An Extended Pyrrolobenzodiazepine鈥揚olyamide Conjugate with Selectivity for a DNA Sequence Containing the ICB2 Transcription Factor Binding Site

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• 作者：Federico Brucoli ; Rachel M. Hawkins ; Colin H. James ; Paul J. M. Jackson ; Geoff Wells ; Terence C. Jenkins ; Tom Ellis ; Minal Kotecha ; Daniel Hochhauser ; John A. Hartley ; Philip W. Howard ; David E. Thurston
• 刊名：Journal of Medicinal Chemistry
• 出版年：2013
• 出版时间：August 22, 2013
• 年：2013
• 卷：56
• 期：16
• 页码：6339-6351
• 全文大小：534K
• 年卷期：v.56,no.16(August 22, 2013)
• ISSN：1520-4804

文摘

The binding of nuclear factor Y (NF-Y) to inverted CCAAT boxes (ICBs) within the promoter region of DNA topoisomerase II伪 results in control of cell differentiation and cell cycle progression. Thus, NF-Y inhibitory small molecules could be employed to inhibit the replication of cancer cells. A library of pyrrolobenzodiazepine (PBD) C8-conjugates consisting of one PBD unit attached to tri-heterocyclic polyamide fragments was designed and synthesized. The DNA-binding affinity and sequence selectivity of each compound were evaluated in DNA thermal denaturation and DNase I footprinting assays, and the ability to inhibit binding of NF-Y to ICB1 and ICB2 was studied using an electrophoretic mobility shift assay (EMSA). 3a was found to be a potent inhibitor of NF-Y binding, exhibiting a 10-fold selectivity for an ICB2 site compared to an ICB1-containing sequence, and showing low nanomolar cytotoxicity toward human tumor cell lines. Molecular modeling and computational studies have provided details of the covalent attachment process that leads to formation of the PBD鈥揇NA adduct, and have allowed the preference of 3a for ICB2 to be rationalized.