Abstract
Bioactive natural products are compounds derived from a living organism that elicit specific biological responses in another. Throughout history, humans have leveraged natural products through traditional medicines, potions, and oils to alleviate a variety of ailments. Nevertheless, despite the proven efficacy of Samoan medicinal plants, very little is known about the bioactive natural products responsible for their observed healing effects. Therefore, this PhD research aimed to investigate their chemical compositions, with a focus on identifying novel bioactive natural products, and establishing a scientific basis for their traditional uses.
To maximize the likelihood of discovering new compounds, an extensive literature review was conducted to identify commonly used medicinal plants with distributions mainly confined within the Pacific Islands. This led to the selection of ten species for investigation. However, due to availability, only nine of these species were chemically profiled using a dereplication approach developed in the present study.
The dereplication approach described here involved the use of LC-MS/MS and SIRIUS, an in silico annotation tool. These techniques were used in combination with ELSD and 1H NMR analysis to provide robust annotations of major components of the examined species.
The chemical screening revealed several known potent bioactive natural products as major components, identified for the first time in the Samoan species investigated in the present study. These included geraniin, procyanidins, rutin, astragalin and verbascoside (Figure I), all of which have entered clinical trials due to their potent pharmacological effects. The reported bioactivities of these major components not only correlated with the traditional applications of the examined species, but also uncovered their potential in a broader range of therapeutic areas.
For example, this study identified procyanidins (Figure I) as major components in the leaf and stembark of matalafi, both widely used in Samoa for the treatment of inflammation-induced diseases and neurological symptoms. A recent study has elucidated one of the mechanisms of action of matalafi leaf to occur through iron-chelation, and identified rutin and nicotiflorin, which were isolated in small amounts, to play a role in this iron-chelation activity. Procyanidins are also known for their iron-chelation properties as well as anticonvulsant and neuroprotective effects. This suggests procyanidins as potential major mediators of the traditional uses of matalafi, with the possibility of enhanced activity through synergistic interactions with rutin and nicotiflorin. The presence of procyanidins also indicated the potential of matalafi in treating diabetes, obesity, and cardiovascular diseases.
Results also revealed significant intraspecific variations in the compositions of certain species, with some displaying substantial differences between their ethanolic extract and juice sample that mimics traditional formulations, indicating the need for further work in this area. Among the investigated species, fuemanogi was found to contain many previously undescribed natural products (Figure II) structurally similar to piperine, the primary component of black pepper with several recognized pharmacological activities. For better insight into its chemical space, a variation study was conducted on ethanolic extracts of samples representing different fuemanogi populations across Samoa. Findings revealed three putative chemotypes. The first and most prevalent chemotype was composed mainly of the previously mentioned piperine-type amides, the second was characterized by piperchabamide as the main component, and the third, by the abundance of diayangambin (Figure II).
Intriguingly, the piperamides in the first chemotype were isolated in both their E and Z isomeric forms from ethanolic extracts. Considering the known susceptibility of piperine to photoisomerization, experiments were carried out to determine whether the Z isomers were genuine natural products and not products of light exposure during post-harvest processes. Z isomers were not only determined to be authentic natural products but also represented the main isomeric form found in traditional preparations, although E-1-cinnamoyl piperidine (113, Figure I) was identified as the most abundant component. Additionally, the Z isomer of a methoxylated ilepcimide (267) was also found to occur in high amounts. Previous studies have demonstrated antibacterial effects of 113, and potent anticonvulsant and antidepressant effects of ilepcimide, correlating with traditional uses of fuemanogi leaf in treating infections, wounds, and neurological symptoms, including depression and epilepsy.
The high amounts of the new natural product 267 in the fuemanogi leaf, and its structural similarity to ilepcimide, suggested potential anticonvulsant and antidepressant uses. As a result, it was tested for antidepressant effects using a MAO B inhibition assay. Results revealed no significant activity, suggesting the involvement of an alternative mechanism, or synergism.
This study has significantly expanded our understanding of the chemistry of Samoan medicinal plants. It has isolated new bioactive natural products and provided a scientific basis for the traditional uses of many Samoan medicinal species, bringing to light their previously undiscovered medicinal potential. Beyond ensuring consistency in the efficacy and safety of Samoan herbal remedies, this study has significantly contributed to the groundwork for future developments that could yield socioeconomic benefits through the utilization of Samoan natural products. Furthermore, this research represents a step toward advancing the field of natural products chemistry in Samoa.