Tigliane and Daphnane Diterpenoids From Thymelaeaceae Family: Chemistry, Biology Activity and Potential in Drug Discovery [ Summary].
This review focuses on the naturally occurring Tigliane and Daphnane diterpenoids derived from Thymelaeaceae plants. It describes their chemical structure, distribution, isolation procedure, structural identification, chemical production, and biological activity.
Looking at the chemical structure, the article describes how Tigliane diterpenoids possess a fused tetracyclie structure, where the D-ring forms a gem-dimethylcyclo propane ring. Although most of the known tiglianes have been isolated from the Euphorbiaceae family, those isolated from the Thymelaeaceae family have diverse patterns of oxidative modifications of the B-ring.
Daphnane diterpenoids possess a transfused tricycle structure, which is characterized by an isopropenyl group attached to the C-ring. In contrast to tigliane diterpenoids, many daphnane diterpenoids are obtained from Thymelaeaceae family rather than Euphorbiaceae family.
Examples of tigliane diterpenoids from the Thymelaeaceae family include phorbol and phorbol esters. Daphnane diterpenoids from the Thymelaeaceae family are classified based on their chemical structure characteristics. This includes:
1. Orthoester Acylate
2. Polyhydroxy Daphnane and
3. Macrocyclic Daphnane Orthoester [MDO]
In the distribution, investigations into the Thymelaeaceae family have reported the isolation of diterpenoids from 17 genera, but mostly from Daphne, Stellera, Wikstroemia, and Pimelia. The ones with abundant diterpenoids are Daphne genkwa and Stellera chamaejasme.
While orthoester daphnanes are the most commonly distributed diterpenoids in plants in the Thymelaeaceae family, only tiglianes are reported from Aquilaria and macrocyclic daphnane orthoesters [MDOs] from Dorca and Edgeworthia.
Tigliane and daphnane diterpenoids are isolated through the following process:
Dried plants are extracted using an organic solvent [ethanol or methanol].
Liquid partitioning
Silica gel and ODS silica gel column chromatography to fractionate extracts
Use of revered-phase preparatory HPIC for isolation and purification
Furthermore, the structural determination of both Tigliane and Daphnane diterpenoids is done primarily through NMR spectral analysis. Though the ¹H and ¹³C NMR spectra of tigliane and daphnane diterpenoids are similar, they are differentiated through the observation of the gem-dimethylcyclopropane group in tiglianes or the isopropenyl group in daphnanes.
EDO spectroscopy is commonly used to determine the absolute configuration of tiglianes, but it is not applied to daphnanes as they lack chromophore in their structure. Meanwhile, X-crystathography has been found to be useful for polyhydroxy daphnane with a 4, 7-epoxy structure and macrocyclic daphnane orthoester [MDO] with a bicyclo-heptane A-ring structure.
Phorbol was the first Tigliane diterpenoids to be synthesized. It is discovered that casbene is the source of Tigliane and Daphnane diterpenoids. This starts with a reaction catalyzed by casbene synthase from geranyl geranyl diphosphate [CGPP], generating casbene. Casbene then undergoes ring-closing reactions to form lathyrane, leading to tigliane. Then the cyclopropane ring of tigliane opens to form an isopropyl group to form daphnane. The skeletons are further modified by further oxygenation and esterification reactions to give rise to tigliane and daphnane diterpenoids.
Biological activity: The article focuses on the anti-cancer and anti-HIV activities of Tigliane and Daphnane diterpenoids.
Phorbol esters (Tiglianes) are known to stimulate protein kinase C by acting as a substitute for diacylglycerol, a naturally occurring second messenger. Daphnane diterpenoids also have the same function. PKC plays a role in the regulation of protein synthesis, DNA expression, and cell transformation.
Tigliane and daphnane diterpenoids exhibit antiproliferative activity through the activation of the PKC signaling pathway. E.g., Tigilanol and Mezerein While they exhibit anti-HIV activity through the inhibition of HIV-1 replication while activating latent HIV-1 in CD4+ T cells, e.g., prostate
In conclusion, this review explores Tigliane and Daphnane diterpenoids from Thymelaeaceae plants, found in 17 genera. These diterpenoids have fused structures and are found in Daphne genkwa and Stellera chamaejasme. Isolated through extraction, liquid partitioning, silica gel, ODS silica gel column chromatography, and NMR spectral analysis, they have anti-cancer and anti-HIV activities.
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Reference:
Otsuki, K., & Li, W. (2023, June 9). Tigliane and daphnane diterpenoids from Thymelaeaceae family: chemistry, biological activity, and potential in drug discovery. Journal of Natural Medicines, 77(4), 625–643. https://doi.org/10.1007/s11418-023-01713-x
