title: Metal cation complexation and activation of reversed CPyI analogues of CC-1065 and duocarmycin SA: partitioning the effects of binding and catalysis.
abstract: The synthesis and examination of a novel class of reversed CPyI analogues of CC-1065 and the duocarmycins are described. Capable of a unique metal cation activation of DNA alkylation, these agents allowed the effects of the DNA binding domain (10(4)-fold increase in DNA alkylation rate and efficiency) to be partitioned into two components: that derived from enhanced DNA binding affinity and selectivity (10-80-fold) and that derived from a contribution to catalysis (250-5000-fold). In addition, the reversed enantiomeric selectivity of these sequence selective DNA alkylating agents provides further strong support for a previously disclosed model where it is the noncovalent binding selectivity of the compounds, and not the alkylation subunit or the source of catalysis, that controls the DNA alkylation selectivity.
authors.affiliation: Department of Chemistry and The Skaggs Institute for Chemical Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, USA.
authors.forename: D A
authors.initials: DA
authors.lastname: Ellis
authors.forename: S E
authors.initials: SE
authors.lastname: Wolkenberg
authors.forename: D L
authors.initials: DL
authors.lastname: Boger
mesh_terms: D000477:Alkylating Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D002384:Catalysis; D004247:DNA / Q000737:chemistry / Q000378:metabolism; D000080890:Duocarmycins; D007211:Indoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D007700:Kinetics; D007933:Leucomycins / Q000737:chemistry / Q000494:pharmacology; D007939:Leukemia L1210 / Q000188:drug therapy; D011758:Pyrroles / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D015363:Quinolones / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D013237:Stereoisomerism
chemical_list: C412579:1,2,9,9a-tetrahydrocyclopropa(c)pyrido(3,2-e)indol-4-one-7-carboxylate; D000477:Alkylating Agents; D000903:Antibiotics, Antineoplastic; D000080890:Duocarmycins; D007211:Indoles; D007933:Leucomycins; D011758:Pyrroles; D015363:Quinolones; C066098:duocarmycin SA; C018782:CC 1065; D004247:DNA