RT Journal Article
SR Electronic
T1 Synthesis and Structure–Activity Relationships of Tetrahydro-β-carboline Derivatives as Anticancer and Cancer-chemopreventive Agents
JF Anticancer Research
JO Anticancer Res
FD International Institute of Anticancer Research
SP 4425
OP 4433
DO 10.21873/anticanres.12744
VO 38
IS 8
A1 MINGMING ZHANG
A1 EUN-JUNG PARK
A1 TAMARA P. KONDRATYUK
A1 JOHN M. PEZZUTO
A1 DIANQING SUN
YR 2018
UL http://ar.iiarjournals.org/content/38/8/4425.abstract
AB Background/Aim: 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. Materials and 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. Conclusion: our results provided promising β-carboline leads for further optimization and development with therapeutic potential as new chemopreventive and chemotherapy agents.