title: A novel achiral seco-amino-cyclopropylindoline (CI) analog of CC-1065 and the duocarmycins: design, synthesis and biological studies.
abstract: The design, synthesis and DNA binding properties of a novel achiral and amino-containing seco-cyclopropylindoline analog (seco-amino-CI-TMI, 1) of the duocarmycins are described. Thermal induced DNA cleavage studies on pUC18 DNA revealed compound 1 to preferentially bind in the minor groove and to covalently react with AT-rich sequences, particularly at the underlined adenine-N3 group of 5'-AAAAA(865)-3'. This sequence specificity is similar to adozelesin and CC-1065. Using a 4-day continuous exposure, compound 1 inhibited the growth of K562 human chronic myeloid leukemia cells in culture. Compound 1 has appreciable cytotoxicity (IC50 value of 1.30 microM) relative to compound 2 (0.15 microM), the corresponding racemic and hydroxy-seco-CI-TMI analog. These results indicate that the aminophenethyl chloride group present in compound 1 has similar sequence specific and cytotoxic properties to the hydroxy-containing seco-precursors of CC-1065 and the duocarmycins. Moreover, the results suggest that the chiral center present in the natural products is not absolutely necessary for biological activity. The novel aminophenethyl halide moiety is, therefore, a useful template from which to develop future achiral analogs of CC-1065 and the duocarmycins.
authors.affiliation: Department of Chemistry, Furman University, 3300 Poinsett Highway, Greenville, SC 29613, USA.
authors.forename: James L
authors.initials: JL
authors.lastname: Toth
authors.forename: John D
authors.initials: JD
authors.lastname: Trzupek
authors.forename: Lloyd V
authors.initials: LV
authors.lastname: Flores
authors.forename: Konstantinos
authors.initials: K
authors.lastname: Kiakos
authors.forename: John A
authors.initials: JA
authors.lastname: Hartley
authors.forename: William T
authors.initials: WT
authors.lastname: Pennington
authors.forename: Moses
authors.initials: M
authors.lastname: Lee
mesh_terms: D000903:Antibiotics, Antineoplastic / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D045744:Cell Line, Tumor; D018360:Crystallography, X-Ray; D015195:Drug Design; D004354:Drug Screening Assays, Antitumor; D000080890:Duocarmycins; D006801:Humans; D007211:Indoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D020128:Inhibitory Concentration 50; D020014:K562 Cells; D015394:Molecular Structure; D011758:Pyrroles / Q000737:chemistry; D013237:Stereoisomerism
chemical_list: C121852:6-amino-3-(chloromethyl)-1-((5,6,7-trimethoxyindol-2-yl)carbonyl)indoline; D000903:Antibiotics, Antineoplastic; D000080890:Duocarmycins; D007211:Indoles; D011758:Pyrroles; C066098:duocarmycin SA; C018782:CC 1065