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Functionalized Spirocyclic Heterocycle Synthesis and Cytotoxicity Assay
Published on: February 9, 2021
Design, synthesis and structure-activity relationship study of novel indole-pyrrole scaffold compounds targeting
Qi Zhao1, Jingmei Liang1, Jin Zhou1
1School of Pharmaceutical Sciences, Fujian Provincial Key Laboratory of Innovative Drug Target Research, Xiamen University, Xiamen, Fujian, 361102, China.
Abstract:
Nur77, an orphan nuclear receptor, is involved in the development and progression of multiple tumors. In our previous study, we have shown that the protein level of Nur77 is elevated in colon tumors compared to adjacent normal tissues, highlighting its potential as a promising target for colorectal cancer therapy. Significantly, we have identified BI1071 as a Nur77-targeting compound that induces apoptosis in colorectal cancer cells. Based on the scaffold of BI1071, by substituting the indole group of BI1071 with a pyrrolyl group on one side, we rationally designed and synthesized a series of novel BI1071 analogues named SIM-C-PhCF3+Cl- targeting Nur77, and the structure-activity relationship of these BI1071 derivatives was summarized. From this series of compounds, A6 exhibited the strongest binding affinity to Nur77 (Kd = 0.40 ± 0.05 μM) and the most potent anti-proliferative activity against HCT116 and MC38 colorectal tumor cell lines, with IC50 values of 0.53 ± 0.06 μM and 0.16 ± 0.007 μM, respectively. Interestingly, unlike BI1071, which triggers Nur77-dependent apoptosis, compound A6 suppressed colon cancer cell proliferation predominantly by inducing Nur77-dependent mitotic arrest. Collectively, our findings provide a foundation for further investigation and development of Nur77-targeting antimitotic molecules toward colorectal cancer therapy.
Insights
Novel compounds targeting Nur77 (nuclear receptor) show promise for colorectal cancer therapy. Compound A6 effectively inhibits colon cancer cell proliferation by inducing mitotic arrest, offering a new therapeutic strategy.
Area of Science:
- Oncology
- Molecular Biology
- Medicinal Chemistry
Background:
- Nur77, an orphan nuclear receptor, is implicated in various tumor developments.
- Elevated Nur77 protein levels in colon tumors suggest its potential as a therapeutic target for colorectal cancer.
- BI1071 is a previously identified Nur77-targeting compound that induces apoptosis in colorectal cancer cells.
Purpose of the Study:
- To design and synthesize novel Nur77-targeting analogues of BI1071.
- To evaluate the structure-activity relationship of these analogues.
- To investigate the anti-proliferative mechanism of the most potent compound.
Main Methods:
- Rational design and synthesis of BI1071 analogues by modifying the indole group to a pyrrolyl group.
- Assessment of Nur77 binding affinity and anti-proliferative activity against colorectal cancer cell lines (HCT116, MC38).
- Investigation of the mechanism of action, specifically focusing on apoptosis versus mitotic arrest.
Main Results:
- A series of novel Nur77-targeting compounds (SIM-C-PhCF3+Cl-) were synthesized.
- Compound A6 demonstrated the highest binding affinity to Nur77 (Kd = 0.40 ± 0.05 μM) and potent anti-proliferative activity (IC50 values of 0.53 ± 0.06 μM and 0.16 ± 0.007 μM).
- Compound A6 induced Nur77-dependent mitotic arrest, distinct from BI1071's apoptosis-inducing mechanism.
Conclusions:
- Compound A6 is a potent Nur77-targeting agent with significant anti-proliferative effects on colorectal cancer cells.
- The findings highlight a novel mechanism of action (mitotic arrest) for Nur77-targeting compounds in colorectal cancer.
- These results provide a basis for developing new antimitotic therapies for colorectal cancer targeting Nur77.
