Novel naphthoquinone-1H-1,2,3-triazole hybrids: Design, synthesis and evaluation as inductors of ROS-mediated
Acácio S de Souza1, Deborah S Dias2, Ruan C B Ribeiro3
1Universidade Federal Fluminense, Faculdade de Farmácia, Departamento de Tecnologia Farmacêutica, CEP 24241-000 Niterói, RJ, Brazil.
Abstract:
The search for novel anticancer drugs is essential to expand treatment options, overcome drug resistance, reduce toxicity, promote innovation, and tackle the economic impact. The importance of these studies lies in their contribution to advancing cancer research and enhancing patient outcomes in the battle against cancer. Here, we developed new asymmetric hybrids containing two different naphthoquinones linked by a 1,2,3-1H-triazole nucleus, which are potential new drugs for cancer treatment. The antitumor activity of the novel compounds was tested using the breast cancer cell lines MCF-7 and MDA-MB-231, using the non-cancer cell line MCF10A as control. Our results showed that two out of twenty-two substances tested presented potential antitumor activity against the breast cancer cell lines. These potential drugs, named here 12g and 12h were effective in reducing cell viability and promoting cell death of the tumor cell lines, exhibiting minimal effects on the control cell line. The mechanism of action of the novel drugs was assessed revealing that both drugs increased reactive oxygen species production with consequent activation of the AMPK pathway. Therefore, we concluded that 12g and 12h are novel AMPK activators presenting selective antitumor effects.
Insights
Two novel naphthoquinone-triazole hybrids, 12g and 12h, show selective anticancer activity against breast cancer cells by activating the AMPK pathway and increasing reactive oxygen species. These compounds represent promising new drug candidates.
Area of Science:
- Medicinal Chemistry
- Oncology
- Drug Discovery
Background:
- Developing novel anticancer drugs is crucial for improving treatment options and overcoming drug resistance.
- Asymmetric hybrids offer a promising scaffold for new therapeutic agents.
- Targeting cancer cell-specific pathways is key to reducing toxicity.
Purpose of the Study:
- To synthesize and evaluate novel asymmetric hybrids containing naphthoquinones and a 1,2,3-1H-triazole nucleus as potential anticancer drugs.
- To assess the antitumor activity of these compounds against breast cancer cell lines.
- To elucidate the mechanism of action of the most promising candidates.
Main Methods:
- Synthesis of asymmetric hybrids linking two naphthoquinones via a 1,2,3-1H-triazole core.
- Antitumor activity screening using MCF-7 and MDA-MB-231 breast cancer cell lines, with MCF10A as a non-cancer control.
- Assessment of reactive oxygen species (ROS) production and AMPK pathway activation.
Main Results:
- Two novel compounds, 12g and 12h, demonstrated significant antitumor activity against breast cancer cell lines.
- Compounds 12g and 12h effectively reduced cancer cell viability and induced cell death.
- Minimal toxicity was observed in the non-cancerous MCF10A cell line.
- Mechanism studies revealed increased ROS production and subsequent AMPK pathway activation by 12g and 12h.
Conclusions:
- Compounds 12g and 12h are identified as novel AMPK activators with selective antitumor effects.
- These compounds hold potential as new therapeutic agents for breast cancer treatment.
- The naphthoquinone-triazole hybrid scaffold is a promising platform for developing targeted cancer therapies.
