Traditional uses, chemical composition and pharmacological activities of Alstonia R. Br. (Apocynaceae): A review

Mi-xue Zhao; Jing Cai; Ying Yang; Jian Xu; Wen-yuan Liu; Toshihiro Akihisa; Wei Li; Takashi Kikuchi; Feng Feng; Jie Zhang

doi:10.1016/j.arabjc.2023.104857

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Review article

08 2023

:16;

104857

doi:

10.1016/j.arabjc.2023.104857

Traditional uses, chemical composition and pharmacological activities of Alstonia R. Br. (Apocynaceae): A review

Mi-xue Zhao^{^a}, Jing Cai^{^a}, Ying Yang^{^a}, Jian Xu^{^a}, Wen-yuan Liu^{^b}, Toshihiro Akihisa^{^a,^c}, Wei Li^{^d}, Takashi Kikuchi^{^d}, Feng Feng^{^a,^e}, Jie Zhang^{^a,⁎}

a School of Traditional Chinese Pharmacy, China Pharmaceutical University, 639 Longmian Avenue, Nanjing 211112, China

b School of Pharmacy, China Pharmaceutical University, Nanjing 211112, China

c Research Institute for Science and Technology, Tokyo University of Science, 2641 Yamazaki, Noda, Chiba 278-8510, Japan

d Faculty of Pharmaceutical Sciences, Toho University, Miyama 2-2-1, Funabashi, Chiba 274-8510, Japan

e Jiangsu Food and Pharmaceutical Science College, Huaian, Jiangsu 223003, China

⁎Corresponding author. cpunmc_zj@163.com (Jie Zhang)

Received: 2022-10-15, Accepted: 2023-3-23,

Disclaimer:
This article was originally published by Elsevier and was migrated to Scientific Scholar after the change of Publisher.

Abstract

Abstract

Alstonia R. Br. (Apocynaceae) is widely used in the traditional therapeutic systems. Due to its rich natural active ingredients, it is used in China, India, Thailand, Malaysia, Philippines, Africa, Australia and other countries to treat malaria, dysentery, asthma, fever, epilepsy, skin diseases, snake bites, and so on. The aim of this review is to describe in detail the botanical properties, traditional uses, chemical compositions, pharmacological activities and toxicity of the genus Alstonia for analyzing the value of this plant in clinical applications. There was information on the genus Alstonia collected through the internet searches such as Baichain Library, Web of Science, China National Knowledge Infrastructure (CNKI), Baidu Scholar, PubMed, Wan Fang Database and ACS, etc. The keywords used include genus Alstonia, folk medicinal uses, botanical studies, chemical composition, pharmacological activities, bioactivities and other relevant terminology. The scientific names and geographic location of the genus Alstonia were provided in the Subject Database of the Flora of China, the Plant List (www.theplantlist.org), the WFO Plant List (www.worldfloraonline.org) and the World Checklist of Selected Plant Families (http://wcsp.science.kew.org/qsearch.do). Currently, at least 400 compounds were isolated from genus Alstonia, including alkaloids, triterpenes, flavonoids, volatile oils, phenolic acids, etc. Through extensive pharmacological experiments, it was demonstrated that genus Alstonia had good pharmacological effects in vitro and in vivo, including β₂AR, vasodilatory, antifungal, antineoplastic, antiplasmodial, anti-inflammatory, antibacterial, antioxidant, analgesic, and radioprotective activities, etc. Many studies also confirmed that the combination of the genus Alstonia with other traditional Chinese medicines could improve effectiveness. This review demonstrates that the genus Alstonia has high clinical application and medicinal value, which will bring the attention of pharmacologists and clinicians to the territory of natural products Additionally, bioactivity-related mechanisms and structure–activity relationships of chemical components are not clear. Only by bridging the gap between bioactivity-related mechanisms and structure–activity relationships of chemical components can the development of Alstonia plants be further promoted.

Keywords

Alstonia R. Br. (Apocynaceae)

Chemical components

Biological activities

Traditional uses

1 Introduction

Various natural products exist in nature. And natural products are rich in chemical components with different structure, such as flavonoids, triterpenes, steroids, alkaloids, etc., which are a critical treasure trove for the discovery of new drug lead compounds. In traditional applications, these plants can be used medicinally to treat disease and have great advantages over other chemical drugs, such as Alstonia. The genus Alstonia is a tropical plant with widespread distribution throughout the world, mainly in Africa, Indo-Malaya, Australia, Asia and other regions (Narine et al., 2009; Ku et al., 2011).

Approximately 46 species of the genus Alstonia are known worldwide and can be found at https://wcsp.science.kew.org/qsearch.do, https://www.worldfloraonline.org and https://www.theplantlist.org. Eight of them are located in the regions of Guangdong, Guangxi and Yunnan in China. In traditional medicine, these species are used not only to treat a number of diseases, such as malaria, but also to provide fever-reducing, cough-suppressing and hemostatic effects (Channa et al., 2005; Gandhi and Vinayak, 1990; Wright et al., 1993; Leaman et al., 1995; Kam et al., 1997 ). Total alkaloids (TA) obtained from Alstonia scholaris (L.) R. Br. as a new investigational phytopharmaceutical (No. 2011L01436) are registered in advance of clinical application (Pan et al., 2016). TA are also approved by the Chinese Food and Drug Administration for Phase I/II clinical trials (Shang et al., 2010a, 2010b). Additionally, the genus Alstonia could be used in association with other traditional Chinese medicines to maximize effectiveness, such as the combination of Khaya ivorensis A. Chev. and Alstonia boonei De Wild. as antimalarial prophylaxis (Tepongning et al., 2011).

