4.3 Article

Synthesis and Bio-evaluation of 2-Alkyl Substituted Fluorinated Genistein Analogues against Breast Cancer

Journal

MEDICINAL CHEMISTRY
Volume 18, Issue 5, Pages 589-601

Publisher

BENTHAM SCIENCE PUBL LTD
DOI: 10.2174/1573406417666210830114715

Keywords

Genistein; isoflavone; analogues; breast cancer; chemotherapeutics; estrogen receptors

Funding

  1. Hunan Provincial Hengyang Joint Fund [2020JJ6052]
  2. Hunan Province Education Department [18C0438]
  3. Undergraduate Research Learning and Innovative Experiment Project [2018XJXZ363]

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This study aimed to design and synthesize a series of 2-alkyl substituted fluorinated genistein analogues and evaluate their anti-breast cancer activity. The compounds showed promising results in selectively inhibiting breast cancer cells and may act as PI3K-gamma inhibitors.
Background: Breast cancer is the leading cause of cancer death in women. The current methods of chemotherapy for breast cancer generally have strong adverse reactions and drug resistance. Therefore, the discovery of novel anti-breast cancer lead compounds is urgently needed. Objective: This study aimed to design and synthesize a series of 2-alkyl substituted fluorinated genistein analogues and evaluate their anti-breast cancer activity. Methods: Target compounds were obtained in a multistep reaction synthesis. The anti-tumor activity of compounds I-1 similar to 1-35 was evaluated with MCF-7, MDA-MB-231, MDA-MB-435, and MCF-10A cell lines in vitro, with tamoxifen as the positive control. Molecular docking was used to study the interaction between the synthesized compounds and PI3K-gamma. Results: A series of 2-alkyl substituted fluorinated genistein analogues was designed, synthesized, and screened for their bioactivity. Most of the compounds displayed better selectivity toward breast cancer cell lines as compared to tamoxifen. Among these analogues, 1-2, 1-3, 1-4, 1-9, 1-15, and 1-17 have the strongest selective inhibition of breast cancer cells. Compounds 1-10, 1-13, 1-15, 1-17, and I-33 were found to have significant inhibitory effects on breast cancer cells. Molecular docking studies have shown that these compounds may act as PI3K gamma inhibitors and may further exhibit anti-breast cancer effects. Conclusion: Most of the newly synthesized compounds could highly, selectively inhibit breast cancer cell lines. The experimental results indicate that the synthesized analogs may also have obvious selective inhibitory effects on other malignant proliferation cancer cells.

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