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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.
Giddens, Anna C; Lee, Ho H; Lu, Guo-Liang; Miller, Christian K; Guo, Jun; Lewis Phillips, Gail D; Pillow, Thomas H; Tercel, Moana.
Afiliação
  • Giddens AC; Auckland Cancer Society Research Centre, Faculty of Medical and Health Sciences, The University of Auckland, Private Bag 92019, Auckland 1142, New Zealand.
  • Lee HH; Auckland Cancer Society Research Centre, Faculty of Medical and Health Sciences, The University of Auckland, Private Bag 92019, Auckland 1142, New Zealand.
  • Lu GL; Auckland Cancer Society Research Centre, Faculty of Medical and Health Sciences, The University of Auckland, Private Bag 92019, Auckland 1142, New Zealand.
  • Miller CK; Auckland Cancer Society Research Centre, Faculty of Medical and Health Sciences, The University of Auckland, Private Bag 92019, Auckland 1142, New Zealand.
  • Guo J; Genentech Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
  • Lewis Phillips GD; Genentech Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
  • Pillow TH; Genentech Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
  • Tercel M; 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.
Bioorg Med Chem ; 24(22): 6075-6081, 2016 11 15.
Article em En | MEDLINE | ID: mdl-27745990
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 IC50 range, with in vitro properties that compare favourably with established microtubule-targeted ADC payloads.
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Texto completo: 1 Bases de dados: MEDLINE Assunto principal: Reagentes de Ligações Cruzadas / Indóis / Anticorpos / Antineoplásicos Limite: Humans Idioma: En Revista: Bioorg Med Chem Assunto da revista: BIOQUIMICA / QUIMICA Ano de publicação: 2016 Tipo de documento: Article País de afiliação: Nova Zelândia

Texto completo: 1 Bases de dados: MEDLINE Assunto principal: Reagentes de Ligações Cruzadas / Indóis / Anticorpos / Antineoplásicos Limite: Humans Idioma: En Revista: Bioorg Med Chem Assunto da revista: BIOQUIMICA / QUIMICA Ano de publicação: 2016 Tipo de documento: Article País de afiliação: Nova Zelândia