Isolation, Synthesis, and Structure–Activity Relationship Study on Daphnane and Tigliane Diterpenes as HIV Latency-Reversing Agents

Abstract

Three new diterpenes, stellejasmins A (<b>1</b>) and B (<b>2</b>) and 12-<i>O</i>-benzoylphorbol-13-heptanoate (<b>3</b>), were isolated from the roots of <i>Stellera chamaejasme</i> L. The structures of <b>1</b>-<b>3</b> were elucidated by extensive NMR and mass spectroscopic analyses. Compounds <b>1</b> and <b>2</b> are the first derivatives containing a hydroxy group at C-2 in the family of daphnane and tigliane diterpenes. The presence of a chlorine atom in <b>1</b> is unique in the plant metabolite. Compound <b>3</b> has an odd-number acyl group, which is biosynthetically notable. Human immunodeficiency virus (HIV) LTR-driven transcription activity was tested with <b>1</b>-<b>3</b> and 17 known diterpenes isolated from <i>S. chamaejasme</i> L. and <i>Wikstroemia retusa</i> A.Gray. Among these, gnidimacrin (<b>4</b>), stelleralide A (<b>5</b>), and wikstroelide A (<b>20</b>) were highly potent, with EC₅₀ values of 0.14, 0.33, and 0.39 nM, respectively. The structure-activity relationship (SAR) was investigated using 20 natural and eight synthetic diterpenes. This is the first SAR study on natural daphnane and tigliane diterpenes.