Altering Nitrogen Heterocycles of AZD2461 Affords High Affinity Poly(ADP-ribose) Polymerase-1 Inhibitors with Decreased P-Glycoprotein Interactions.
Altering Nitrogen Heterocycles of AZD2461 Affords High Affinity Poly(ADP-ribose) Polymerase-1 Inhibitors with Decreased P-Glycoprotein Interactions.
复制标题
改变 AZD2461 的氮杂环可提供高亲和力的聚 (ADP-核糖) 聚合酶 1 抑制剂，并减少 P-糖蛋白相互作用。
DOI：
10.1021/acsomega.8b00896
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发表时间：
2018
期刊：
影响因子：
4.1
通讯作者：
Mach,RobertH
中科院分区：
文献类型：
--
作者：
Reilly,SeanW;Puentes,LauraN;Hsieh,Chia-Ju;Makvandi,Mehran;Mach,RobertH
Poly(ADP-ribose) polymerase inhibitors (PARPi) are targeted therapeutics with enhanced selectivity and cytotoxicity in BRCA1/2 mutant cancer cells. AZD2461, a congener of FDA approved olaparib, is a potent PARPi with high affinity for PARP-1 and nonsubstrate for P-glycoprotein (P-gp), an attractive characteristic for cancer therapeutics. Analogues of AZD2461 were synthesized and profiled in BRCA1 functional and nonfunctional cell lines, revealing compounds (2,3, and5) of low cytotoxicity and excellent PARP-1 affinities (∼4–8 nM). In comparison to AZD2461, these agents were found to be less stimulating of P-gp, suggesting that these compounds may be excellent candidates for neurological applications where blood brain barrier penetrance is sought.
