Lipid Conjugation of a Photoprotective Meadowfoam (Limnanthes alba) Glucolimnanthin Derivative Reduces Cytotoxicity, Attenuates UV-Induced DNA Damage and Activates DNA Repair in Human Keratinocytes Following UV Radiation

Ultraviolet B (UVB) radiation is a primary cause of DNA damage in the skin, which is often a precursor to skin cancer. Natural products represent a rich source of compounds with unexplored photoprotective properties. Our previous work identified 3-methoxybenzyl isothiocyanate (MBITC), a meadowfoam derivative, as a promising UVB-absorptive agent that reduces DNA damage and cell proliferation; however, its clinical use is limited by dose-dependent cytotoxicity. To address this, we synthesized a novel amide lipid conjugate of MBITC, N-(3-methoxybenzyl)eicos-5-enamide (MBA), and evaluated its photoprotective efficacy and mechanism of action. Our findings demonstrate that MBA exhibited remarkably reduced cytotoxicity compared to its parent compound, while effectively retaining its photoprotective properties. In human primary keratinocyte cultures, MBA significantly reduced UVB-induced DNA damage, as evidenced by a decrease in cyclobutane pyrimidine dimers (p < 0.05) and γ-H2A.X (p < 0.05). Furthermore, MBA increased the expression of DNA damage response (DDR) proteins and DNA damage-binding protein 1 (DDB1) (p < 0.05) and the activation of Ataxia Telangiectasia and Rad3-related protein (ATR) (p < 0.05), a master regulator of DDR and repair pathways. These findings suggest that MBA acts through direct UVB absorption and/or the engagement of DDR pathways following irradiation, highlighting its potential use as a novel photoprotective compound.