Progress in research on novel immunosuppressive active heteroditerpenoids

Natural products with novel structures and diverse activities are an inexhaustible source for the discovery of small-molecule drug lead compounds.
However, the difficulty of confirming the configuration of complex natural products and the low content of them have become the main problem in the continuous advancement of new lead compounds.
The Isodon plant of the Lamiaceae family is one of the important medicinal plant groups in China.
It has the functions of clearing away heat, detoxifying, anti-bacterial, anti-inflammatory, and anti- bioon.
com/course_video/chang-fei-bian-ma-RNA-yu-zhong-liu959063.
html">tumor .
The research team of the important group phytochemistry and function research team of Kunming Institute of Botany, Chinese Academy of Sciences, Puno Baima Tenzin's research group has long been committed to the discovery of novel lead compounds in this genus of plants and the development of innovative drugs.

In recent years, the research team has carried out systematic research on the morphological specific species of the genus Isodon scoparius, and has achieved a series of results: (1) Discovery of a novel rearrangement antipode-Helimanane Type diterpene scopariusins ​​A–C (Org.
Lett.
2013, 15, 314-317); (2) a novel heteroditerpene scopariusic acid ( Org.
Lett.
2013, 15, 4446-4449); (3) discovered novel heteroditerpene scopariusicides A and B with asymmetric cyclobutane fragments, and completed the biomimetic synthesis of scopariusicide A (Org.
Lett.
2015, 17, 6062-6065).

In 2012, the research team discovered for the first time a heteroditerpene (-)-isoscopariusin A with a novel 6/6/4 all-carbon skeleton from the fragrant tea plant, which has significant immunosuppressive activity on T lymphocytes ( IC50 = 0.
36 uM).
However, because the sample is an oily substance, the ideal crystal form cannot be obtained, which makes it difficult to confirm its absolute configuration by X-ray single crystal diffraction analysis; in addition, due to the low content of the sample in the plant, it is difficult to meet the requirements for further development.
The demand for pharmacological research.

In order to solve the above problems, the research team has carried out chemical synthesis research on it since 2015, and has successively developed two generations of synthetic routes.
Using commercially available sclareolide as the starting material, a 12-step gram-level synthesis has been achieved.
The key reactions involved: 1) Cobalt-catalyzed olefin isomerization reaction to prepare trisubstituted olefins; 2) Stereoselective synthesis of a-aryl groups based on the intermolecular [2 + 2] cycloaddition reaction of ketene imine salts Substituted cyclobutanone bioon.
com/tags/%E4%B8%AD%E9%97%B4%E4%BD%93/" target="_blank">intermediates ; 3) The fully substituted cyclobutane skeleton was further constructed through surface-selective homologation reactions; 4) Nickel-catalyzed cross-coupling and carbodiimide-mediated esterification reactions were carried out, respectively.
Perform side chain assembly.
The above research work not only achieved the gram-level synthesis of this new type of heteroditerpenoids, and determined the absolute configuration of the target molecule, but also laid a research foundation for the discovery of lead compounds with immunosuppressive activity.
(bioon.
com" target="_blank">Bioon.
com)