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6-取代的6H-二苯并[c,h][2,6]萘啶-5-酮：具有强效靶向拓扑异构酶I活性和细胞毒性的ARC-111的内酰胺反转类似物。

6-Substituted 6H-dibenzo[c,h][2,6]naphthyridin-5-ones: reversed lactam analogues of ARC-111 with potent topoisomerase I-targeting activity and cytotoxicity.

作者信息

Zhu Shejin, Ruchelman Alexander L, Zhou Nai, Liu Angela, Liu Leroy F, LaVoie Edmond J

机构信息

Department of Pharmaceutical Chemistry, Rutgers, The State University of New Jersey, Piscataway, NJ 08854-8020, USA.

出版信息

Bioorg Med Chem. 2006 May 1;14(9):3131-43. doi: 10.1016/j.bmc.2005.12.028. Epub 2006 Jan 18.

DOI:10.1016/j.bmc.2005.12.028
PMID:16412652
Abstract

6-Substituted 8,9-dimethoxy-2,3-methylenedioxy-6H-dibenzo[c,h][2,6]naphthyridin-5-ones were synthesized and evaluated for topoisomerase I-targeting activity and cytotoxicity. Several of these reversed lactam analogues of ARC-111 exhibited exceptional cytotoxicity with IC50 values ranging from 0.5 to 3.0 nM. In contrast to topotecan, no resistance was observed with several of these reversed lactam analogues in tumor cell lines that overexpressed the efflux transporters MDR1 or BCRP.

摘要

合成了6-取代的8,9-二甲氧基-2,3-亚甲二氧基-6H-二苯并[c,h][2,6]萘啶-5-酮，并对其进行了拓扑异构酶I靶向活性和细胞毒性评估。这些ARC-111的反向内酰胺类似物中有几种表现出异常的细胞毒性，IC50值在0.5至3.0 nM之间。与拓扑替康不同，在过表达外排转运蛋白MDR1或BCRP的肿瘤细胞系中，这些反向内酰胺类似物中有几种未观察到耐药性。

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