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Synthesis and evaluation of 7-(3-aminopropyloxy)-substituted flavone analogue as a topoisomerase II alpha catalytic inhibitor and its sensitizing effect to enzalutamide in castration-resistant prostate cancer cells
- Title
- Synthesis and evaluation of 7-(3-aminopropyloxy)-substituted flavone analogue as a topoisomerase II alpha catalytic inhibitor and its sensitizing effect to enzalutamide in castration-resistant prostate cancer cells
- Authors
- Jeon, Kyung-Hwa; Park, Seojeong; Shin, Jae-Ho; Jung, Ah-Reum; Hwang, Soo-Yeon; Seo, Seung Hee; Jo, Hyunji; Na, Younghwa; Kwon, Youngjoo
- Ewha Authors
- 권영주; 박서정
- SCOPUS Author ID
- 권영주; 박서정
- Issue Date
- 2023
- Journal Title
- EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
- ISSN
- 0223-5234
1768-3254
- Citation
- EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY vol. 246
- Keywords
- TopoisomeraseII? catalytic inhibitor; DNA intercalator; DNA minor Groove binder; Castration-resistant prostate cancer; Sensitization to enzalutamide
- Publisher
- ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
- Indexed
- SCIE; SCOPUS
- Document Type
- Article
- Abstract
- Prostate cancer patients primarily receive androgen receptor (AR)-targeted drugs as a primary treatment option because prostate cancer is associated with highly activated AR signaling. AR amplification made prostate cancer cells viable under treatment of AR-targeted therapy, leading to castration resistance. AR amplification was more common in enzalutamide-resistant patients. As a strategy to overcome castration resistance and to improve the efficacy of enzalutamide, second-generation nonsteroidal antiandrogen drugs for castration-resistant prostate cancer (CRPC) including topoisomerase II (topo II) poisons such as etoposide and mitoxantrone, have been administered in combination with enzalutamide. In the present study, it was confirmed that amplification of topo II alpha, but not I and II beta, was directly and proportionally associated with poor clinical outcome of Prostate cancer. Among a novel series of newly designed and synthesized 7-(3-aminopropyloxy)-substituted flavone analogues, compound 6, the most potent derivative, was further characterized and identified as a topo II alpha catalytic inhibitor that intercalates into DNA and binds to the DNA minor groove with better efficacy and less genotoxicity than etoposide, a topo II poison. Compound 6 showed remarkable efficacy in inhibiting AR-negative CRPC cell growth and sensitizing activity to enzalutamide in AR-positive CRPC cells, thus confirming the potential of topo II alpha catalytic inhibitor to overcome resistance to androgen deprivation therapy.
- DOI
- 10.1016/j.ejmech.2022.114999
- Appears in Collections:
- 약학대학 > 약학과 > Journal papers
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