Phytochemical studies have shown that the genus Alstonia represents a treasure trove as a source of phytoconstituents. In excess of 400 compounds have been isolated from this genus (Wang et al., 2009). Chemical investigation of the alkaloidal constituents was undertaken by Sharp (1938) and Elderfield (1942) (Keogh and Shaw, 1943). So far, the most abundant compounds isolated from this genus are monoterpenoid indole alkaloids (MIAs), and the non-alkaloid components include flavonoids, terpenes, phenolic acids, volatile oils, and so on. MIAs are the products from the condensation of tryptophan with secologanin. It is the second most abundant metabolite of the genus (De, 2011). After comprehensive analysis of phytochemistry and pharmacology, most of the genus's crude extracts and purified compounds are pharmacologically potent. Beyond that, the genus Alstonia also has different pharmacological activities in different parts. A. scholaris is the majority researched and representative species in the genus Alstonia. Despite extensive work and studies on A. scholaris, the number of precursor molecules and herbal preparations available have been extremely small (Pandey et al., 2020).

There was information on the genus Alstonia collected through the internet searches such as Science Network, PubMed, Baichain Library, China National Knowledge Infrastructure (CNKI), Baidu Scholar, Wan Fang Database, and ACS, etc. The keywords used include genus Alstonia, folk medicinal uses, botanical studies, chemical composition, bioactivity, secondary metabolites, and other relevant terminology. The scientific names and geographic location of the genus Alstonia were provided in the Subject Database of the Flora of China, the Plant List (https://www.theplantlist.org), and the World Checklist of Selected Plant Families (https://wcsp.science.kew.org/qsearch.do).

In this review, a comprehensive compilation of botanical information, traditional uses, phytochemistry, bioactivities and toxicity involved in the genus Alstonia is presented. The purpose of this review is to discover lead compounds from the genus Alstonia that provide potential development value and clinical application value. In addition, a clearer structured review of the structure–activity relationships of chemical compositions is expected to afford a more reliable basis for the pharmacological mechanisms and new drug development of Alstonia.

2 Distribution and botanical studies

Genus Alstonia plants are generally shrubs or trees. All the species of the genus Alstonia are known worldwide, eight of which are located in the Guangdong, Guangxi, and Yunnan regions of China. The names and geographical distribution of the identified 46 species are listed in Table S1.

In accordance with Flora of China, Alstonia is a member of the Apocynaceae family. They are mostly trees and shrubs with milk, and their branches grow on wheels. The leaves are usually in whorls of 3–4(-8), rarely opposite. Lateral veins are numerous, crowded and parallel. Flowers are white, yellow, or red, consisting of multiple flowers forming an umbel-like polyglobulus inflorescence, terminal or nearly terminal. Calyx short, sepals are double-covered imbricate arrangement. There are no interior glands, and the corolla is salver-shaped. Crown tube is cylindrical, expanding above the middle, without corona at the throat. Corolla lobes are covered to the left at the time of the buds (Chinese species). Stamens are separated from the stigma and the anthers are oblong. Ovary is composed of two detached carpels, with multiple ovules per carpel. Flowering style is filiform, whereas stigmas are clubbed. Flower disk consists of 2 ligulate scales, which are alternate with the carpels. Seeds are flat and covered at both ends by long marginal hairs.

A. scholaris is a representative species of the genus Alstonia, which has a typical milky white latex that cuts the bark and flows freely. The genus is distributed primarily in tropical Africa, Asia, and Australia. In the evergreen rainforest of tropical West Africa, Alstonia becomes a tremendous tree, thriving on damp river banks (Adotey et al.,2012).

3 Traditional uses

A number of plants in the genus Alstonia have been used in folk medicine from ancient times. For example, in the tribes of the Indian Gulf Islands, the leaves of Alstonia macrophylla Wall. ex G. Don are commonly decocted to treat stomach pains (Dagar and Dagar, 1991). In West and Central Africa, A. boonei is regarded as a medicinal plant by local people. A. boonei is widely used in the treatment of malaria, intestinal helminths, rheumatism, hypertension, and so on (Terashima, 2003; Betti, 2004; Abel and Busia, 2005 ). The flowers of A. scholaris can be used as a CNS depressant (Sood and Thakur, 2015) and also to treat respiratory problems and asthma (Anonymous, 1985). When ear pain, boils and injuries occur, the latex of A. scholaris is combined with oil as a treatment for the disease (Bhardwaj and Gakhar, 2005). Alstonia mairei H. Lév. is used in folklore as an essential medicinal plant for stopping bleeding and dissolving poison (Li et al., 1995; Wang, 2014).

The genus Alstonia bark is most generally used in traditional medicine, but the most commonly used part is the thick bark of mature trees (Adotey et al., 2012). Alstonia's bark has a natural analgesic effect and serves as one of the analgesic herbs (Abbiw, 1990). In daily treatment, the bark not only treats rheumatism, inflammation, pain, malaria, diabetes (mild hypoglycemia), but also exerts anthelmintic, antimicrobial and antibiotic effects (Hadi and Bremner, 2001; Fakae et al., 2000; Kam et al., 1997 ). The decoction of Alstonia also provides mild antibacterial action and may relieve the soreness involved with malarial fevers (Adotey et al., 2012). The fresh bark of Alstonia is used to make an herbal tincture for snake, rat or scorpion poisoning (Adotey, et al., 2012). The cold infusion is used orally to expel roundworms and nematodes (Abbiw, 1990). Extracts of the leaves have been developed commercially as typical herbal medicines and are also hospital prescription drug, available in pharmacies (Cai et al., 2008). In Table 1, the traditional uses (edible and medicinal) of the genus Alstonia are provided.

