Design, Synthesis, Biological Evaluation and In Silico Study of Benzyloxybenzaldehyde Derivatives as Selective...

Area of Science:

• Biochemistry
• Medicinal Chemistry
• Oncology

Background:

• Aldehyde dehydrogenase 1A3 (ALDH1A3) is overexpressed in various cancers, correlating with poor treatment outcomes.
• Targeting ALDH1A3 presents a potential therapeutic strategy for improving cancer treatment efficacy.

Purpose of the Study:

• To design, synthesize, and evaluate novel ALDH1A3-selective inhibitors.
• To assess the selectivity and cytotoxicity of designed compounds against ALDH1A1, ALDH1A3, and ALDH3A1 isoforms.

Main Methods:

• In silico design based on physiological substrate resemblance.
• Chemical synthesis of ALDH1A3-selective candidates.
• In vitro enzyme inhibition assays (ALDH1A1, ALDH1A3, ALDH3A1) and cytotoxicity assays using A549 and H1299 cell lines.
• Computational docking studies to predict binding interactions.

Main Results:

• Two compounds, ABMM-15 and ABMM-16, demonstrated potent and selective inhibition of ALDH1A3 (IC50 values of 0.23 µM and 1.29 µM, respectively).
• ABMM-15 and ABMM-16 exhibited no significant cytotoxicity in tested cancer cell lines.
• Computational analysis supported favorable binding of ABMM-15 and ABMM-16 to the ALDH1A3 active site.

Conclusions:

• The benzyloxybenzaldehyde scaffold is a promising starting point for developing novel ALDH1A3 inhibitors.
• ABMM-15 and ABMM-16 represent potential lead compounds for therapeutic strategies targeting ALDH1A3 in cancer treatment.