Structure and activity relationship of several novel CC-1065 analogs.
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-P388 leukemia activity. At the optimal dosage, U-68,415 produced 4 out of 6 long-term (greater than 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 greater than U-66,694 greater than U-68,819 greater than 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.(ABSTRACT TRUNCATED AT 250 WORDS)
Li
L H
LH
Upjohn Company, Kalamazoo, Michigan 49001.
Wallace
T L
TL
DeKoning
T F
TF
Warpehoski
M A
MA
Kelly
R C
RC
Prairie
M D
MD
Krueger
W C
WC
D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology*; D002470:Cell Survival / Q000187:drug effects; D004273:DNA, Neoplasm / Q000096:biosynthesis; D004259:DNA-Directed DNA Polymerase / Q000302:isolation & purification; D000080890:Duocarmycins; D007211:Indoles; D007933:Leucomycins / Q000494:pharmacology*; D007939:Leukemia L1210 / Q000201:enzymology / Q000473:pathology; D007941:Leukemia P388 / Q000188:drug therapy; D051379:Mice; D012334:RNA, Neoplasm / Q000096:biosynthesis; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured / Q000187:drug effects* / Q000473:pathology
D000903:Antibiotics, Antineoplastic; D004273:DNA, Neoplasm; D000080890:Duocarmycins; D007211:Indoles; D007933:Leucomycins; D012334:RNA, Neoplasm; C018782:CC 1065; D004259:DNA-Directed DNA Polymerase