Synthesis and Structure-Activity Relationships of Tetrahydro-β-carboline Derivatives as Anticancer and Cancer-chemopreventive Agents.

OBJECTIVE

There is an unmet clinical need to develop new anticancer and chemopreventive agents. The aim of the present study was to identify β-carboline derivatives with cancer chemopreventive and therapeutic potential.

METHODS

Forty-eight tetrahydro-β-carboline derivatives were synthesized and evaluated for their anticancer and chemopreventive activities, through induction of quinone reductase 1 (QR1), aromatase inhibition, as well as inhibition of nitric oxide (NO) production.

RESULTS

2-((1-Bromonaphthalen-2-yl)methyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole demonstrated the most potent activity in the QR1 induction assay with an induction ratio value of 3.2 (CD=1.3 μM). The R-isomer of the amide derivative (2-((1-bromonaphthalen-2-yl)methyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-3-yl)(4-methylpiperazin-1-yl)methanone was the most potent inhibitor of NO production with a 50% inhibitory concentration, IC50=6.54 μM and had a low cytotoxic effect (IC50=17.98 μM) on RAW 264.7 cells. Subsequent computational docking study revealed that this compound binds to the active site of inducible nitric oxide synthase with favorable interactions.

CONCLUSIONS

our results provided promising β-carboline leads for further optimization and development with therapeutic potential as new chemopreventive and chemotherapy agents.