Table 1 The traditional uses of genus Alstonia.

Alstonia plants	Parts of the plant	Edible methods	Traditional and clinical uses	Reference
Alstonia scholaris (L.) R. Br.	Ripe fruits	–	Curing for syphilis, insanityand epilepsy	(Jahan et al., 2009)
	Milky juice	–	Curing for ulcers, wounds and rheumatic pain	(Varshney and Goyal, 1995)
	Bark	Decoction	Curing for falciparum malaria, asthma, hypertension, lung cancer and pneumonia	(Varshney and Goyal, 1995)
		Powdered bark	Curing for malaria, diarrhea, and dysentery	(Kirtikar and Basu, 1918; Akhtar et al., 1992)
	Leaves	–	Curing cough, chronic bronchitis, asthma, fever and other respiratory infections after infection	(Dey and De, 2011; Sharma et al., 2001)
	Flowers		Curing for respiratory problems and asthma	(Anonymous, 1985)
	Root	–	Curing for treat gum or dental problems	(Pan et al., 2014)
	Latex	Mixed with oil	Curing for earache, boils, and wounds healing	(Bhardwaj and Gakhar, 2005)
Alstonia yunnanensis Diels	Root	–	Curing for headache, fever and hypertension	(Chen et al., 1983)
Alstonia venenata R. Br.	The whole plant	–	Curing for insanity and epilepsy	(Ray and Dutta, 1973)
Alstonia angustifolia A. DC.	Leaves	–	Curing for relapsing fever of spleen area	(Ray and Dutta, 1973)
Alstonia macrophylla Wall. ex G. Don	Leaves and bark	Decoction	Curing for stomachache, skin diseases and urinary infection	(Dagar and Dagar, 1991; Bhargava, 1983)
	Leaves	Copra oil mixed with heated leaves	Curing for sprains, bruises, dislocated joints and muscle injuries	(Asolkar and Kakkar, 1992)
	Bark	Powdered form	Curing for antipyretic and dysentery Aid in the menstrual cycle	(Changwichit et al., 2011; Chattopadhyay et al., 2004)
	Bark	Powdered form mixed with water	Curing for astringent and skin diseases	(Das et al., 2008)
Alstonia boonei De Wild.	Stem bark	Decoction	Curing for astringent, alternative tonic, diarrhea and a febrifuge for relapsing fevers	(Abbiw, 1990)
	Leaves and latex	–	Curing for rheumatic and muscular pain and hypertension	(Abbiw, 1990)
Alstonia congensis Engl.	Leaves	Aqueous decoction	Curing for diarrhoea	(Lumpu et al., 2012)
Alstonia mairei H. Lév.	–	–	Curing for haemostasis, disintoxication	(Li et al., 1995; Wang, 2014)

—: not mentioned.

4 Chemical components

In addition to volatile oils, a total of 392 chemical constituents are obtained from genus Alstonia. The chemical composition of Alstonia plants (as shown in Table S2.) involves alkaloids (1–319), triterpenes (320–362), flavonoids (363–379), fatty acid (380), phenolic acids (381–388), lignans (389–391), and ester (392).

The earliest study of the phytochemical composition of Alstonia plants could be dated in the 19th century. In 1875, a new crystalline alkaloid belonging to the aluammiline alkaloids was isolated from the bark of the genus Alstonia, which was named Echitamine (Goodson, 1932). After that, with the development of two-dimensional nuclear magnetic resonance (2D NMR) and quadrupole time of flight mass spectrometer (Q-TOF-MS), this technique for the chemical composition of genus Alstonia identification was provided a new method. Until 21st century, with the proposed bioactivity-oriented separation strategies, more bioactive components have been identified (El-Askary et al., 2012). In addition, bioactive-based liquid chromatography-coupled electrospray ionization tandem ion trap/time of flight mass spectrometry (HPLC-ESI-MS/MS) technology was also applied to detect bioactive components in Alstonia plants (Hou et al., 2012a).

4.1

4.1 Alkaloids (1–319)

Alkaloids are a highly diverse set of compounds. They are mainly distributed in the Apocynaceae family, such as Alstonia R. Br. Alkaloids are only associated with the presence of nitrogen atoms in heterocyclic rings and are the main active and typical components of genus Alstonia. So far, 319 alkaloids have been obtained in the genus Alstonia, mainly divided into MIAs, bisindole alkaloids and other alkaloids. MIAs constituted a broad and various population of natural products characterized by the combination of indole units with extensively modified monoterpenoid molecules (Zhang et al., 2020). In the genus Alstonia, the MIAs are mainly corynantheine-strychnine alkaloids (1–157), sarpagine alkaloids (158–174), ajmaline alkaloids (175–201), macroline alkaloids (202–240), eburnamine and kopsifoline alkaloids (241–261). Because of their impressive structures and wide range of bioactivities, MIAs were often located on the list of popular molecules in natural product synthesis (Zhang et al., 2009; Xu et al., 2014; Adams et al., 2012; Pan et al., 2016 ). (Tables 2-5 ) show that the alkaloids identified from different species of the genus Alstonia. The proportions of the different types with alkaloids in the genus Alstonia are shown in the Fig. 1.

