Phainanoids A–F, A New Class of Potent Immunosuppressive Triterpenoids with an Unprecedented Carbon Skeleton from Phyllanthus hainanensis

Abstract

Phainanoids A-F (1-6), six highly modified triterpenoids with a new carbon skeleton by incorporating two unique motifs of a 4,5- and a 5,5-spirocyclic systems, were isolated from Phyllanthus hainanensis. Their structures with absolute configurations were determined by spectroscopic data, chemical methods, and X-ray crystallography. Compounds 1-6 exhibited exceptionally potent immunosuppressive activities in vitro against the proliferation of T and B lymphocytes. The most potent one, phainanoid F (6), showed activities against the proliferation of T cells with IC50 value of 2.04 ± 0.01 nM (positive control CsA = 14.21 ± 0.01 nM) and B cells with IC50 value of <1.60 ± 0.01 nM (CsA = 352.87 ± 0.01 nM), which is about 7 and 221 times as active as CsA, respectively. The structure-activity relationships of 1-6 are discussed.

Synthesis of [3.4]‐Spirooxindoles through Cascade Carbopalladation of Skipped Dienes

“…Thus it is possible to incorporate rings from 3 to 8 members at the 3‐position of the aforementioned nuclei. More specifically, the introduction of conformationally constrained cyclobutyl rings confer interesting properties to many bioactive molecules and drugs . Some examples of 3,3‐cyclobutyl‐spirooxindoles include the marine alkaloid welwitindolinone A isonitrile which shows antifungal properties, compounds with RSV antiviral activity, or bromodomain and p38α inhibitors, among others (Figure ).…”

Strategies to diversify natural products for drug discovery

“…), a member of the drug class of statins for treating high cholesterol, mimics the pharmacophore of the fungus‐derived secondary metabolite mevastatin ( 149 ) . Recently, the Yue group discovered a new class of triterpenoids, including a potent immunosuppressive agent, phainanoid F ( 151 ), which inhibited the proliferation of T lymphocytes with an IC 50 value of 2.04 nM and B lymphocytes with an IC 50 value of 1.60 nM and was more powerful than the positive control CsA . Complex structures and promising biological activities have made it a highly attractive target for analogue ( 152 ) studies …”

“…2 Recently, the Yue group discovered a new class of triterpenoids, including a potent immunosuppressive agent, phainanoid F (151), which inhibited the proliferation of T lymphocytes with an IC 50 value of 2.04 nM and B lymphocytes with an IC 50 value of 1.60 nM and was more powerful than the positive control CsA. 275 Complex structures and promising biological activities have made it a highly attractive target for analogue (152) studies. 276 Deuteration of compounds can also be a successful approach toward diversifying natural products that feature biologically relevant molecular scaffolds.…”

Optimizing hairy root production from explants of Phyllanthus hainanensis, a shrub used for traditional herbal medicine

“…Among the Phyllanthus spp., the shrub, P. hainanensis, has become a focus due to the recent discovery of phainanoids in extracts of this species [13,14] . Phainanoids, a class of metabolites with immunosuppressive properties, have great potential in treating diseases such as breast cancer, diabetes, hyperlipidemia and hypertension.…”

“…Phainanoids, a class of metabolites with immunosuppressive properties, have great potential in treating diseases such as breast cancer, diabetes, hyperlipidemia and hypertension. Six phainanoids, A-F, have been isolated from root extracts of P. hainanensis and shown to exhibit potent immunosuppressive activities [13,14] . The species has a tropical and subtropical distribution, occurring in parts of Hunan, Guangxi and Hainan of China [15] .…”