Synthesis and structure-activity relationship of 13-hexylberberine analogues as CD36 antagonists

Scavenger receptor CD36 could bind and endocytose oxLDL into macrophages which were then differentiated into foam cells that constitute the atherosclerotic lesion core, and was considered to be a potential target to treat atherosclerosis.  In the establishment of the compound library of berberine (BBR, 1) analogues, we discovered that 13-hexylberberine (2) showed an antagonistic activity against CD36.  Taking 2 as the lead compound, 21 derivatives were synthesized and their antagonistic activities were evaluated via an ELISA-like high-throughput screening (HTS) model.  The primary structure-activity relationships were studied.  It was  indicated that the introduction of suitable groups at the 2- and 3-position of the aromatic ring A or at the 9-position of the aromatic ring D could enhance the activity.  Among the 21 studied compounds, 7g bearing  a benzyloxyl group at the 9-position provided a highest CD36 antagonistic activity with the IC₅₀ value of 7.7 μmol·L⁻¹.  Besides, its antagonistic activity was further verified with Sf9 insect cell HTS model.  So berberine analogues are a new family of CD36 receptor antagonists and worthy to be studied further.