Design, synthesis, and biological evaluation of potent 1,2,3,4-tetrahydroi-soquinoline derivatives as anticancer agents targeting NF-kappa B signaling pathway

Abstract

The multifunctional transcription factor, nuclear factor-kappa B (NF-kappa B), is broadly involved in multiple human diseases, such as cancer and chronic inflammation, through abnormal modulations of the NF-kappa B signaling cascades. In patients with several types of cancer diseases, NF-kappa B is excessively activated, which could result in the stimulation of proliferation and/or suppression of apoptosis. Herein, we present a new series of 1,2,3,4-tetrahydroisoquinoline derivatives with good anticancer activities against various human cancer cell lines, which are rationally designed based on our novel NF-kappa B inhibitors. The SAR studies demonstrated that compound 5d with a methoxy group at the R-3 position exhibits the most anti-proliferative activity with GI(50) values, ranging 1.591 to 2.281 mu M. Similar to KL-1156, the compound 5d (HSR1304) blocked NF-kappa B nuclear translocation step in LPSstimulated MDA-MB-231 cells, probably leading to cytotoxic potency against tumor cells. Together with known potent NF-kappa B inhibitors containing diverse core heterocyclic moieties, the 1,2,3,4-tetrahydroisoquinoline derivatives can provide structural diversity, enhancing a potential for the development of a novel class of anticancer drugs.