Table 5 Pharmacological activities of the genus Alstonia.

pharmacological activities	Name	Description	In vivo/In vitro	Reference
Antifertility activity	$β$ -amyrin α-amyrin	oral administration of the exact at a dose of 200 mg/day in 60 days did not cause weight loss, while the weight of the test, epididymis, seminal vesicles, and abdominal prostate decreased	In vivo	(Gupta et al., 2002)
	Llupiolacetate Rhazine	oral administration of the exact at a dose of 200 mg/day in 60 days did not cause weight loss, while the weight of the test, epididymis, seminal vesicles, and abdominal prostate decreased	In vivo	(Gupta et al., 2002)
	Venenative Yohimbine	oral administration of the exact at a dose of 200 mg/day in 60 days did not cause weight loss, while the weight of the test, epididymis, seminal vesicles, and abdominal prostate decreased	In vivo	(Gupta et al., 2002)
Anticancer activity	ASE	the combination of 180 mg/kg of ASE and 8 mg/kg of BCLL showed the maximum antitumor effect	In vivo	(Jagetia and Baliga, 2004)
	ASE	significant increase in reduced glutathione, superoxide dismutase and catalase but decrease in lipid peroxidation was measured in ASE administered experimental groups than the carcinogen treatedcontrol.	In vivo	(Jahan et al., 2009)
	ASERS	tumors were relieved at 240 mg/kg body weight, where the maximum antitumor effect was observed. As 240 mg/kg ASERS showed toxic manifestations, the next lower dose of 210 mg/kg was considered as the best effective dose	In vitro	(Jagetia and Baliga, 2006)
	Echitamine	in vivo researchs with methylanthracene-induced fibroid rats showed that the anticancer activity of echidna extended to the in vivo system and a significant decrease in tumor growth was observed	In vivo	(Baliga, 2010)
Cytotoxic activity	Alstobrogalin	alstobrogalin was weakly cytotoxic towards MDA-MB-231 and MCF7 cells (IC₅₀ 25.3 and 24.1 µM, respectively), but inactive towards MDA-MB-468, SKBR3, and T47D cells (IC₅₀ > 30 µM)	In vitro	(Krishnan et al., 2019)
	15-hydroxyangustilobine A	15-hydroxyangustilobine A was the active component (IC50 of 26 μ M in MCF-7 cells). 15 hydroxyangustilobine A was shown to cause cell cycle arrest in the G2/M phase (MCF-7 cells) and to trigger apoptosis	In vitro	((Spiegler et al., 2021)
	Alstomairine B	demonstrated cytotoxic activity against all tumor cell lines tested (IC₅₀ = 9.2 µM)	In vitro	(Yan et al., 2017)
	Alstomairine C	exhibited cytotoxic activity against all tumor cell lines tested with an IC₅₀ value of 13.0 µM	In vitro	(Yan et al., 2017)
	Angustilobine C	had moderate cytotoxicity towards drug-sensitive KB and vincristine-resistant at IC₅₀ of 7.76 and 7.33 µg/mL, respectively	In vitro	(Ku et al., 2011)
	ScholarisinⅥ	possessed significant cytotoxicities against all tumor cell lines tested, with low IC₅₀ values (<30 μM)	In vitro	(Wang et al., 2013)
	Perakine N₄-oxide Raucaffrinoline N₄-oxide Vinorine N₄-oxide	possessed higher cytotoxic activities against astrocytoma and glioma cell (CCF-STTG1, CHG-5, SHG-44 and U₂₅₁) with lower IC₅₀ value than against human skin cancer (SK-MEL-2) and human breast cancer (MCF-7 cells)	In vitro	(Cao et al., 2012)0

