The DNA phosphate backbone is not involved in catalysis of the duocarmycin and CC-1065 DNA alkylation reaction.
The rates of DNA alkylation were established for the reaction of (+)-duocarmycin SA (1) with the native duplex d(G(1)TCAATTAGTC(11))*d(G(12)ACTAATTGAC(22)), an 11 bp deoxyoligonucleotide that contains a single high-affinity alkylation site that has been structurally characterized at exquisite resolution, and modified duplexes in which the four backbone phosphates proximal to the C4 carbonyl of bound 1 were replaced with methylphosphonates. All were found to react at comparable rates establishing that these backbone phosphates do not participate in catalysis of the DNA alkylation reaction.
Ambroise
Yves
Y
Department of Chemistry and The Skaggs Institute for Chemical Biology, The Scripps Research Institute, 10550North Torrey Pines Road, La Jolla, CA 92037, USA.
Boger
Dale L
DL
D000465:Algorithms; D000478:Alkylation; D000903:Antibiotics, Antineoplastic / Q000737:chemistry*; D002384:Catalysis; D004247:DNA / Q000737:chemistry*; D000080890:Duocarmycins; D007211:Indoles; D007700:Kinetics; D007933:Leucomycins / Q000737:chemistry*; D009682:Magnetic Resonance Spectroscopy; D010710:Phosphates / Q000737:chemistry; D011758:Pyrroles / Q000737:chemistry*
D000903:Antibiotics, Antineoplastic; D000080890:Duocarmycins; D007211:Indoles; D007933:Leucomycins; D010710:Phosphates; D011758:Pyrroles; C066098:duocarmycin SA; C018782:CC 1065; D004247:DNA