Chemistry, School of Environmental & Life Sciences, The University of Newcastle, University Drive, Callaghan, NSW 2308, Australia; Medicinal Chemistry, School of Pharmacy, Binzhou Medical University, Yantai 264003, China.
Chemistry, School of Environmental & Life Sciences, The University of Newcastle, University Drive, Callaghan, NSW 2308, Australia.
Bioorg Med Chem Lett. 2022 Apr 1;61:128591. doi: 10.1016/j.bmcl.2022.128591. Epub 2022 Jan 31.
Virtual screening identified N-(6-((4-bromobenzyl)amino)hexyl)-3,5-bis(trifluoromethyl)benzenesulfonamide (1) a lead compound that bound to the S100A2-p53 binding groove. S100A2 is a Ca binding protein with implications in cell signaling and is known to be upregulated in pancreatic cancer. It is a validated pancreatic cancer drug target. Lead 1, inhibited the growth of the MiaPaCa-2 pancreatic cancer cell line (GI = 2.97 μM). Focused compound libraries were developed to explore the SAR of this compound class with 4 libraries and 43 compounds total. Focused library (Library 1) development identified lipophillic sulfonamides as preferred for MiaPaCa-2 activity, with -CF and -C(CH) substituents well tolerated (MiaPaCa-2 GI < 6 μM). Contraction of the hexylamino spacer to ethyl (Library 2) and propyl (Library 3) proved beneficial to activity against a broad spectrum panel of cancer cell lines: HT29 (lung), MCF-7 (breast), A2780 (ovarian), H460 (colon), A431 (skin), Du145 (prostate), BE2-C (neuroblastoma), U87 and SJ-G2 (glioblastoma) (cohort-1); and a pancreatic cancer cell line panel: MiaPaCa-2, BxPC-3, AsPC-1, Capan-2, HPAC and PANC-1 (cohort-2). With a marked preference for a propyl linker the observed GI values ranged from 1.4 to 30 μM against cohort-1 and 1.4-30 μM against cohort-2 cell lines. In Library 4 the terminal aromatic moiety was explored with 4-substituted analogues preferred (with activity of 48 (4-Cl) > 47 (3-Cl) > 46 (2-Cl)) against the cell lines examined. The introduction of bulky aromatic moieties was well tolerated, e.g. dihydrobenzo[b][1,4]dioxine (51) returned cohort-2 GI values of 1.2-3.4 μM. In all instances the observed docked binding poses and binding scores were consistent with the observed cytotoxicity. This in turn supports, but does not prove, that these analogues function via S100A2-p53 binding groove inhibition.
虚拟筛选鉴定出 N-(6-((4-溴苄基)氨基)己基)-3,5-双(三氟甲基)苯磺酰胺（1），这是一种与 S100A2-p53 结合槽结合的先导化合物。S100A2 是一种具有细胞信号传导意义的 Ca 结合蛋白，已知在胰腺癌中上调。它是一个经过验证的胰腺癌药物靶点。先导化合物 1 抑制 MiaPaCa-2 胰腺癌细胞系的生长（GI=2.97μM）。开发了聚焦化合物文库以探索该化合物类别的 SAR，共开发了 4 个文库和 43 个化合物。聚焦文库（文库 1）的开发确定亲脂性磺酰胺是 MiaPaCa-2 活性的首选，带有-CF 和-C(CH)取代基可很好耐受（MiaPaCa-2 GI<6μM）。将己基氨基间隔子收缩为乙基（文库 2）和丙基（文库 3），有利于对广谱癌症细胞系的活性：HT29（肺）、MCF-7（乳腺）、A2780（卵巢）、H460（结肠）、A431（皮肤）、Du145（前列腺）、BE2-C（神经母细胞瘤）、U87 和 SJ-G2（胶质母细胞瘤）（队列 1）；以及胰腺癌细胞系面板：MiaPaCa-2、BxPC-3、AsPC-1、Capan-2、HPAC 和 PANC-1（队列 2）。由于对丙基接头有明显的偏好，观察到的 GI 值范围为 1.4 至 30μM，针对队列 1 和 1.4 至 30μM，针对队列 2 细胞系。在文库 4 中，探索了末端芳香部分，发现带有取代基的 4-取代类似物具有活性（48（4-Cl）>47（3-Cl）>46（2-Cl）），对所检查的细胞系有效。引入大体积芳香部分可很好耐受，例如二氢苯并[b][1,4]二恶烷（51）使队列 2 的 GI 值为 1.2-3.4μM。在所有情况下，观察到的对接结合构象和结合评分与观察到的细胞毒性一致。这反过来支持，但不能证明，这些类似物通过 S100A2-p53 结合槽抑制发挥作用。
