Quinoline alkaloids can be isolated from natural plant sources, e.g. Ephedra pachyclada and Galipea longiflora Kraus, and they have a long history of being used as medication for treating tropical disorders, such as malaria and leishmaniasis. We have previously developed an effective catalyst for the asymmetric hydrogenation of quinoline compounds. In the pursuit of anti-cancer agents with high activity and low toxicity, we found that certain 1,2,3,4-tetrahydroquin-8-ol derivatives (e.g. 83b1) can be conveniently obtained through the asymmetric hydrogenation of their precursors. The lead compound was examined by the bioinformatics-based molecular docking analysis using the Similarity Ensemble Approach (SEA), which relates proteins based on the set-wise chemical similarity among their ligands, for identifying the target proteins to which the compound binds as a ligand. Interestingly 83b1 was found to have significant binding effect to PPARδ which is a widely known oncoprotein as a nuclear receptor that causes the overexpression of COX-2 and over-production of PGE2 which promote tumor growth. Biological studies showed that 83b1 exhibited inhibitory effect on esophageal cancer (EC) cell lines comparable with cisplatin (CDDP) in a dose-dependent manner and showed much lower cytotoxic effects on the non-tumor epithelial cells. The expression of COX-2 and COX-2 derived PGE2 were also down-regulated by 83b1 in a dose-dependent manner in the EC cell lines. Furthermore, 83b1 significantly reduced the tumor size in nude mice xenografts of EC.

Asymmetric catalytic hydrogenation of quinolines leading to compounds with high anti-cancer activity and low toxicity

256th National Meeting (2018)

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