CC-1065 and the duocarmycins: unraveling the keys to a new class of naturally derived DNA alkylating agents.
Key studies defining the DNA alkylation properties and selectivity of a new class of exceptionally potent, naturally occurring antitumor antibiotics including CC-1065, duocarmycin A, and duocarmycin SA are reviewed. Recent studies conducted with synthetic agents containing deep-seated structural changes and the unnatural enantiomers of the natural products and related analogs have defined the structural basis for the sequence-selective alkylation of duplex DNA and fundamental relationships between chemical structure, functional reactivity, and biological properties. The agents undergo a reversible, stereoelectronically controlled adenine-N3 addition to the least substituted carbon of the activated cyclopropane within selected AT-rich sites. The preferential AT-rich non-covalent binding selectivity of the agents within the narrower, deeper AT-rich minor groove and the steric accessibility to the alkylation site that accompanies deep AT-rich minor groove penetration control the sequence-selective DNA alkylation reaction and stabilize the resulting adduct. For the agents that possess sufficient reactivity to alkylate DNA, a direct relationship between chemical or functional stability and biological potency has been defined.
Boger
D L
DL
Department of Chemistry, Scripps Research Institute, La Jolla, CA 92037, USA.
Johnson
D S
DS
D000477:Alkylating Agents; D000903:Antibiotics, Antineoplastic; D001483:Base Sequence; D001665:Binding Sites; D016384:Consensus Sequence; D004247:DNA / Q000737:chemistry*; D000080890:Duocarmycins; D007211:Indoles; D007933:Leucomycins; D008958:Models, Molecular; D008969:Molecular Sequence Data; D015394:Molecular Structure; D009690:Nucleic Acid Conformation; D011758:Pyrroles; D013329:Structure-Activity Relationship
D000477:Alkylating Agents; D000903:Antibiotics, Antineoplastic; D000080890:Duocarmycins; D007211:Indoles; D007933:Leucomycins; D011758:Pyrroles; C066098:duocarmycin SA; C018782:CC 1065; D004247:DNA