title: Molecular basis for sequence selective DNA alkylation by (+)- and ent-(-)-CC-1065 and related agents: alkylation site models that accommodate the offset AT-rich adenine N3 alkylation selectivity.
abstract: A detailed evaluation of the DNA alkylation selectivity of (+)-CC-1065, ent-(-)-CC-1065 and a series of aborted and extended analogs possessing the CPI alkylation subunit is detailed and the refinement of a model that accommodates the offset AT-rich adenine N3 alkylation selectivity of the enantiomeric agents is presented. The natural enantiomers bind in the minor groove in the 3'-->5' direction starting from the adenine N3 alkylation site across a 2 base (N-BOC-CPI; i.e. 5'-AA), 3.5 base (CPI-CDPI1/CPI-PDE-I1; i.e. 5'-AAA), 5 base (CC-1065/CPI-CDPI2; i.e. 5'-AAAAA) or 6.5 base (CPI-CDPI3; i.e. 5'-AAAAAA) AT-rich site. In contrast, the unnatural enantiomers bind in the reverse 5'-->3' direction in the minor groove and the binding site necessarily starts at the first 5' base preceding the adenine N3 alkylation site and extends across the alkylation site to the adjacent 3' bases covering an AT-rich site of 2 bases (N-BOC-CPI; e.g., 5'-AA), 5 bases (CC-1065/CPI-CDPI2; eg. 5'-AAAAA), or 6.5 bases (CPI-CDPI3; e.g. 5'-AAAAAA). Notably, the model accommodates the unusual observation that both enantiomers of N-BOC-CPI alkylate the same sites within duplex DNA (5'-AA > 5'-TA) and the required reversed binding orientation of the enantiomeric agents. The reversed binding orientation is required to permit access to the electrophilic cyclopropane and the resulting offset AT-rich alkylation selectivity is the natural consequence of the diastereomeric relationship of the adducts. Three dimensional models of the natural and unnatural enantiomer alkylations are presented which clearly illustrate the offset binding sites. A fundamentally simple model for the CC-1065 DNA alkylation reaction, that accommodates the behavior of both enantiomers, is provided in which the sequence selectivity is derived from the noncovalent binding selectivity of the agents preferentially in the narrower, sterically more accessible AT-rich minor groove, the inherent steric accessibility to the adenine N3 alkylation site that accompanies deep penetration of the agent into the minor groove within an AT-rich site, and the 2 base-pair (N-BOC-CPI), 3.5 base-pair (CPI-PDE-I1/CPI-CDPI1), 5 base-pair (CC-1065/CPI-CDPI2), or 6.5 base-pair (CPI-CDPI3) site size required to permit agent binding in the minor groove at the alkylation site.(ABSTRACT TRUNCATED AT 400 WORDS)
authors.affiliation: Department of Chemistry, Scripps Research Institute, La Jolla, CA 92037.
authors.forename: D L
authors.initials: DL
authors.lastname: Boger
authors.forename: D S
authors.initials: DS
authors.lastname: Johnson
authors.forename: W
authors.initials: W
authors.lastname: Yun
authors.forename: C M
authors.initials: CM
authors.lastname: Tarby
mesh_terms: D000478:Alkylation; D000903:Antibiotics, Antineoplastic / Q000737:chemistry / Q000494:pharmacology*; D001482:Base Composition; D001483:Base Sequence; D001665:Binding Sites; D004247:DNA / Q000737:chemistry* / Q000187:drug effects* / Q000235:genetics; D004279:DNA, Viral / Q000737:chemistry / Q000187:drug effects / Q000235:genetics; D000080890:Duocarmycins; D007211:Indoles; D007933:Leucomycins / Q000737:chemistry / Q000494:pharmacology*; D008958:Models, Molecular; D008969:Molecular Sequence Data; D013539:Simian virus 40 / Q000235:genetics; D013237:Stereoisomerism
chemical_list: D000903:Antibiotics, Antineoplastic; D004279:DNA, Viral; D000080890:Duocarmycins; D007211:Indoles; D007933:Leucomycins; C066962:CPI-CDPI(2); C018782:CC 1065; D004247:DNA