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

Three
new diterpenes, stellejasmins A (1) and B (2) and 12-O-benzoylphorbol-13-heptanoate
(3), were isolated from the roots of Stellera
chamaejasme L. The structures of 1–3 were elucidated by extensive NMR and mass spectroscopic
analyses. Compounds 1 and 2 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 1 is unique in the plant metabolite. Compound 3 has an odd-number acyl group, which is biosynthetically notable.
Human immunodeficiency virus (HIV) LTR-driven transcription activity
was tested with 1–3 and 17 known
diterpenes isolated from S. chamaejasme L. and Wikstroemia retusa A.Gray.
Among these, gnidimacrin (4), stelleralide A (5), and wikstroelide A (20) 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.

本研究从瑞香狼毒（Stellera chamaejasme L.）的根部分离得到3种新型二萜类化合物：stellejasmins A（1）、B（2）与12-O-苯甲酰基佛波醇-13-庚酸酯（3）。通过全面的核磁共振（Nuclear Magnetic Resonance, NMR）波谱与质谱分析，明确了化合物1~3的化学结构。化合物1与2是瑞香烷（daphnane）和大戟烷（tigliane）二萜类家族中，首批在C-2位引入羟基的衍生物。化合物1分子中氯原子的存在，在该植物的代谢产物中尚属首例。化合物3带有奇数碳链的酰基结构，该特征在生物合成研究中具有显著意义。本研究以化合物1~3，以及从瑞香狼毒（S. chamaejasme L.）和凹叶荛花（Wikstroemia retusa A.Gray）中分离得到的17种已知二萜类化合物为测试样本，评估了其人类免疫缺陷病毒（Human Immunodeficiency Virus, HIV）长末端重复序列（Long Terminal Repeat, LTR）介导的转录活性。其中，gnidimacrin（4）、stelleralide A（5）与wikstroelide A（20）活性极强，其半数有效浓度（Half Maximal Effective Concentration, EC50）分别为0.14 nM、0.33 nM和0.39 nM。本研究借助20种天然二萜与8种合成二萜类化合物，对其构效关系（Structure-Activity Relationship, SAR）进行了系统探究。这是首个针对天然瑞香烷型与大戟烷型二萜类化合物的构效关系研究。