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. 2024 Oct 31;29(21):5155.
doi: 10.3390/molecules29215155.

Design, Synthesis and Biological Activity Evaluation of β-Carboline Derivatives Containing Nitrogen Heterocycles

Guiyun Wu  1 , Wenhang Wang  1 , Fulian Li  1 , Chenlu Xu  1 , Yue Zhou  1 , Zhurui Li  1 , Bingqian Liu  1 , Lihui Shao  2 , Danping Chen  1 , Song Bai  3 , Zhenchao Wang  1   2
Affiliations

Design, Synthesis and Biological Activity Evaluation of β-Carboline Derivatives Containing Nitrogen Heterocycles

Guiyun Wu et al. Molecules. .

Abstract

A series of β-carboline derivatives containing nitrogen heterocycles were designed and synthesized. All compounds were screened for their antitumor activity against four human tumor cell lines (A549, K562, PC-3, T47D). Notably, compound N-(4-(morpholinomethyl)phenyl)-2-((5-(1-(3,4,5-trimethoxyphenyl)-9H-pyrido[3,4-b]indol-3-yl)-1,3,4-oxadiazol-2-yl)thio)acetamide (8q) exhibited significant inhibitory activity against PC-3 cells with an IC50 value of 9.86 µM. Importantly, compound 8q effectively suppressed both the proliferation and migration of PC-3 cells. Mechanistic studies revealed that compound 8q induced cell apoptosis and caused the accumulation of reactive oxygen species (ROS), leading to cell cycle arrest in the G0/G1 phase in PC-3 cells.

Keywords: ROS; antitumor; apoptosis; cell cycle; β-carboline derivatives.

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Conflict of interest statement

The authors declare that they have no known competing financial interest or personal relationships that could have appeared to influence the work reported in this paper.

Figures

Figure 1
Figure 1
Chemical structures of β-carboline derivatives with multiple activities.
Figure 2
Figure 2
The design concept of β-carboline derivatives.
Scheme 1
Scheme 1
Synthetic route of target compounds 7 and 8 series.
Figure 3
Figure 3
(A) Compound 8q inhibited the colony formation of PC-3 cells (scale bar: 100 μm). (B) The effect of compound 8q at 10 μM, 20 μM and 30 μM concentration and Harmine at 30 μM concentration on the migration of PC-3 cells. (C) Quantitative analysis of PC-3 cells’ migration rate using Image J software (2.1.0/1.53c). One-way ANOVA followed by Dunnett’s multiple-comparisons test was performed using GraphPad Prism 9 (* p < 0.05, ** p < 0.01, *** p < 0.001).
Figure 4
Figure 4
(A) Compound 8q at 10 μM and Harmine at 30 μM concentrations induced apoptosis of PC-3 cells. (B) Quantitative analysis of PC-3 cell apoptosis using Flow Jo-V10 software. One-way ANOVA followed by Dunnett’s multiple-comparisons test was performed using GraphPad Prism 9 (**** p < 0.0001). (C) Compound 8q at 10 μM concentration and Harmine at 30 μM increased the level of reactive oxygen species in PC-3 cells. (D) Quantitative analysis of reactive oxygen species in PC-3 cells using Flow Jo-V10 software. One-way ANOVA followed by Dunnett’s multiple-comparisons test was performed using GraphPad Prism 9 (* p < 0.05, **** p < 0.001).
Figure 5
Figure 5
(A) Flow cytometry detection of the effect of compound 8q on the distribution of PC-3 cell cycle at concentrations of 10 μM, 20 μM and 30 μM. (B) Quantitative analysis of cell cycles in PC-3 cells using Flow Jo-V10 software. β-Tubulin as an internal reference. One-way ANOVA followed by Dunnett’s multiple-comparisons test was performed using GraphPad Prism 9. (C) Western blot analysis of the effect of 8q on the expression of Cyclin D1 in cells. (D) Analyzed protein grayscale values using Image J software (2.1.0/1.53c). β-Tubulin as an internal reference. One-way ANOVA followed by Dunnett’s multiple-comparisons test was performed using GraphPad Prism 9 (* p < 0.05).
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