Oxoazabenzo[de]anthracenes Conjugated to Amino Acids: Synthesis and Evaluation as DNA-Binding Antitumor Agents
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- 作者：Nathalie Dias ; Jean-Franç ; ois Goossens ; Brigitte Baldeyrou ; Amé ; lie Lansiaux ; Pierre Colson ; Alberto Di Salvo ; Jeanne Bernal ; Agnes Turnbull ; David J. Mincher ; and Christian Bailly
- 刊名：Bioconjugate Chemistry
- 出版年：2005
- 出版时间：July 2005
- 年：2005
- 卷：16
- 期：4
- 页码：949 - 958
- 全文大小：547K
- 年卷期：v.16,no.4(July 2005)
- ISSN：1520-4812
文摘
We report the synthesis of an original series of oxoazabenzo[de]anthracenes conjugated to an aminoacid: Ala, Phe, Pro, Lys, or Gly (4a-e, respectively). The compounds, derived from 1,8-dihydroxyanthracene-9,10-dione, were studied for DNA binding and cytotoxicity. Melting temperature,fluorescence quenching, and surface plasmon resonance methods all indicated that the lysine derivative4d binds to DNA much more strongly that the Pro, Ala, and Gly conjugates whereas the Phe analogueshowed the lowest DNA binding capacity. These compounds form intercalation complexes with DNA,as judged from electric linear dichroism and topoisomerase I-based DNA unwinding experiments.Preferential binding of 4d to defined sequences such as 5'-CTAAAGG and 5'-ATGC was evidenced byDNase I footprinting. This Lys conjugate was found to be over 20 times more cytotoxic to CEM humanleukemia cells than the other conjugates, with an IC50 in the submicromolar range. A highantiproliferative activity, likely attributable to the enhanced DNA binding capacity, is maintaineddespite the incapacity of the compound to stabilize topoisomerase-DNA covalent complexes. The cellcycle effects of 4d consisted in an S phase accumulation of cells coupled with a pro-apoptotic action(appearance of hypodiploid sub-G1 cells) which were confirmed by measuring the inhibition of BrdUincorporation into DNA and labeling of phosphatidylserine residues with annexin V-FITC by meansof flow cytometry. Altogether, the work provides interesting structure-activity relationships in theoxoazabenzo[de]anthracene-amino acid conjugate series and identifies the lysine derivative 4d as apromising candidate for further in vivo evaluation and drug design.