Drimane based substituted pyrano-oxepines from labdane diterpene sclareol; stereoselective synthesis, molecular docking simulations and in silico ADMET prediction studies

Abstract

Sclareol, a labdane diterpene alcohol, has been studied for the stereoselective synthesis of drimane-based aryl, alkyl, and heteroaryl substituted pyrano-oxepines. The synthesis process involves two main steps: first, generating a homoallylic alcohol from sclareol, followed by TMSOTf-mediated Prins cyclization using various aldehydes. This approach is characterized by its broad substrate scope, short reaction times, and complete stereoselectivity. The synthesized derivatives were fully characterized using a various spectroscopic techniques, including 1D and 2D NMR, high-resolution mass spectrometry (HRMS), and X-ray diffraction. To investigate their potential as anticancer agents, all synthesized compounds underwent molecular docking studies against BRCA1 proteins, which are key targets in breast cancer therapy. The analysis revealed that the derivatives exhibited better binding affinity values, ranging from −6.6 to −8.3 kcal/mol, compared to the parent molecule sclareol, which had a binding affinity of −5.6 kcal/mol. Notably, compound 14 displayed the most favorable interaction with a binding affinity of −8.3 kcal/mol. Furthermore, ADMET studies and normal mode analysis (NMA) simulations indicated that the synthesized drimane-based pyrano[3,4]oxepines possess favorable drug-like properties and structural stability. These compounds exhibit ideal physicochemical characteristics, excellent oral bioavailability, promising pharmacokinetic behavior, and minimal toxicity risk. These results highlight the potential of drimane-based pyrano[3,4]oxepine derivatives as promising candidates for the development of effective breast cancer inhibitors.