Name	Description	In vivo/In vitro	Reference
Scholarisin I	possessed significant cytotoxicities against all tumor cell lines tested, with low IC₅₀ values (< 30 μM)	In vitro	(Wang et al., 2013)
Angustilobine B	angustilobine B was cytotoxic to KB cells	In vitro	(Tan et al., 2010)
Alstonine	alstonine was reported to have antitumor effects in transplantable YC8 lymphoma ascites-bearing mice (BALB/C mice) and in Ehrlich ascites carcinoma-bearing swiss mice	In vivo	(Baliga, 2010)
Vincadifformine Echitoveniline	displayed cytotoxicity against A549 lung cancer cells and the IC₅₀ values ranged from 5.6 to 77.1 μM	In vitro	(Li et al., 2022a, 2022b)
Vincadifformine Echitoveniline		In vitro	(Li et al., 2022a, 2022b)
Tabersonine Tetrahydroalstonine	displayed cytotoxicity against A549 lung cancer cells and the IC₅₀ values ranged from 5.6‐77.1 μM	In vitro	(Li et al., 2022a, 2022b)
Tabersonine Tetrahydroalstonine		In vitro	(Li et al., 2022a, 2022b)
16- methoxytabersonine 19-acetoxy-11-methoxytabersonine	displayed cytotoxicity against A549 lung cancer cells and the IC₅₀ values ranged from 5.6‐13.1 μM	In vitro	(Li et al., 2022a, 2022b)
16- methoxytabersonine 19-acetoxy-11-methoxytabersonine		In vitro	(Li et al., 2022a, 2022b)
19-hydroxytabersonine Vandrikidine	displayed cytotoxicity against A549 lung cancer cells and the IC₅₀ values ranged from 5.6‐77.1 μM	In vitro	(Li et al., 2022a, 2022b)
19-hydroxytabersonine Vandrikidine		In vitro	(Li et al., 2022a, 2022b)
Isovallesiachotamine	had potent cytotoxicity against A549 lung cancer cells and the IC₅₀ values ranged from 5.6‐13.1 μM	In vitro	(Li et al., 2022a, 2022b)
Angustilongine A Angustilongine B	displayed significant in vitro growth inhibitory activity against a range of human cancer cell lines, including KB, vincristine-resistant KB, PC-3, LNCaP, MCF7, MDA-MB-231, HT-29, HCT 116, and A549 cells within the range of 0.3‐8.3 Μm	In vitro	(Yeap et al., 2018)
Angustilongine A Angustilongine B		In vitro	(Yeap et al., 2018)
Alstomairine D Alstomairine G	displayed cytotoxicity against A549 lung cancer cells and IC₅₀ values ranged from 5.6 to 77.1 μM	In vitro	(Li et al., 2022a, 2022b)
Alstomairine D Alstomairine G		In vitro	(Li et al., 2022a, 2022b)
Lochnericine Alstomairine E	displayed cytotoxicity against A549 lung cancer cells and IC₅₀ values ranged from 5.6 to 13.1 μM	In vitro	(Li et al., 2022a, 2022b)
Lochnericine Alstomairine E		In vitro	(Li et al., 2022a, 2022b)
Yohimbine-17-O-3′,4′,5′-Trimethoxybenzoate	displayed cytotoxicity against A549 lung cancer cells and IC₅₀ values ranged from 5.6 to 13.1 μM	In vitro	(Li et al., 2022a, 2022b)
(E)-16-formyl-5α-Methoxystrictamine	displayed marked cytotoxicities against all the tumor cell lines tested and IC₅₀ value was low (< 30 μM)	In vitro	(Wang et al., 2013)
Alstomairine D Alstomairine E	showed cytotoxicity against A549 lung cancer cells tested. The IC₅₀ of alstomairines D and E ranged from 5.6 to 77.1 μM and 5.6 to 13.1 μM, respectively	In vitro	(Li et al., 2022a, 2022b)
Alstomairine D Alstomairine E		In vitro	(Li et al., 2022a, 2022b)

pharmacological activities	Name	Description	In vivo/In vitro	Reference
Vasorelaxant activity	Undulifolin	with uleine skeleton showed moderate activity (33.3% at 3 × 10^-5 M)	In vitro	(Koyama et al., 2008)
	Alstilobanine A	possessing angustilodine skeleton without an ether linkage showed more potent activity (44.3% at 3 × 10⁵ M)	In vitro	(Koyama et al., 2008)
	Alstilobanine C	showed moderate activity (28.0% at 3 × 10^-5 M) with uleine skeleton	In vitro	(Koyama et al., 2008)
	Alstilobanine B	with uleine skeleton showed moderate activity (21.2% at 3 × 10^-5 M)	In vitro	((Koyama et al., 2008)
	Alstilobanine E	with an ether linkage showed moderate activity the weakest activity (6.8% at 3 × 10^-5 M)	In vitro	(Koyama et al., 2008)
	Alstilobanine D	showed weak activity (10.0% at 3×10^-5 M) against phenylephrine (PE, 3 × 10⁷ M)-induced contractions ofthoracic rat aortic rings with endothelium	In vitro	(Koyama et al., 2008)
	Alstonamic acid	possessing seco skeleton showed a weak activity (35.0% at 3 × 10^-5 M)	In vitro	(Koyama et al., 2008)
	6,7-secoangustilobine B	showed weak activity (7.0% at 3 × 10^-5 M) against phenylephrine (PE, 3 × 10⁷ M)-induced contractions ofthoracic rat aortic rings with endothelium	In vitro	(Koyama et al., 2008)
	Alstiphyllanine A	showed vasorelaxant activity against phenylephrine induced contraction of isolated rat aorta (70% at 3 × 10^-5 M)	In vitro	(Hirasawa et al., 2009)
	Alstiphyllanine B	had vasorelaxant activity against phenylephrine-induced constriction in isolated rat aorta (35% at 3 × 10^-5 M)	In vitro	(Hirasawa et al., 2009)
	Alstiphyllanine C	showed vasorelaxant activity against phenylephrine-induced constriction in isolated rat aorta (40% at 3 × 10 ^-5 M)	In vitro	(Hirasawa et al., 2009)
	Alstiphyllanine D	had vasorelaxant activity against phenylephrine-induced constriction in isolated rat aorta (42% at 3 × 10^-5 M)	In vitro	(Hirasawa et al., 2009)
	Vincamajine-17-O-veratrate	showed that they relaxed phenylephrine (PE)-induced contractions	In vitro	(Arai et al., 2012)
	Vincamajine-17-O-3′,4′,5′-Trimethoxybenzoate	showed that they relaxed phenylephrine (PE)-induced contractions	In vitro	(Arai et al., 2012)
	AlstiphyllanineI	showed that they relaxed phenylephrine (PE)-induced contractions	In vitro	(Arai et al., 2012)
	AlstiphyllanineJ	showed that they relaxed phenylephrine (PE)-induced contractions	In vitro	(Arai et al., 2012)
	AlstiphyllanineL	showed that they relaxed phenylephrine (PE)-induced contractions	In vitro	(Arai et al., 2012)
	AlstiphyllanineM	showed that they relaxed phenylephrine (PE)-induced contractions	In vitro	(Arai et al., 2012)
	AlstiphyllanineN	showed that they relaxed phenylephrine (PE)-induced contractions	In vitro	(Arai et al., 2012)
	AlstiphyllanineO	showed that they relaxed phenylephrine (PE)-induced contractions	In vitro	(Arai et al., 2012)

