Structure and activity relationship of several novel CC-1065 analogs

Summary

CC-1065 was found to cause delayed toxicity at therapeutic doses, therefore, a large number of analogs have since been synthesized. A series of analogs with simplified but closely related structures were chosen for this investigation because some were found to be superior to CC-1065 in the treatment of several experimental tumors. The inhibition of L1210 cell growth by U-68,415 was comparable to that by CC-1065. A similar situation was true in terms of their in vivo potency; however, U-68,415 was superior to CC-1065 in terms of anti-P 388 leukemia activity. At the optimal dosage, U-68,415 produced 4 out of 6 long-term (> 30 day) survivors; whereas CC-1065 produced a mere 62% increase of life span (ILS) and no long-term survivors. The order of antitumor potency and effectiveness of the CC-1065 analogs was U-68,415 > U-66,694 > U-68,819 > U-66,664, which was parallel to the inhibition of L1210 cell growth. CC-1065 and all the analogs tested here inhibited DNA synthesis approximately 10 times more than RNA synthesis. Protein synthesis was the least inhibited. On a molar basis, U-68,415 was about 6–9 times more inhibitory toward cellular DNA synthesis than CC-1065, yet the interaction and/or binding of CC-1065 to DNA determined by circular dichroism, DNA melting or differential cytotoxicity assay was much stronger than that of U-68,415. The order of binding of these analogs to calf thymus DNA was U-68,415 > U-66,694 > U-68,819 > U-66,664, and was parallel to that of DNA synthesis inhibition which was in turn parallel to cell growth inhibition and antitumor potential. These results collectively suggest that the cellular DNA is a major site of the action of CC-1065 analogs; however, time course studies reveal that the inhibition of cellular DNA synthesis could not wholly account for their cytotoxicity. Hence, the precise mechanism of action of these agents is not yet fully understood. U-68,415, which exhibited superior activity against a number of tumors and did not cause delayed death in mice, warrants further investigation. U-68,415 is a racemate and two chiral isomers were recently isolated. Therefore, further investigation of both U-68,415 and its chiral isomers is necessary.