Trinh Trieu N, McLaughlin Eileen A, Gordon Christopher P, Bernstein Ilana R, Pye Victoria J, Redgrove Kate A, McCluskey Adam
Chemistry, Priority Research Centre for Chemical Biology, University of Newcastle, University Drive Callaghan, NSW 2308, Australia.
Biology, Priority Research Centre for Chemical Biology, University of Newcastle, University Drive Callaghan, NSW 2308, Australia.
Org Biomol Chem. 2017 Apr 5;15(14):3046-3059. doi: 10.1039/c6ob01959e.
Leveraging our quinolone-1-(2H)-one based Hedgehog signalling pathway (HSP) inhibitors we have developed two new classes of HSP inhibitors based on: l-tryptophan and benzo[1,3]dioxol-5-ylmethyl-[2-(1H-indol-3-yl)-ethyl]-amine. Synthesis of focused compound libraries identified six l-tryptophan based inhibitors, and two stimulators, of Gli at 10 μM compound concentration. 2,4-Dichloro-13 and indole 16 suppressed mRNA expression of Ptch in Shh LIGHT2 cells, with 13 suppressing and 16 stimulating Gli mRNA expression. Focused library development of the benzo[1,3]dioxol-5-ylmethyl-[2-(1H-indol-3-yl)-ethyl]-amine scaffold afforded two sub-micro molar potent inhibitors of Gli expression with 5-methoxy-1H-indole-2-carboxylic acid benzo[1,3]dioxol-5-ylmethyl-[2-(1H-indol-3-yl)-ethyl]-amide 29 and 5-chloro-1H-indole-2-carboxylic acid benzo[1,3]dioxol-5-ylmethyl-[2-(1H-indol-3-yl)-ethyl]-amide 30 returning IC values of 0.5 and 0.24 μM, respectively. Neither 29 nor 30 acted directly on Smo with our data supporting inhibition of the HSP downstream of Smo.
利用我们基于喹诺酮 - 1 - (2H) - 酮的刺猬信号通路（HSP）抑制剂，我们开发了两类新的HSP抑制剂，它们基于：L - 色氨酸和苯并[1,3]二氧杂环戊烯 - 5 - 基甲基 - [2 - (1H - 吲哚 - 3 - 基) - 乙基] - 胺。在10 μM化合物浓度下，聚焦化合物库的合成鉴定出六种基于L - 色氨酸的Gli抑制剂和两种刺激剂。2,4 - 二氯 - 13和吲哚16抑制了Shh LIGHT2细胞中Ptch的mRNA表达，其中13抑制而16刺激Gli mRNA表达。苯并[1,3]二氧杂环戊烯 - 5 - 基甲基 - [2 - (1H - 吲哚 - 3 - 基) - 乙基] - 胺支架的聚焦文库开发得到了两种亚微摩尔强效Gli表达抑制剂，5 - 甲氧基 - 1H - 吲哚 - 2 - 羧酸苯并[1,3]二氧杂环戊烯 - 5 - 基甲基 - [2 - (1H - 吲哚 - 3 - 基) - 乙基] - 酰胺29和5 - 氯 - 1H - 吲哚 - 2 - 羧酸苯并[1,3]二氧杂环戊烯 - 5 - 基甲基 - [2 - (1H - 吲哚 - 3 - 基) - 乙基] - 酰胺30的IC值分别为0.5和0.24 μM。根据我们的数据支持Smo下游的HSP抑制，29和30均未直接作用于Smo。
