ANTITUMOR AGENTS .6. SYNTHESIS AND ANTITUMOR-ACTIVITY OF RING A-MODIFIED, RING B-MODIFIED, AND RING C-MODIFIED DERIVATIVES OF CAMPTOTHECIN

Eleven ring A-, ring B-, and ring C-modified analogues of the antitumo r alkaloid camptothecin (1) were prepared and evaluated for cytotoxici ty and antitumor activity against P388 mouse leukemia. Among the six r ing A-modified analogues, hexacyclic compound (14) retained the same o rder of activity as 1. Most of the ring B- and ring C-modified analogu es displayed greatly reduced activity, whereas compound (39), which ha s an alkylidene group at position 5, was found to be as active as 1. T hese results confirmed the necessity of the intact rings A, B, and C o f 1 for antitumor activity. Further, the higher activity of 14 and 39 suggest that the ''northern'' part of the camptothecin molecule may be a suitable site for functionalization to obtain more potent analogues of 1.