Discovery of N-(Naphtho[1,2-b]Furan-5-Yl) Benzenesulfonamides as Novel Selective Inhibitors of Triple-Negative Breast Cancer (TNBC)
Abstract
:1. Introduction
2. Results and Discussion
2.1. Three-Dimensional Similarity Search and Bioassays
2.2. Hit Follow-up and Expansion
3. Materials and Methods
3.1. Overall Protocol
3.2. Three-Dimensional Similarity Search
3.3. Water Solubility Prediction and Structure Cluster Analysis
3.4. Two-Dimensional Similarity Search
3.5. Cell Viability Assays
4. Conclusions
Supplementary Materials
Acknowledgments
Author Contributions
Conflicts of Interest
Abbreviations
TNBC | triple-negative breast cancer |
ER | estrogen receptor |
PR | progesterone receptor |
HER2 | human epidermal growth factor receptor 2 |
VEGF | the vascular epidermal growth factor |
3D | three-dimensional |
ROCS | Rapid Overlay of Chemical Structures |
2D | two-dimensional |
ECFP_6 | extended connectivity fingerprints of maximum diameter 6 |
FCFP_6 | function class fingerprints of maximum diameter 6 |
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Sample Availability: Samples of the compounds 2-5, 2-8, 3-1 to 3-40 are available from the authors. |
Compound | IC50 (μM) | ||
---|---|---|---|
MDA-MB-231 | SUM-159 | MCF-7 | |
B09 | ~20 | >40 | 1.45 |
C10 | 2.32 | 3.45 | 20 |
Compound | IC50 (μM) | ||||
---|---|---|---|---|---|
MDA-MB-231 | MDA-MB-453 | SUM-159 | BT-20 | MCF-7 | |
Tamoxifen | 2.03 | 3.64 | 13.48 | 8.54 | 9.08 |
IC-163 | >40 | >40 | >40 | >40 | >40 |
C10 | 5.34 | 2.30 | 11.13 | 10.63 | 9.38 |
2-1 | 4.36 | 3.19 | 30.76 | 13.34 | 13.97 |
2-3 | 7.99 | 8.59 | >40 | >40 | >40 |
2-5 | 3.12 | 2.95 | 2.91 | >40 | >40 |
2-6 | 4.97 | 3.36 | 19.21 | 25.02 | >40 |
2-7 | 3.95 | 3.65 | >40 | >40 | >40 |
2-8 | 2.96 | 3.09 | 2.50 | 10.10 | >40 |
2-9 | 6.22 | 4.61 | 18.06 | >40 | >40 |
2-11 | 6.92 | 5.72 | >40 | >40 | >40 |
Compound | R1 | R2 | R3 | Inhibition% | ||
---|---|---|---|---|---|---|
MDA-MB-231 | SUM-159 | MCF-7 | ||||
3-17 | -OCH2CH3 | -CH3 | -CH3 | 68.567 | 60.956 | 40.549 |
3-8 | -CH2CH3 | -OH | -CH3 | −1.131 | 0.221 | −6.706 |
3-32 | -CH(CH3)2 | -OH | -CH3 | 24.718 | −0.964 | −7.568 |
3-1 | -Cl | -OH | -CH3 | 31.450 | −0.754 | −12.178 |
3-9 | -OCH2CH3 | -OCH3 | -CH3 | 63.008 | 60.778 | 24.251 |
3-37 | -OCH2CH3 | -OCH2CH3 | -CH3 | 59.687 | 66.789 | 42.503 |
3-23 | -OCH2CH3 | -OCH2CH2OCH3 | -CH3 | 62.014 | 49.127 | 14.707 |
3-20 | -CH2CH3 | -OCH3 | -CH3 | 53.486 | 65.439 | 31.221 |
3-11 | -CH2CH3 | -OCH2CH3 | -CH3 | 41.115 | 0.175 | 13.005 |
3-22 | -CH2CH3 | -OCH2CH3 | -Ph | 53.616 | −0.556 | 2.238 |
3-4 | -CH(CH3)2 | -OCH3 | -CH3 | 37.770 | −0.319 | 14.222 |
3-31 | -CH(CH3)2 | -OCH2CH3 | -CH3 | 32.074 | −1.330 | 2.952 |
3-30 | -H | -OCH3 | -CH3 | 50.872 | 0.862 | 29.311 |
3-14 | -CH3 | -OCH3 | -CH3 | 62.843 | 48.214 | 10.194 |
2-5 | -OCH3 | -OCH3 | -CH3 | 31.005 | 56.793 | - |
3-10 | -F | -OCH3 | -CH3 | 64.477 | 35.466 | 34.480 |
3-33 | -Cl | -OCH3 | -CH3 | 32.822 | −0.507 | 2.819 |
3-29 | -Br | -OCH3 | -CH3 | 45.039 | 1.3243 | 14.480 |
3-34 | -COOH | -OCH3 | -CH3 | 10.991 | −0.042 | 2.848 |
3-26 | -H | -OCH2Ph | -CH3 | 51.036 | 1.581 | 25.556 |
