Molecular basis for sequence-specific DNA alkylation by CC-1065.
CC-1065 is a potent antitumor antibiotic that binds covalently to N3 of adenine in the minor groove of DNA. The CC-1065 molecule is made up of three repeating pyrroloindole subunits, one of which (the left-hand one or A subunit) contains a reactive cyclopropyl function. The drug reacts with adenines in DNA in a highly sequence-specific manner, overlapping four base pairs to the 5'-side of the covalently modified base. Concomitant with CC-1065 covalent binding to DNA is an asymmetric effect on local DNA structure which extends more than one helix turn to the 5'-side of the covalent binding site. The DNA alkylation, sequence specificity, and biological potency of CC-1065 and a select group of trimeric synthetic analogues were evaluated. The results suggest that (a) noncovalent interactions between this series of compounds and DNA do not lead to the formation of complexes stable enough to be detected by footprinting methods, (b) sequence specificity and alkylation intensity can be modulated by the substituents on the nonreactive middle and right-hand segments, and (c) biological potency correlates well with ability to alkylate DNA. In addition, the extent and the sequence specificity of covalent adduct formation between linear DNA fragments and three analogues comprised of the CC-1065 alkylating subunit linked to zero (analogue A), one (analogue AB), or two (analogue ABC) nonreactive indole subunits were compared.(ABSTRACT TRUNCATED AT 250 WORDS)
Hurley
L H
LH
Division of Medicinal Chemistry, College of Pharmacy, University of Texas, Austin 78712.
Lee
C S
CS
McGovren
J P
JP
Warpehoski
M A
MA
Mitchell
M A
MA
Kelly
R C
RC
Aristoff
P A
PA
D000478:Alkylation; D000818:Animals; D000903:Antibiotics, Antineoplastic; D001483:Base Sequence; D055598:Chemical Phenomena; D002621:Chemistry; D004247:DNA; D003850:Deoxyribonuclease I; D000080890:Duocarmycins; D007211:Indoles; D007933:Leucomycins / Q000627:therapeutic use; D007939:Leukemia L1210 / Q000188:drug therapy; D007941:Leukemia P388 / Q000188:drug therapy; D051379:Mice; D013329:Structure-Activity Relationship
D000903:Antibiotics, Antineoplastic; D000080890:Duocarmycins; D007211:Indoles; D007933:Leucomycins; C018782:CC 1065; D004247:DNA; D003850:Deoxyribonuclease I