Synthesis, Anti-adipogenic, and Insulin-sensitizing Potential of Benzosuberene-alkyl Sulfone (BSAS) Analogues

Obesity and diabetes are the leading cause of mortality worldwide. Promising modulators exhibiting insulin sensitivity and anti-adipogenic actions are highly desirable. Organic sulfone analogues are prominent structural units present in diverse bioactive molecules. However, sulfones-derived anti-adipogenic agents are currently unavailable. Therefore, different benzosuberene-alkyl sulfone (BSAS) analogues were synthesized inspired by the molecular diversity of the essential oil of Cedrus deodara. Among the series, five BSAS analogues were assessed in-silico for their binding towards native Peroxisome Proliferator-Activated Receptor Gamma (PPAR gamma) and further validated in-vitro for their anti-adipogenic potential in differentiated 3T3-L1 pre-adipocytes. Their ability to improve insulin sensitivity was also examined in L6 myotubes to ascertain their role in insulin resistance. Our results demonstrated that BSAS-1 was the partial PPAR gamma agonist. It has reduced adipogenesis efficiently by downregulating adipogenic genes, resulting in lower triglyceride levels. BSAS-1 lowered oxidative stress, protected myotubes from insulin resistance, and improved glucose uptake by promoting GLUT4 translocation. Overall, BSAS-1 has the potential to treat obesity and obesity-induced insulin resistance.