pharmacological activities	Name	Description	In vivo/In vitro	Reference
	Alstolarine A	exhibited promising vasorelaxant activities against KCl-induced contraction of rat renal arteries with EC₅₀ values of 4.6 µM	In vitro	(Zhang et al., 2020)
	Alstolarine B	exhibited promising vasorelaxant activities against KCl-induced contraction of rat renal arteries with EC₅₀ values of 6.7 µM	In vitro	(Zhang et al., 2020)
	Melosline C	exhibited potent vasorelaxant activityon renal arteries with EC₅₀ value of 38.62 μmol·L⁻¹	In vitro	(Zhang et al., 2019)
	Melosline D	exhibited potent vasorelaxant activityon renal arteries with EC₅₀ value of 41.43 μmol·L⁻¹	In vitro	(Zhang et al., 2019)
	Alstoschonoid A	showed significant vasorelaxant activity with relaxation rates above 90% at 200 μM and exhibited moderate vasorelaxant activity with IC₅₀ values between 41.87 and 93.30 μM by further studies	In vitro	(Zhang et al., 2022)
	Alstochonine B		In vitro	(Zhang et al., 2022)
	Methyl 4- [2-hydroxy-2-(4-hydroxy-3- methoxyphenyl) -l (hydroxymethyl) ethyl] ferulate	exhibited significant vasodilatory activity at 200 μM with a relaxation rate of>90% and by further studies showed moderate vasodilatory activity having IC50 values between 41.87 and 93.30 μM	In vitro	(Zhang et al., 2022)
	(‐) ‐ (7R,7′R,7″R,8S,8′S,8″S)-4′,4″-dihydroxy-3,3′,3′′,5‐tetramethoxy-7, 9′:7′,9-diepoxy-4,8′′-oxy-8, 8′-sesquineolignan-7″,9′′-diol	exhibited significant vasodilatory activity at 200 μM with a relaxation rate of>90% and by further studies showed moderate vasodilatory activity having IC50 values between 41.87 and 93.30 μM	In vitro	(Zhang et al., 2022)
	(‐) ‐ (7R,7′R,7′′R,8S,8′S,8′′S)-4′,4′′-dihydroxy-3,3′,3′′,5,5′‐pentamethoxy-7,9′:7′,9-diepoxy-4,8′′-oxy-8,8′-sesquineolignan-7′′,9′′-diol	exhibited significant vasodilatory activity at 200 μM with a relaxation rate of>90% and by further studies showed moderate vasodilatory activity having IC50 values between 41.87 and 93.30 μM	In vitro	(Zhang et al., 2022)
	Alstochonine A	showed moderate vasorelaxant activity (IC₅₀ values of 93.30 ± 10.81)	In vitro	(Zhang et al., 2022)
Antifungal activity	Δ³-alstovenine	Δ³-alstovenine at 250–1000 mg/L inhibited the spore germination of most of the tested fungi	In vitro	(Singh et al., 1999)
	Tricin-4′-O-β-L-arabinoside	showed significant antifunga activity against salmonella typhimurium (MTCC-98), candida albicans (IAO-109)	In vitro	(Parveen et al., 2010)
	The leaves extract of A. scholaris	the extract was applied against eight five fungal strains	In vitro	Altaf et al., 2019

pharmacological activities	Name	Description	In vivo/In vitro	Reference
	The leaves and bark of A. venenata	Fungal studies were conducted on crude extracts of plants to test their fungicidal properties against human pathogens, plant pathogens and industrially important strains of fungi	In vitro	(Ray and Dutta, 1973)
	Scholarisin I	demonstrated antifungal activity for two fungi (G. pulicaris and C. nicotianae) and the MIC values were 0.64–0.69 mM	In vitro	(Wang et al., 2013)
	ScholarisinⅡ	demonstrated antifungal activity for two fungi (G. pulicaris and C. nicotianae) and the MIC values were 1.37‐1.44 mM	In vitro	(Wang et al., 2013)
	ScholarisinIII	demonstrated antifungal activity for two fungi (G. pulicaris and C. nicotianae) and the MIC values were 1.80‐1.91 mM	In vitro	(Wang et al., 2013)
	(3R,5S,7R,15R,16R,19E)-scholarisine F	demonstrated antifungal activity for two fungi (G. pulicaris and C. nicotianae) and the MIC values were 1.55‐1.71 mM	In vitro	(Wang et al., 2013)
Antibacterial activity	The crude methanolic extracts of ASE	exhibiting improved and broader spectrum of antibacterial activity	In vitro	(Khan et al., 2013)
	Scholarisine T	exhibited significant antibacterial effects on Escherichia coli and MIC value was 0.78 µg/mL.	In vitro	(Yu et al., 2018)
	Scholarisine U	showed remarkable antibacterial activity against Bacillus subtilis and MIC value was 3.12 µg/mL exhibited significant antibacterial effects on Escherichia coli and MIC value was 0.78 µg/mL	In vitro	(Yu et al., 2018)
	Scholarisine V	exhibited significant antibacterial effects on Escherichia coli and MIC value was 0.78 µg/mL.	In vitro	(Yu et al., 2018)
	Tricin-4′-O-β-L-arabinoside	showed antibacterial activity against staphylococcus aureus (IAO-SA-22), escherichia coli (K-12)	In vitro	(Parveen et al., 2010)
Antimicrobial activity	Tricin-4′-O-β-L-arabinoside	showed significant antimicrobial activity using agar well diffusion method	In vitro	(Parveen et al., 2010)
	The crude extract of AM	antimicrobial activity was exhibited against various strains of Escherichia coli, Staphylococcus aureus, Staphylococcus saprophyticus, Proteus mirabilis, Trichophyton mentagrophytes var mentagrophytes, MicrosporµM gypseum, Streptococcus faecalis and Trichophyton rubrum. The minimum inhibitory concentration (MIC) values range from 64 to 1000 µg/ml for bacteria and 32‐128 mg/ml for dermatophytes However, the strains of Pseudomonas aeruginosa, Klebsiella sp. and Vibrio cholerae demonstrated resistance to the extract treatment up to 2000 µg/ml, while two yeasts were resistant even at a concentration of 128 mg/ml	In vitro	(Chattopadhyay et al., 2004)
	ASE	the current study on A. scholaris revealed valuable phytochemical constituents with significant antimicrobial properties and further suggested that the minimum inhibitory concentration (MIC) values of the extracts should be investigated in future studies	In vitro	(Altaf et al., 2019)

