title: Analogues of DNA minor groove cross-linking agents incorporating aminoCBI, an amino derivative of the duocarmycins: Synthesis, cytotoxicity, and potential as payloads for antibody-drug conjugates.
abstract: A Pd-catalysed amination method is used to convert seco-CBI, a synthetic analogue of the alkylating subunit of the duocarmycin natural products, from the phenol to amino form. This allows efficient enantioselective access to the more potent S enantiomer of aminoCBI and its incorporation into analogues of DNA minor groove cross-linking agents. Evaluation in a panel of nine human tumour cell lines shows that the bifunctional agents containing aminoCBI are generally less cytotoxic than their phenolCBI analogues and more susceptible to P-glycoprotein-mediated resistance. However, all bifunctional agents are potent cytotoxins, some in the sub-pM IC50range, with in vitro properties that compare favourably with established microtubule-targeted ADC payloads.
authors.affiliation: Auckland Cancer Society Research Centre, Faculty of Medical and Health Sciences, The University of Auckland, Private Bag 92019, Auckland 1142, New Zealand.
authors.forename: Anna C
authors.initials: AC
authors.lastname: Giddens
authors.affiliation: Auckland Cancer Society Research Centre, Faculty of Medical and Health Sciences, The University of Auckland, Private Bag 92019, Auckland 1142, New Zealand.
authors.forename: Ho H
authors.initials: HH
authors.lastname: Lee
authors.affiliation: Auckland Cancer Society Research Centre, Faculty of Medical and Health Sciences, The University of Auckland, Private Bag 92019, Auckland 1142, New Zealand.
authors.forename: Guo-Liang
authors.initials: GL
authors.lastname: Lu
authors.affiliation: Auckland Cancer Society Research Centre, Faculty of Medical and Health Sciences, The University of Auckland, Private Bag 92019, Auckland 1142, New Zealand.
authors.forename: Christian K
authors.initials: CK
authors.lastname: Miller
authors.affiliation: Genentech Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
authors.forename: Jun
authors.initials: J
authors.lastname: Guo
authors.affiliation: Genentech Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
authors.forename: Gail D
authors.initials: GD
authors.lastname: Lewis Phillips
authors.affiliation: Genentech Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
authors.forename: Thomas H
authors.initials: TH
authors.lastname: Pillow
authors.affiliation: Auckland Cancer Society Research Centre, Faculty of Medical and Health Sciences, The University of Auckland, Private Bag 92019, Auckland 1142, New Zealand. Electronic address: m.tercel@auckland.ac.nz.
authors.forename: Moana
authors.initials: M
authors.lastname: Tercel
mesh_terms: D000906:Antibodies / Q000737:chemistry / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D003432:Cross-Linking Reagents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D000080890:Duocarmycins; D006801:Humans; D007211:Indoles / Q000737:chemistry / Q000494:pharmacology*; D015394:Molecular Structure; D011760:Pyrrolidinones / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship
chemical_list: D000906:Antibodies; D000970:Antineoplastic Agents; D003432:Cross-Linking Reagents; D000080890:Duocarmycins; D007211:Indoles; D011760:Pyrrolidinones; C058289:duocarmycin A
keywords: AminoCBI; Antibody–drug conjugate; DNA cross-linking agent; Duocarmycin; Pyrrolobenzodiazepine