STRUCTURE-ACTIVITY-RELATIONSHIPS OF CYCLIC ENEDIYNES RELATED TO DYNEMICIN-A .2. SYNTHESIS AND ANTITUMOR-ACTIVITY OF 9-SUBSTITUTED AND 12-SUBSTITUTED ENEDIYNES EQUIPPED WITH ARYL CARBAMATE MOIETIES

Novel enediyne compounds 4-8, simple analogues of dynemicin A (1) equi pped with the phenyl or 4-chlorophenyl carbamate moiety, were synthesi zed and evaluated for DNA-cleaving ability, in vitro cytotoxicity, and in vivo antitumor activity. As a result of the SAR study, it was reve aled that the size and character of the substituents (R-1 and R-2) at the C9 position critically influenced both the stability and antitumor activity of the enediyne compounds. We found that the 9-deoxy compoun d 6a, a stable and less bulky enediyne having a hydrogen as the R-1 an d R-2 substituents, showed a significant in vivo activity with a T/C o f 215% at a daily dosage of 2.0 mg/kg for 4 days. The incorporation of an oxygen-containing functional group as the R-3 substituent on a ben zene 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. Furthermor e, 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 mechan istic 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 carbam ate moiety under neutral conditions. (C) 1997 Elsevier Science Ltd.