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

作者：Giddens Anna C; Lee Ho H; Lu Guo Liang; Miller Christian K; Guo Jun; Phillips Gail D Lewis; Pillow Thomas H; Tercel Moana^*

来源：Bioorganic & Medicinal Chemistry, 2016, 24(22): 6075-6081.

DOI：10.1016/j.bmc.2016.09.068

• DNA cross-linking agent
• AminoCBI
• Duocarmycin
• Pyrrolobenzodiazepine
• Antibody-drug conjugate

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.

• 出版日期2016-11-15