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. (C) 1997 Elsevier Science Ltd.