pharmacological activities	Name	Description	In vivo/In vitro	Reference
Marginal activity	Crude alkaloidal extracts from the roots	crude extracts of alkaloids obtained from plant roots exhibited weak activity against experimental U14 tumors in mice	In vivo	(Chen et al., 1983)
SGLT inhibitory activity	Alstiphyllanine E	indicated inhibitory activity against SGLT1 and SGLT2 with 60.3% and 80.5% inhibition values	In vitro	(Arai et al., 2010)
	Burn-amine-17-O-3′,4′,5′-trimethoxybenzoate	indicated inhibitory activity against SGLT1 and SGLT2 with 53.0% and 87.3% inhibition values	In vitro	(Arai et al., 2010)
	Alstiphyllanine F	indicated inhibitory activity against SGLT1 and SGLT2 with 65.2% and 103.8% inhibition values	In vitro	(Arai et al., 2010)
	AlstiphyllanineD	indicated inhibitory activity agains SGLT₁ and SGLT₂ with 89.9% and 101.4% inhibition values	In vitro	(Arai et al., 2010)
	10-methoxy-N₁-methylburnamine-17-O-veratrate	indicated inhibitory activity agains SGLT₁ and SGLT₂ with 98.5% and 102.6% inhibition values	In vitro	(Arai et al., 2010)
β₂AR activity	Z-alstoscholarine	compared with the control, Z-alstoscholarine showed significant effects	In vitro	(Hou et al., 2012a)
	Akuammidine	compared with the control, akuammidine showed significant effects	In vitro	(Hou et al., 2012a)
	19,20-(E)-vallesamine	compared with the control, 19,20-(E)-vallesamine showed significant effects	In vitro	(Hou et al., 2012a)
	E-alstoscholarine	compared with the control, E-alstoscholarine showed significant effects	In vitro	(Hou et al., 2012a)
	12-hydroxy-echitamidine N_b-oxide (HENO)	compared with the control, HENO showed significant effects	In vitro	(Hou et al., 2012a)
	Scholaricine	displayed much poorer β₂ AR activation	In vitro	(Hou et al., 2012a)
	Picrinine	displayed much poorer β₂ AR activation	In vitro	(Hou et al., 2012a)
	11-methoxygelsemamide	indicated potential activity for β₂ AR	In vitro	(Hou et al., 2012b)
	Alstomaline	displayed potential activity for β₂ AR	In vitro	(Hou et al., 2012b)
	Alloyohimbine	displayed potential activity for β₂ AR	In vitro	(Hou et al., 2012b)
	19E-Vallesamine	displayed potential activity for β₂ AR	In vitro	(Hou et al., 2012b)
	Pseudoyohimbine	indicated potential activity for β₂ AR	In vitro	(Hou et al., 2012b)
	Picrinine	indicated potential activity for β₂ AR	In vitro	(Hou et al., 2012b)
	Picralinal	indicated potential activity for β₂ AR	In vitro	(Hou et al., 2012b)
Spasmolytic activity	The crude extract of A. scholaris	in isolated rabbit jejunum preparation, the As. Cr produced inhibition of spontaneous and high K⁺ (80 mM) ‐induced contractions, with respective EC₅₀ values of 1.04 (0.73‐1.48) and 1.02 mg/mL (0.56‐1.84; 95% CI), thus showing spasmolytic activity mediated possibly through calcium channel blockade (CCB)	In vitro	(Shah et al., 2010)

