Bis-Cinnamamide Derivatives as APE/Ref-1 Inhibitors for the Treatment of Human Melanoma

Authors

Razan Alhazmi, Chapman UniversityFollow
Shirley Tong, Chapman UniversityFollow
Shaban Darwish, Chapman UniversityFollow
Elina Khanjani, Chapman UniversityFollow
Bharti Khungar, Chapman UniversityFollow
Swati Chawla, Chapman UniversityFollow
Zhonghui Zheng, University of California, IrvineFollow
Richard Chamberlain, University of California, IrvineFollow
Keykavous Parang, Chapman UniversityFollow
Sun Yang, Chapman UniversityFollow

Document Type

Article

Publication Date

4-21-2022

Abstract

Human malignant melanoma exhibits imbalances in redox status, leading to activation of many redox-sensitive signaling pathways. APE/Ref-1 is a multifunctional protein that serves as a redox chaperone that regulates many nuclear transcription factors and is an important mechanism in cancer cell survival of oxidative stress. Previous studies showed that APE/Ref-1 is a potential druggable target for melanoma therapy. In this study, we synthesized a novel APE/Ref-1 inhibitor, bis-cinnamoyl-1,12-dodecamethylenediamine (2). In a xenograft mouse model, compound 2 treatment (5 mg/kg) significantly inhibited tumor growth compared to the control group, with no significant systemic toxicity observed. We further synthesized compound 2 analogs to determine the structure-activity relationship based on their anti-melanoma activities. Among those, 4-hydroxyphenyl derivative (11) exhibited potent anti-melanoma activities and improved water solubility compared to its parental compound 2. The IC₅₀ of compound 11 was found to be less than 0.1 μM. Compared to other known APE/Ref-1 inhibitors, compound 11 exhibited increased potency in inhibiting melanoma proliferation. As determined by luciferase reporter analyses, compound 2 was shown to effectively inhibit H₂O₂-activated AP-1 transcription activities. Targeting APE/Ref-1-mediated signaling using pharmaceutical inhibitors is a novel and effective strategy for melanoma treatment with potentially high impact.

Comments

This article was originally published in Molecules, volume 27, in 2022. https://doi.org/10.3390/molecules27092672

Recommended Citation

Alhazmi, R.; Tong, S.; Darwish, S.; Khanjani, E.; Khungar, B.; Chawla, S.; Zheng, Z.; Chamberlin, R.; Parang, K.; Yang, S. Bis-Cinnamamide Derivatives as APE/Ref-1 Inhibitors for the Treatment of Human Melanoma. Molecules 2022, 27, 2672. https://doi.org/10.3390/molecules27092672

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