14-Hydroxygelsenicine (HGE) is a gelsedine-type indole alkaloid naturally found in some plants of the Gelsemium genus (Gelsemium elegans and Gelsemium sempervirens). G. elegans was used in traditional Chinese medicine as a remedy for a plethora of conditions such as skin ulcers and dermatitis, pain related to cancer, rheumatic arthritis, psoriasis as well as to treat bone fractures. It can also be found under the names “Duan Chang Cao”, “Gou Wen” and “heartbreak grass”. G. elegans is also known for its toxic effects; it is used by hilltribes of southeastern Asia as an effective means of committing suicide and has been linked to certain types of toxic honey, where HGE was the most abundant component. Gelsedine-type alkaloids from G. elegans usually express high toxicity, with gelsenicine being one of the most toxic. However, toxicity of HGE has not yet been thoroughly researched. More recent studies have shown that alkaloids derived from G. elegans have anti-tumor, anti-inflammatory, analgesic, and immunomodulation properties, with the toxic dose being close to the therapeutic dose.
Structure and reactivity
The organic compound 14-Hydroxygelsenicine (HGE or Spiro[3H-indole-3,7'(6'H)-[3,6]methano[3H]oxepino[4,3-b]pyrrol]-2(1H)-one, 2'-ethyl-3'a,4',8',8'a-tetrahydro-9'-hydroxy-1-methoxy-, (3S,3'R,3'aS,6'S,8'aS,9'R)- ) is an indole alkaloid which falls under the gelsedine type group belonging to gelsemium alkaloids. HGE has, like all gelsedine-type alkaloids, a oxabicyclo[3.2.2] nonane core and a spiro-N-methyl indolinone moiety connected to it, which is an indole structural intertwined with a derivative of hydroxamic acid. The difference between HGE and gelsenicine is the oxygenation at C14. The binding energy of HGE to key targets is low in comparison to other alkaloids with higher LD50 values. The methoxy and carbonyl groups of the indole nucleus of HGE increase the possibility of hydrogen bonding with the target proteins; this increases the affinity between the ligand and the receptor. There is a difference in toxicity levels between the isotopes of HGE and humantendine (HGE is 0.295 mg·kg−1 p.o. and humantendine 0.21 mg·kg−1 i.p.). This points to a different reactivity between the isotopes.
Synthesis
It has been suggested that biologically, HGE is created via oxygenation at C14 of gelsedilam, a lactam derivative of gelsenicine. In the laboratory, (-)-14-Hydroxygelsenicine can be synthesized from a related alkaloid (-)-14-hydroxygelsedilam. The process includes acetylation of the C14 hydroxy group (yielding (-)-14-acetoxygelsedilam), followed by introducing a two-carbon unit onto C20. This introduction was done by converting lactam into a N-Boc derivative and treating it with ethylmagnesium bromide followed by trifluoroacetic acid. Lactam is converted into N-Boc via protonation of the nitrogen atom, creating an unstable intermediate, followed by a reaction with an N-Boc-reagent.
Another option for synthesis of HGE is via the partial reduction of the C14-C15 epoxide of the dihydroxygelsenicine compound. The epoxide functionality is introduced through treatment with TBHP and Triton B. Formal cis hydration of the C14-C15 double bond yields (-)-14-hydroxygelsenicine.
Reactions
HHGE can react biogenetically with 7-deoxygelsemide, creating gelseiridone. The hydroxamic acid moiety of HGE can rearrange in the presence of a strong base and at low temperatures, creating isocyanates. The resulting isocyanates could then react with skin proteins.
In the liver of humans and rats, HGE can be metabolized via hydroxylation, reduction, N-dimethyl ether and glucuronic acid binding reaction. HGE reacts with CNS neuron currents of rats of the γ-aminobutyric acid (GABA) receptor, because HGE most likely delays the closing of the CL- ion channel of the GABA receptor. This reaction doesn’t occur in bees, because they have alternative or compensatory ionotropic receptors. This reaction doesn’t occurs in bees, because they have alternative or compensatory ionotropic receptors.
Available forms
Humantendine, humantenidine and HGE are three known isomers of the compound.
Mechanism of action
HGE was shown to exhibit selective osteoclast inhibitory activity by inducing osteoclast apoptosis and inhibiting their proliferation. This is likely through increasing the expression of apoptotic factors caspase 9 and reducing the expression of inflammatory factors IL-6 and mitogenic factors c-Jun.