title: Demonstration of a pronounced effect of noncovalent binding selectivity on the (+)-CC-1065 DNA alkylation and identification of the pharmacophore of the alkylation subunit.
abstract: Studies on the structural origin of the DNA alkylation selectivity of the antitumor antibiotic (+)-CC-1065 are detailed. The sites of alkylation of double-stranded DNA were examined for simple derivatives of 7-methyl-1,2,8,8a-tetrahydrocycloprop[1,2-c]pyrrolo[3,2-e]indol- 4(5H)-one (CPI), (+)-CC-1065, and agents incorporating the parent 1,2,7,7a-tetrahydrocycloprop[1,2-c]indol-4-one (CI) left-hand subunit. The CI subunit of the agents is a much more reactive alkylating agent than the natural CPI alkylation subunit of CC-1065. Consequently, simple derivatives of CI were found to alkylate double-stranded DNA under milder conditions than were simple derivatives of CPI, and the marked similarities in the CI and CPI DNA alkylation profiles illustrate that CI represents the minimum pharmacophore of CPI. Comparisons of the DNA alkylation profiles of (+)-N-butyloxycarbonyl-CPI, (+)-N-acetyl-CPI, and (+)-CC-1065 revealed distinctions in the CPI and (+)-CC-1065 sites of alkylation, whereas the incorporation of the reactive CI electrophile into an analog of CC-1065 (CI-CDPI2) (CDPI, N3-carbamoyl-1,2-dihydro-3H-pyrrolo[3,2-e]indole-7-carboxylic acid) provided an agent that possesses the characteristic CC-1065 DNA alkylation profile (site selectivity and relative site intensity). These observations suggest that the noncovalent binding selectivity of the agents may restrict the number of available DNA alkylation sites and play a productive role in controlling the sequence-selective alkylation by effectively delivering the electrophile to A + T-rich minor groove regions of DNA possessing accessible adenine N-3 alkylation sites. In turn, the noncovalent binding selectivity may be derived from preferential binding within the narrower, sterically more accessible A + T-rich minor groove of double-stranded DNA.
authors.affiliation: Department of Chemistry, Purdue University, West Lafayette, IN 47907.
authors.forename: D L
authors.initials: DL
authors.lastname: Boger
authors.forename: H
authors.initials: H
authors.lastname: Zarrinmayeh
authors.forename: S A
authors.initials: SA
authors.lastname: Munk
authors.forename: P A
authors.initials: PA
authors.lastname: Kitos
authors.forename: O
authors.initials: O
authors.lastname: Suntornwat
mesh_terms: D000478:Alkylation; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology*; D001483:Base Sequence; D001665:Binding Sites; D004279:DNA, Viral / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D000080890:Duocarmycins; D007211:Indoles; D007933:Leucomycins / Q000378:metabolism / Q000494:pharmacology*; D008969:Molecular Sequence Data; D015394:Molecular Structure; D015345:Oligonucleotide Probes; D013539:Simian virus 40 / Q000235:genetics; D013329:Structure-Activity Relationship
chemical_list: D000903:Antibiotics, Antineoplastic; D004279:DNA, Viral; D000080890:Duocarmycins; D007211:Indoles; D007933:Leucomycins; D015345:Oligonucleotide Probes; C018782:CC 1065