School of Chemistry, UNSW Sydney, Sydney, NSW 2052, Australia.
Children's Cancer Institute, Lowy Cancer Research Centre, UNSW Sydney, Sydney, NSW 2052, Australia.
Molecules. 2020 Mar 18;25(6):1377. doi: 10.3390/molecules25061377.
The dihydropyranoindole scaffold was identified as a promising target for improving the anti-cancer activity of HDAC inhibitors from the preliminary screening of a library of compounds. A suitable methodology has been developed for the preparation of novel dihydropyranoindoles via the Hemetsberger indole synthesis using azido-phenylacrylates, derived from the reaction of corresponding alkynyl-benzaldehydes with methyl azidoacetate, followed by thermal cyclization in high boiling solvents. Anti-cancer activity of all the newly synthesized compounds was evaluated against the SH-SY5Y and Kelly neuroblastoma cells as well as the MDA-MB-231 and MCF-7 breast adenocarcinoma cell lines. Biological studies showed that the tetracyclic systems had significant cytotoxic activity at higher concentration against the neuroblastoma cancer cells. More importantly, these systems, at the lower concentration, considerably enhanced the SAHA toxicity. In addition to that, the toxicity of designated systems on the healthy human cells was found to be significantly less than the cancer cells.
二氢吡喃并吲哚骨架被确定为一种有前途的目标，可通过对化合物库的初步筛选来提高 HDAC 抑制剂的抗癌活性。已经开发出一种合适的方法，用于通过 Hemetsberger 吲哚合成制备新型二氢吡喃并吲哚，该方法使用叠氮基苯丙烯酸酯，由相应的炔基苯甲醛与甲基叠氮乙酸酯反应得到，然后在高沸点溶剂中进行热环化。所有新合成的化合物的抗癌活性都针对 SH-SY5Y 和 Kelly 神经母细胞瘤细胞以及 MDA-MB-231 和 MCF-7 乳腺癌细胞系进行了评估。生物研究表明，四环系统在较高浓度下对神经母细胞瘤癌细胞具有显著的细胞毒性。更重要的是，这些系统在较低浓度下，大大增强了 SAHA 的毒性。此外，指定系统对健康人类细胞的毒性明显低于癌细胞。
