鉴定 2-取代吡咯并[1,2-b]哒嗪衍生物为新型 PARP-1 抑制剂。
Identification of 2-substituted pyrrolo[1,2-b]pyridazine derivatives as new PARP-1 inhibitors.
机构信息
College of Chemistry and Chemical Engineering, Central South University, Changsha, Hunan 410083, PR China; State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, PR China.
State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, PR China.
出版信息
Bioorg Med Chem Lett. 2021 Jan 1;31:127710. doi: 10.1016/j.bmcl.2020.127710. Epub 2020 Nov 24.
A library of new 2-substituted pyrrolo[1,2-b]pyridazine derivatives were rapidly assembled and identified as PARP inhibitors. Structure-activity relationship for this class of inhibitor resulted in the discovery of most potent compounds 15a and 15b that exhibited about 29- and 5- fold selective activity against PARP-1 over PARP-2 respectively. The antiproliferative activity of the as-prepared compounds were demonstrated by further celluar assay in BRCA2-deficient V-C8 and BRCA1-deficient MDA-MB-436 cell lines, displaying that compound 15b could robustly reduce the corresponding cell proliferation and growth with CCs of 340 and 106 nM respectively. The PK property of 15b was also investigated here.
一个新的 2-取代吡咯并[1,2-b]哒嗪衍生物文库被快速合成并鉴定为 PARP 抑制剂。该抑制剂类别的构效关系研究导致发现了最有效的化合物 15a 和 15b，它们对 PARP-1 的选择性活性分别约为 PARP-2 的 29 倍和 5 倍。通过在 BRCA2 缺陷型 V-C8 和 BRCA1 缺陷型 MDA-MB-436 细胞系中的进一步细胞测定，证明了所制备的化合物的抗增殖活性，显示化合物 15b 能够分别以 340 和 106 nM 的 CC 有效地降低相应的细胞增殖和生长。这里还研究了 15b 的 PK 特性。
Zotero 插件