Recent Developments in Common Dietary Phytoconstituents: Insights into Structure-activity Relationship and...

Breast cancer continues to threaten women's lives globally. Dietary phytochemicals are useful in combating breast cancer in preclinical and clinical research. Poor water solubility and bioavailability contribute to the failure of these drugs in clinical trials. Structural modifications in these phytochemicals have proved effective in addressing their challenges. The present review focuses on recent updates on structural modifications of dietary phytochemicals that resulted in better antibreast cancer activity and bioavailability of these derivatives. Recent medicinal chemistry efforts have focused on improving their anti-breast cancer potential through Structure-Activity Relationship (SAR)-guided modification. Key strategies include aromatic substitutions (e.g., replacing hydroxy/methoxy groups with electron-withdrawing groups or introducing heterocycles) and carbonyl engineering (e.g., carbonyl deletion and cyclization of carbonyl groups). These approaches, together with the addition of aliphatic side chains to enhance lipophilicity, have generated more potent curcumin, EGCG, genistein, quercetin, and resveratrol derivatives. The literature demonstrates that several novel drug delivery strategies, such as solid dispersion, cyclodextrin inclusion, microemulsion, and nano-drug delivery systems of structurally modified phytochemicals (curcumin, resveratrol, genistein, and quercetin) have improved their pharmacokinetic and pharmacodynamic properties as compared to their parent compounds. Selected derivatives and nanoformulations showed improved therapeutic indices, with lower off-target toxicity and greater tolerability in vivo compared with the parent compounds, demonstrating the potential for improvement in the safety profile of the dietary phytoconstituents through semisynthetic modifications. However, further detailed investigation on the anti-breast cancer potential, safety profile, and pharmacokinetics of these semisynthetic derivatives will improve their reliability and guide the research community toward their better therapeutic application.