Advocacy for the Medicinal Plant Artabotrys hexapetalus (Yingzhao) and Antimalarial Yingzhaosu Endoperoxides

Abstract

The medicinal plant Artabotrys hexapetalus (synonyms: A.uncinatus and A. odoratissimus) is known as yingzhao in Chinese. Extracts of the plant have long been used in Asian folk medicine to treat various symptoms and diseases, including fevers, microbial infections, ulcers, hepatic disorders and other health problems. In particular, extracts from the roots and fruits of the plant are used for treating malaria. Numerous bioactive natural products have been isolated from the plant, mainly aporphine (artabonatines, artacinatine) and benzylisoquinoline (hexapetalines) alkaloids, terpenoids (artaboterpenoids), flavonoids (artabotrysides), butanolides (uncinine, artapetalins) and a small series of endoperoxides known as yingzhaosu A-to-D. These natural products confer antioxidant, anti-inflammatory and antiproliferative properties to the plant extracts. The lead compound yingzhaosu A displays marked activities against the malaria parasites Plasmodium falciparum and P. berghei. Total syntheses have been developed to access yingzhaosu compounds and analogues, such as the potent compound C14-epi-yingzhaosu A and simpler molecules with a dioxane unit. The mechanism of action of yingzhaosu A points to an iron(II)-induced degradation leading to the formation of two alkylating species, an unsaturated ketone and a cyclohexyl radical, which can then react with vital parasitic proteins. A bioreductive activation of yingzhaosu A endoperoxide can also occur with the heme iron complex. The mechanism of action of yingzhaosu endoperoxides is discussed, to promote further chemical and pharmacological studies of these neglected, but highly interesting bioactive compounds. Yingzhaosu A/C represent useful templates for designing novel antimalarial drugs.

Keywords: Artabotrys hexapetalus; endoperoxide; malaria; natural products; yingzhaosu.

Figure 1

Yingzhao plant and yingzhaosu compounds. (a) The plant yingzhao (Artabotrys uncinatus (L.) Meer.) with a view of the young fruits, the leaves and the flower (drawing: Prof. J.-P. Hénichart). The plant is largely distributed in Southeast Asia. The plant is native to countries such as India, Thailand, Vietnam, and Sri Lanka (and other counties in green) and has been introduced in Indonesoia, China, Japan (and other countries in purple) (https://powo.science.kew.org/taxon/urn:lsid:ipni.org:names:72395-1, accessed on 14 September 2022). (b) Structure of the four yingzhaosu compounds, all isolated from yingzhao.

Figure 2

Structure of selected natural products isolated from different parts of yingzhao. Detailed botanical information on yingzhao can be found at http://www.instituteofayurveda.org/plants/plants_detail.php?i=75&s=Local_name (accessed on 14 September 2022).

Figure 3

Structure of other natural products isolated from yingzhao.

Figure 4

An efficient synthesis of yingzhaosu A from (S)-limonene and the TMS-protected enol ether in the presence of oxygen afforded the compound in 8 steps with an overall yield of 7.3% (a). The intermediate product (trimethylsilyloxy-enone peroxide) was converted into yingzhaosu A and its C14-epimer, via a chemoselective reduction [93] (b).

Figure 5

Synthetic derivatives of yingzhaosu A, such as arteflene (also known as Ro-42-1611) and the synthesized compounds 14b [103], 2c [25] and 25 [104].

Figure 6

Reactions of yingzhaosu A or arteflene in the presence of iron and oxygen (Fenton reaction) lead to the formation of an oxygen-centered radical and then the release of alkylating species (unsaturated ketone and cyclohexyl radical), responsible for the parasiticidal properties (adapted from [114,115]).

Figure 7

Proposed scheme for the reaction of yingzhaosu A with heme [116].

Figure 8

A schematic illustration of the pharmacological potential of yingzhaosu A, isolated from the plan yingzhao, for the treatment of parasitic diseases, viral diseases and cancer.