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Design, Synthesis, Antiproliferative Evaluation, and Molecular Docking Studies of N-(3-Hydroxyindole)-Appended β-Carbolines/Tetrahydro-β-Carbolines Targeting Triple-Negative and Non-Triple-Negative Breast Cancer

The present manuscript pertains to the design and synthesis of a series of 3-hydroxyindole-substituted β-carbolines/tetrahydro-β-carbolines with an aim to explore their antiproliferative structure–activity relationship against breast cancer. The conjugate with an optimum combination of a flexible tetrahydro-β-carboline core, a tertiary alcoholic group along with a chloro substituent on the indole ring, proved to be the most active compound. It displayed IC50 values of 13.61 and 22.76 μM against MCF-7 (ER+) and MDA-MB-231 (ER−) cells, respectively. The docking studies were found to be consistent with experimental results owing to the stronger binding affinity of the synthesized conjugates via hydrophobic and H-bonding interactions.


Figure S29
Graph comparing the percentage cell death of MCF-7 and MDA-MB 231 cells at selected concentrations of test compounds 8a, 8b, and 8c. 40 µM Plumbagin was used as a positive control. Data are mean ± standard deviation S.D. (n=6). A one-way ANOVA analysis showed P < 0.0001 (***) significance for both MCF7 and MDA-MB-231. Furthermore, the Bartlett's test for equal variance showed P < 0.005 (**) significance for MCF-7 cells and P < 0.01 (*) significance for MDA-MB 231 cells for compound 8d. This was different for compounds 8e and 8f, where the Bartlett's test for equal variance showed P < 0.0001 (***) for both MCF-7 and MDA-MB 231 cells. Post hoc analysis (Dunnett's multiple comparison test) was performed to compare significance of treated samples to the untreated samples, where *p ≤ 0.05, **p ≤ 0.01 and ***p ≤ 0.001 show significant difference.

Figure S30
Graph comparing the percentage cell death of MCF-7 and MDA-MB 231 cells at selected concentrations of test compounds 9a, 9b, and 9c. 40 µM Plumbagin was used as a positive control. Data are mean ± standard deviation S.D. (n=6). A one-way ANOVA analysis showed P < 0.0001 (***) significance for both MCF7 and MDA-MB-231. Furthermore, the Bartlett's test for equal variance showed P < 0.0001 (***) significance for both MCF-7 and MDA-MB 231 cells across all compounds. Post hoc analysis (Dunnett's multiple comparison test) was performed to compare significance of treated samples to the untreated samples, where *p ≤ 0.05, **p ≤ 0.01 and ***p ≤ 0.001 show significant difference.

Figure S31
Graph comparing the percentage cell death of MCF-7 and MDA-MB 231 cells at selected concentrations of test compounds 9a, 9b, and 9c. 40 µM Plumbagin was used as a positive control. Data are mean ± standard deviation S.D. (n=6). A one-way ANOVA analysis showed P < 0.0001 (***) significance for both MCF7 and MDA-MB-231. Furthermore, the Bartlett's test for equal variance showed P < 0.0001 (***) significance for both MCF-7 and MDA-MB 231 cells across all compounds. Post hoc analysis (Dunnett's multiple comparison test) was performed to compare significance of treated samples to the untreated samples, where *p ≤ 0.05, **p ≤ 0.01 and ***p ≤ 0.001 show significant difference.

Figure S32
Graph comparing the percentage cell death of MCF-7 and MDA-MB 231 cells at selected concentrations of test compounds 9d, 10d, and 9e. 40 µM Plumbagin was used as a positive control. Data are mean ± standard deviation S.D. (n=6). A one-way ANOVA analysis showed P < 0.0001 (***) significance for both MCF7 and MDA-MB-231. Furthermore, the Bartlett's test for equal variance showed P < 0.0001 (***) significance for both MCF-7 and MDA-MB 231 cells across all compounds. Post hoc analysis (Dunnett's multiple comparison test) was performed to compare significance of treated samples to the untreated samples, where *p ≤ 0.05, **p ≤ 0.01 and ***p ≤ 0.001 show significant difference.

Figure S33
Graph comparing the percentage cell death of MCF-7 and MDA-MB 231 cells at selected concentrations of test compounds 10e, 9f, and 10f. 40 µM Plumbagin was used as a positive control. Data are mean ± standard deviation S.D. (n=6). A one-way ANOVA analysis showed P < 0.0001 (***) significance for both MCF7 and MDA-MB-231. Furthermore, the Bartlett's test for equal variance showed P < 0.0001 (***) significance for both MCF-7 and MDA-MB 231 cells across all compounds. Post hoc analysis (Dunnett's multiple comparison test) was performed to compare significance of treated samples to the untreated samples, where *p ≤ 0.05, **p ≤ 0.01 and ***p ≤ 0.001 show significant difference.