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

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.

SUBMITTER: Alhazmi R

PROVIDER: S-EPMC9103902 | biostudies-literature | 2022 Apr

REPOSITORIES: biostudies-literature

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

Alhazmi Razan R Tong Shirley S Darwish Shaban S Khanjani Elina E Khungar Bharti B Chawla Swati S Zheng Zhonghui Z Chamberlin Richard R Parang Keykavous K Yang Sun S

Molecules (Basel, Switzerland) 20220421 9

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-dode ...[more]

PMID: 35566022

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Project description:Cinnamic acid is a plant metabolite with antimicrobial, anticancer, and antioxidant properties. Its synthetic derivatives are often more effective in vitro than parent compounds due to stronger biological activities. In our study, we synthesized ten new N–(4–chloro–2–mercapto–5–methylphenylsulfonyl)cinnamamide derivatives, containing two pharmacophore groups: cinnamic acid moiety and benzenesulfonamide. The antimicrobial activity of the obtained compounds was estimated using different types of Gram-positive and Gram-negative bacteria, fungus species of Candida albicans, as well as clinical strains. The compounds were evaluated on biofilm formation and biofilm formed by Staphylococcus clinical strains (methicillin–resistance S. aureus MRSA and methicillin–resistance coagulase–negative Staphylococcus MRCNS). Furthermore, blood bacteriostatic activity test was performed using S. aureus and S. epidermidis. In cytotoxic study, we performed in vitro hemolysis assay on domestic sheep peripheral blood and MTT [3–(4,5–dimethylthiazol–2–yl)–2,5–diphenyltetrazolium bromide] assay on human cervical HeLa, ovarian SKOV-3, and breast MCF-7 cancer cell lines. We also estimated antioxidant activity of ten compounds with 2,2-diphenyl-1-picrylhydrazyl (DPPH) and 2,2′–azino–bis(3–ethylbenzthiazoline–6–sulfonic acid) (ABTS) assays. Our results showed a significant antimicrobial activity of the compounds. All of them were active on Staphylococcus and Enterococcus species (MIC was 1–4 µg/mL). The compounds 16d and 16e were the most active on staphylococci clinical strains and efficiently inhibited the biofilm formation and biofilm already formed by the clinical staphylococci. Moreover, the hemolytic properties of the tested compounds occurred in higher quantities (>32.5 µg/mL) than the concentrations that inhibited both the growth of bacteria in the blood and the formation and growth of biofilm. The results of MTT assay showed that compounds 16c, 16d, 17a, and 17d demonstrated the best activity on the cancer cells (the IC50 values were below 10 µg/mL). Compound 16f was the least active on the cancer cells (IC50 was > 60 µg/mL). Antiradical tests revealed that compounds 16f and 17d had the strongest antioxidant properties within the tested group (IC50 was 310.50 ± 0.73 and 574.41 ± 1.34 µg/mL in DPPH, respectively, and 597.53 ± 1.3 and 419.18 ± 2.72 µg/mL in ABTS assay, respectively). Our study showed that the obtained cinnamamide derivatives can be used as potential antimicrobial therapeutic agents.

Dataset Information

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

Publications

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

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