Stereoelectronic factors influencing the biological activity and DNA interaction of synthetic antitumor agents modeled on CC-1065.
The synthesis, physicochemical properties, and biological activities of a series of novel spiro cyclopropyl compounds, modeled on the potent antitumor antibiotic CC-1065 (1), are described. Many of these synthetic analogues are significantly more effective than 1 against murine tumors. In particular, compound 27 exhibits high activity and potency. Structure-activity analysis supports a molecular mechanism for biological action involving hydrophobic interaction of the drug with DNA and acid-catalyzed alkylation of DNA.
Warpehoski
M A
MA
Research Laboratories, Upjohn Company, Kalamazoo, Michigan 49001.
Gebhard
I
I
Kelly
R C
RC
Krueger
W C
WC
Li
L H
LH
McGovren
J P
JP
Prairie
M D
MD
Wicnienski
N
N
Wierenga
W
W
D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000138:chemical synthesis / Q000378:metabolism*; D055598:Chemical Phenomena; D002627:Chemistry, Physical; D002942:Circular Dichroism; D004247:DNA / Q000378:metabolism*; D000080890:Duocarmycins; D005260:Female; D007211:Indoles; D007933:Leucomycins / Q000138:chemical synthesis / Q000378:metabolism* / Q000494:pharmacology; D007939:Leukemia L1210 / Q000188:drug therapy; D007941:Leukemia P388 / Q000188:drug therapy; D051379:Mice; D008811:Mice, Inbred DBA; D012995:Solubility
D000903:Antibiotics, Antineoplastic; D000080890:Duocarmycins; D007211:Indoles; D007933:Leucomycins; C018782:CC 1065; D004247:DNA