Design, synthesis and biological evaluation of naphthalene-1,4-dione analogues as anticancer agents

Area of Science:

• Biochemistry
• Oncology
• Medicinal Chemistry

Background:

• The Warburg effect, or aerobic glycolysis, is a key metabolic hallmark of most cancers.
• Targeting cancer-specific metabolic pathways offers a strategy for selective cancer therapies with reduced side effects.
• Kelch-like ECH-associated protein 1 (Keap1) is a potential target for modulating cancer metabolism.

Purpose of the Study:

• To synthesize and evaluate analogues of a hit compound (BH10) targeting Keap1.
• To identify novel molecules with improved potency and selectivity against cancer cells.
• To explore the therapeutic potential of disrupting the Warburg effect for cancer treatment.

Main Methods:

• Synthesis of a library of BH10 analogues based on its chemical scaffold.
• In vitro assessment of compound cytotoxicity against cancer and normal cell lines.
• Determination of IC50 values and selectivity ratios for potent analogues.

Main Results:

• Several analogues demonstrated significant potency, with IC50 values around 1 μM.
• Compound 44, an imidazole derivative, exhibited a favorable balance of potency and selectivity.
• Compound 44 achieved an IC50 of 6.4 μM and a selectivity ratio of 3.6, indicating enhanced cancer cell toxicity.

Conclusions:

• BH10 analogues represent a promising class of compounds for targeting cancer metabolism.
• Compound 44 demonstrates potential as a selective agent against cancer cells by disrupting the Warburg effect.
• Further investigation into compound 44 and related molecules may lead to novel anti-cancer therapeutics.