Reversibility of the covalent reaction of CC-1065 and analogues with DNA.
Covalent DNA adducts of the antitumor antibiotic CC-1065 and its analogues undergo a retrohomologous Michael reaction in aqueous/organic solvent mixtures to regenerate the initial cyclopropylpyrroloindole (CPI) structure and, presumably, intact DNA. This reaction, which at higher temperatures competes with depurination of the N3-alkylated adenine, also occurs to a significant extent at 37 degrees C in neutral aqueous solution. Tritium-labeled adozelesin, covalently bonded to a 3-kilobase DNA restriction fragment which was exhaustively extracted to remove unbonded drug, was efficiently transferred to a 1-kilobase fragment upon coincubation for 20 h at 37 degrees C in aqueous buffer. Covalent adducts of adozelesin, but not CC-1065, on calf thymus DNA were cytotoxic to L1210 cells after incubation for 3 days at 37 degrees C, indicating that reversal of DNA alkylation can mediate potent cellular effects for simplified CC-1065 analogues.
Warpehoski
M A
MA
Medicinal Chemistry Research, Upjohn Laboratories, Upjohn Company, Kalamazoo, Michigan 49001.
Harper
D E
DE
Mitchell
M A
MA
Monroe
T J
TJ
D000478:Alkylation; D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000378:metabolism*; D001572:Benzofurans; D002417:Cattle; D002470:Cell Survival / Q000187:drug effects; D002942:Circular Dichroism; D003509:Cyclohexanecarboxylic Acids / Q000378:metabolism / Q000494:pharmacology; D053138:Cyclohexenes; D004247:DNA / Q000187:drug effects / Q000378:metabolism*; D000080890:Duocarmycins; D007211:Indoles; D007933:Leucomycins / Q000737:chemistry / Q000378:metabolism*; D007939:Leukemia L1210 / Q000473:pathology; D015394:Molecular Structure; D012996:Solutions; D013056:Spectrophotometry, Ultraviolet; D014316:Tritium; D014407:Tumor Cells, Cultured
D000903:Antibiotics, Antineoplastic; D001572:Benzofurans; D003509:Cyclohexanecarboxylic Acids; D053138:Cyclohexenes; D000080890:Duocarmycins; D007211:Indoles; D007933:Leucomycins; D012996:Solutions; D014316:Tritium; C018782:CC 1065; C060090:adozelesin; D004247:DNA