Novel Indole-Containing Hybrids Derived from Millepachine: Synthesis, Biological Evaluation and Antitumor Mechanism Study
Abstract
:1. Introduction
2. Results and Discussion
2.1. Chemistry
2.2. In Vitro Antiproliferative Activity Evaluation and SAR Summary
2.3. Cytotoxicity of Compound 14b in Human Normal Cells Activities
2.4. Cytotoxicity of Compound 14b towards Drug-Resistant Cancer Cell Lines
2.5. Compound 14b Inhibited Tubulin Polymerization
2.6. Compound 14b Induced Cell Cycle Arrest at the G2/M Phase
2.7. Induction of Apoptosis by Compound 14b
2.8. Compound 14b Treatment Leads to ROS Accumulation and MMP Decrease
2.9. The Metabolic Stability of Compound 14b
3. Materials and Methods
3.1. Chemistry
3.1.1. General Procedures for Known Compounds
3.1.2. General Procedures for Preparation of Compounds 5a-5b
- (E)-3-(1H-indol-3-yl)-1-(8-methoxy-2,2-dimethyl-2H-chromen-6-yl)prop-2-en-1-one (5a)
- (E)-1-(8-methoxy-2,2-dimethyl-2H-chromen-6-yl)-3-(1-methyl-1H-indol-3-yl)prop-2-en-1-one (5b)
3.1.3. General Procedures for Preparation of Compounds 11a-11b, 14a-14b, 19a-19b and 21a-21b
- (1H-indol-4-yl)(5-methoxy-2,2-dimethyl-2H-chromen-8-yl)methanone (11a)
- (5-methoxy-2,2-dimethyl-2H-chromen-8-yl)(1-methyl-1H-indol-4-yl)methanone (11b)
- (1H-indol-5-yl)(5-methoxy-2,2-dimethyl-2H-chromen-8-yl)methanone (14a)
- (5-methoxy-2,2-dimethyl-2H-chromen-8-yl)(1-methyl-1H-indol-5-yl)methanone (14b)
- (1H-indol-4-yl)(8-methoxy-2,2-dimethyl-2H-chromen-6-yl)methanone (19a)
- (8-methoxy-2,2-dimethyl-2H-chromen-6-yl)(1-methyl-1H-indol-4-yl)methanone (19b)
- (1H-indol-5-yl)(8-methoxy-2,2-dimethyl-2H-chromen-6-yl)methanone (21a)
- (8-methoxy-2,2-dimethyl-2H-chromen-6-yl)(1-methyl-1H-indol-5-yl)methanone (21b)
3.2. Cell Lines and Cell Culture
3.3. Biological Evaluation Assays
4. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
Sample Availability
References
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| |||||
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Compds | IC50, Mean ± SE (μΜ) b | ||||
A549 | Caski | HepG2 | C42B | MCF-7 | |
5a | 0.812 ± 0.022 | 1.929 ± 0.035 | 0.963 ± 0.032 | 1.377 ± 0.021 | 1.553 ± 0.014 |
5b | 0.362 ± 0.017 | 0.729 ± 0.033 | 0.461 ± 0.017 | 0.577 ± 0.021 | 0.350 ± 0.011 |
11a | 0.631 ± 0.018 | 0.832 ± 0.011 | 0.998 ± 0.034 | 0.911 ± 0.034 | 0.816 ± 0.045 |
11b | 0.208 ± 0.009 | 0.516 ± 0.012 | 0.454 ± 0.021 | 0.455 ± 0.015 | 0.651 ± 0.024 |
14a | 0.072 ± 0.004 | 0.086 ± 0.009 | 0.142 ± 0.014 | 0.089 ± 0.021 | 0.082 ± 0.011 |
14b | 0.022 ± 0.002 | 0.037 ± 0.003 | 0.074 ± 0.013 | 0.051 ± 0.005 | 0.027 ± 0.006 |
19a | 1.321 ± 0.016 | 2.311 ± 0.019 | 3.098 ± 0.021 | 2.411 ± 0.042 | 1.775 ± 0.004 |
19b | 0.642 ± 0.081 | 1.098 ± 0.032 | 0.898 ± 0.009 | 1.076 ± 0.034 | 1.021 ± 0.015 |
21a | 0.105 ± 0.011 | 0.211 ± 0.012 | 0.441 ± 0.071 | 0.209 ± 0.020 | 0.121 ± 0.021 |
21b | 0.082 ± 0.010 | 0.106 ± 0.012 | 0.097 ± 0.031 | 0.107 ± 0.006 | 0.099 ± 0.031 |
Compd. A | 0.226 ± 0.035 | 0.892 ± 0.024 | 0.758 ± 0.017 | 0.526 ± 0.007 | 0.456 ± 0.021 |
Millepachine | 2.566 ± 0.131 | 6.712 ± 0.233 | 3.881 ± 0.244 | 3.176 ± 0.384 | 4.528 ± 0.338 |
Cell Lines | IC50, Mean ± SE (μM) b | Selectivity Ratio c |
---|---|---|
Hep-G2 | 0.074 ± 0.013 | 16.97 |
L-02 | 1.256 ± 0.214 | |
C42B | 0.051 ± 0.005 | 72.51 |
RWPE-1 | 3.698 ± 0.036 | |
MCF-7 | 0.027 ± 0.006 | 231.7 |
MCF-10A | 6.256 ± 0.311 |
Cell Lines | IC50, Mean ± SE (μM) b | Resistance Index c |
---|---|---|
A549 | 0.022 ± 0.002 | 1.59 |
A549/CDDP d | 0.035 ± 0.021 | |
C42B | 0.051 ± 0.005 | 0.82 |
C42B/ENZR e | 0.042 ± 0.011 | |
MCF-7 | 0.027 ± 0.006 | 1.88 |
MCF-7/DOX f | 0.051 ± 0.024 | |
A2780 | 0.036 ± 0.004 | 1.17 |
A2780/TAX g | 0.042 ± 0.011 | |
HCT-8 | 0.089 ± 0.015 | 1.37 |
HCT-8/VCR h | 0.122 ± 0.036 |
Compd. | Time/min, Remaining% | t1/2, min | ||||||
---|---|---|---|---|---|---|---|---|
30 | 60 | 90 | 120 | 150 | 180 | 240 | ||
14b | 96.18% | 91.38% | 84.14% | 74.45% | 67.75% | 56.17% | 43.43% | 198 |
CA-4 | 70.2% | 28.3% | 20.5% | 18.7% | NT a | NT | NT | ND b |
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Liang, B.; Zou, Q.; Yu, L.; Wang, Y.; Yan, J.; Huang, B. Novel Indole-Containing Hybrids Derived from Millepachine: Synthesis, Biological Evaluation and Antitumor Mechanism Study. Molecules 2023, 28, 1481. https://doi.org/10.3390/molecules28031481
Liang B, Zou Q, Yu L, Wang Y, Yan J, Huang B. Novel Indole-Containing Hybrids Derived from Millepachine: Synthesis, Biological Evaluation and Antitumor Mechanism Study. Molecules. 2023; 28(3):1481. https://doi.org/10.3390/molecules28031481
Chicago/Turabian StyleLiang, Baoxia, Qing Zou, Lintao Yu, Yali Wang, Jun Yan, and Baiqi Huang. 2023. "Novel Indole-Containing Hybrids Derived from Millepachine: Synthesis, Biological Evaluation and Antitumor Mechanism Study" Molecules 28, no. 3: 1481. https://doi.org/10.3390/molecules28031481