Synthesis of Novel Derivatives from Machilin C/D as Antiproliferative Agents against Triple Negative Breast Cancer

Lignans are small polyphenolic compounds that play an active role in plant defense against pathogens and predators. Recently, lignan machilin D was reported to be effective as an anti-tumorigenic agent in triple negative breast cancer (TNBC) tumor-bearing mice. Previous studies have relied on plant-extracted material limiting scalability and diversification of the natural scaffold. Herein, we describe a generalizable one-pot synthesis of machilin D and its derivatives via an iron chloride-induced dimerization of isoeugenol. Employing this synthetic methodology allowed for a robust diversification campaign to access seven (7) new lignan derivatives of the machilin D family with superior anti-proliferative properties in 2D and 3D TNBC models. Overall, this work enables lignan natural product-based drug discovery as a platform to identify new probes to elucidate lignan targets in biology and therapeutics for aggressive cancers such as TNBC.