3-36 | -CH3 | -OCH2CH3 | -CH3 | 16.752 | −0.123 | −4.385 |
2-8 | -OCH3 | -OCH2CH3 | -CH3 | 62.936 | 61.771 | - |
3-3 | -OCH3 | -OCH2CH2CH2CH3 | -CH3 | 51.145 | 42.064 | 29.745 |
3-25 | -OCH3 | -OCH2CH2CH2CH2CH3 | -CH3 | 39.505 | 61.902 | 48.321 |
3-28 | -OCH3 | -OCH2CH3 | -CH2CH2CH3 | 61.911 | 46.000 | 33.448 |
3-12 | -OCH3 | -OCH3 | -C(CH3)3 | 71.378 | 90.386 | 76.319 |
3-39 | -F | -OCH(CH3)2 | -CH3 | 42.330 | −0.193 | 4.948 |
3-13 | -COOH | -OCH2CH3 | -CH3 | 19.635 | −0.635 | 5.137 |
3-40 | -COOH | -OCH2CH3 | -CH2CH2CH3 | 12.487 | 0.000 | 2.525 |
Compound | R4 | R2 | Inhibition% | ||
---|---|---|---|---|---|
MDA-MB-231 | SUM-159 | MCF-7 | |||
3-27 | -OCH3 | 48.153 | 10.205 | 35.546 | |
3-7 | -OCH3 | 0.431 | 0.085 | −4.733 | |
3-6 | -OCH2CH3 | 43.365 | 0.292 | 7.724 | |
3-5 | -OCH3 | 41.065 | 0.757 | 21.98 | |
3-15 | -OCH3 | 45.584 | 0.037 | 18.546 | |
3-38 | -OCH3 | 50.558 | 1.346 | 14.827 | |
3-24 | -OCH3 | 46.563 | 0.233 | 34.910 | |
3-16 | -OCH2CH3 | 48.171 | 0.732 | 43.439 | |
3-35 | -OCH2CH3 | 33.853 | 0.352 | 24.499 | |
3-2 | -OCH2CH3 | 24.255 | −0.884 | 17.700 | |
3-19 | -OH | 19.306 | 0.380 | 16.340 | |
3-18 | -OCH3 | 59.421 | 51.425 | 33.244 |
Compound | IC50 (μM) | |
---|---|---|
MDA-MB-231 | SUM-159 | |
2-5 | 3.12 | 2.91 |
2-8 | 2.96 | 2.50 |
3-3 | 3.25 | 8.66 |
3-9 | 2.68 | 2.66 |
3-12 | 11.91 | 11.53 |
3-17 | 1.77 | 1.94 |
3-18 | 5.20 | 24.15 |
3-20 | 10.04 | 16.97 |
3-28 | >40 | 14.41 |
3-37 | 5.49 | 4.09 |
2-5-COOH | ~24 | 24.25 |
Compound | IC50 (μM) | Calculated Molecular Properties | ||||||
---|---|---|---|---|---|---|---|---|
MDA-MB-231 | MDA-MB-436 | SUM-159 | MCF-7 | MCF-10A | Molecular_Weight | AlogP | ADMET_Solubility_level | |
Tamoxifen | 2.03 | 10.02 | 13.48 | 9.08 | >40 | 371.5 | 6.319 | 1 |
2-5 | 3.12 | 1.99 | 2.91 | >40 | >40 | 425.5 | 3.514 | 2 |
2-8 | 2.96 | 2.80 | 2.50 | >40 | >40 | 439.5 | 3.863 | 2 |
3-3 | 3.25 | 3.36 | 8.66 | ND a | >40 | 467.5 | 4.842 | 1 |
3-9 | 2.68 | 2.08 | 2.66 | ND | >40 | 439.5 | 3.863 | 2 |
3-12 | 11.91 | 7.13 | 11.53 | ND | >40 | 467.5 | 5.063 | 1 |
3-17 | 1.77 | ~0.01 | 1.94 | ND | 0.66 | 423.5 | 3.747 | 2 |
3-37 | 5.49 | 1.41 | 4.09 | ND | > 40 | 453.5 | 4.211 | 2 |
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Share and Cite
Chen, Y.; Tang, Y.; Mao, B.; Li, W.; Jin, H.; Zhang, L.; Liu, Z. Discovery of N-(Naphtho[1,2-b]Furan-5-Yl) Benzenesulfonamides as Novel Selective Inhibitors of Triple-Negative Breast Cancer (TNBC). Molecules 2018, 23, 678. https://doi.org/10.3390/molecules23030678
Chen Y, Tang Y, Mao B, Li W, Jin H, Zhang L, Liu Z. Discovery of N-(Naphtho[1,2-b]Furan-5-Yl) Benzenesulfonamides as Novel Selective Inhibitors of Triple-Negative Breast Cancer (TNBC). Molecules. 2018; 23(3):678. https://doi.org/10.3390/molecules23030678
Chicago/Turabian StyleChen, Ya, Yong Tang, Beibei Mao, Wenchao Li, Hongwei Jin, Liangren Zhang, and Zhenming Liu. 2018. "Discovery of N-(Naphtho[1,2-b]Furan-5-Yl) Benzenesulfonamides as Novel Selective Inhibitors of Triple-Negative Breast Cancer (TNBC)" Molecules 23, no. 3: 678. https://doi.org/10.3390/molecules23030678