pharmacological activities	Name	Description	In vivo/In vitro	Reference
	Akuammidine	the EC₅₀ value for the spasmolytic activity was 243.9 µmol/L	In vitro	(Hou et al., 2012a)
	The total alkaloidal extract of A. scholaris	the EC₅₀ value for the spasmolytic activity of the total alkaloidal extract (500 µg/mL) was 267.5 µmol/L	In vitro	(Hou et al., 2012a)
	Z-alstoscholarine	the EC₅₀ value for the spasmolytic activity was 137.5 µmol/L	In vitro	(Hou et al., 2012a)
	19,20-(E)-vallesamine	the EC₅₀ value for the spasmolytic activity was 74.8 µmol/L	In vitro	(Hou et al., 2012a)
Immunostimulating activity	Ethanol extractions of A. scholaris bark	A. scholaris bark aqueous extracts at 50 and 100 mg/kg of bw were able to stimulate non– specific immune response	In vivo	(Iwo et al., 2000)
	Alstiphyllanine A	displayed intermediate-level antiplasmodial activity against Plasmodium falciparum	In vitro	(Hirasawa et al., 2009)
	Echitamine	exhibited moderate activity against P. falciparum K-1 (IC₅₀ < 30 µM); showed moderate activity against P. falciparum NF54 A19A (IC₅₀ values of 11.07 µM)	In vitro	(Kanyanga et al., 2019)
	6,7-seco-angustilobine B	exhibited moderate activity against P. falciparum K-1 (IC₅₀ < 30 µM); showed moderate activity against P. falciparum NF54 A19A (IC₅₀ values of 21.26 µM)	In vitro	(Kanyanga et al., 2019)
	β-amyrin	exhibited moderate activity against P. falciparum K-1 (IC₅₀ < 30 µM); showed moderate activity against P. falciparum NF54 A19A (IC₅₀ values of 40.70 µM)	In vitro	(Kanyanga et al., 2019)
	The combination stem barks of K. ivorensis and A. boonei	exhibited antimalarial activity in a mouse model of malaria. In mice treated with the combination therapy at 200 mg/kg/day, parasitemia values were 6.2% ± 1.7 and 6.5% ± 0.8 compared to 10.8% ± 1.3 and 12.0% ± 4.0 in the control group (p < 0.01). Doubling the dose of the extract did not significantly increase the parasitemia inhibition	In vitro	(Tepongning et al., 2011)
	Alstiphyllanine B	displayed intermediate-level antiplasmodial activity against Plasmodium falciparum	In vitro	(Hirasawa et al., 2009)
	Alstiphyllanine C	displayed intermediate-level antiplasmodial activity against Plasmodium falciparum	In vitro	(Hirasawa et al., 2009)
	Alstiphyllanine D	displayed intermediate-level antiplasmodial activity against Plasmodium falciparum	In vitro	(Hirasawa et al., 2009)
	Boonein	boonein exhibited anti-P. falciparum K-1 activity with IC50 >64µM; boonein did not response to P. falciparum NF54 A19A	In vitro	(Kanyanga et al., 2019)
	Akuammicine N-oxide	had antiplasmodial activityagainst Plasmodium falciparum (K1, multidrug-resistance strain) with IC₅₀ = 63.2 µg/mL	In vitro	(Salim et al., 2004)
	N_b-demethylalstogustine	had antiplasmodial activityagainst Plasmodium falciparum (K1, multidrug-resistance strain) with IC₅₀ = 6.75 µg/mL	In vitro	(Salim et al., 2004)

pharmacological activities	Name	Description	In vivo/In vitro	Reference
AChE inhibitory activity	Alstolarine B	displayed moderate AChE inhibitory activity at an IC₅₀ value of 19.3 μM (IC50 for control tacrine = 0.3 μM).	In vitro	(Zhang et al., 2020)
	Naresuanoside	displayed moderate AChE and butyrylcholinesterase (BChE) inhibitory effects	In vitro	(Changwichit et al., 2011)
Anti-inflammatory activity	12-ursene-2,3,18,19-tetrol,28 acetate	triterpenoidesters and glycosides showed anti-inflammatory activity	In vivo	(Sultana et al., 2020)
	Alstoprenyol	triterpenoidesters and glycosides showed anti-inflammatory activity	In vivo	(Sultana et al., 2020)
	3β-hydroxy-28-β-acetoxy-5-olea triterpene	triterpenoidesters and glycosides showed anti-inflammatory activity	In vivo	(Sultana et al., 2020)
	TA	the aggregation and invasion of inflammatory cells in lung tissue were inhibited, and lung tissue damage was alleviated. Oxygen saturation was increased and interleukin-1β, monocyte-chemo attractive peptide 1, interleukin −11, matrixmetalloproteinase-12, transforming growth factor-β and vascular endothelial growth factor were significantly decreased. The levels of elastin were significantly increased and fibronectin was decreased. the expression of Bcl-2 was significantly increased and the levels of nuclear factor-κB and β-catenin were decreased	In vivo	(Zhao et al., 2020a)
	Picrinine
	Scholaricine
	19-epischolaricine
	Vallesamine
	Perakine N₄-oxide Raucaffrinoline N₄-oxide Vinorine N₄-oxide	perakine N₄-oxide, rauffrin N₄-oxide and vinorine N₄-oxided selectively inhibited Cox-2 with 94.07%, 88.09% and 94.05% inhibition rates, respectively	In vitro	(Cao et al., 2012)


	Scholarisin I	exhibited inhibition of Cox-2 selectively (>90%) comparable to the standard drug NS-398	In vitro	(Wang et al., 2013)
	Methanolic extract of dried leaves of AM	the extract at a concentration of 200 mg/kg and 400 mg/kg, p.o. and its fractions at 25 mg/kg and 50 mg/kg, p.o. showed the significant dose depen-dent antiinflammatory activity in carrageenan and dextran-induced rats hind paw edema (acutemodels) as well as in cotton pellet-induced granuloma (chronic model) in rats	In vivo	Arunachalam et al., 2002
	24-ethyl-3-O-β-D- glucopyranoside	triterpenoidesters and glycosides showed anti-inflammatory activity	In vivo	(Sultana et al., 2020)
	Lanosta,5ene,24-ethyl-3-O-β-D-glucopyranosideester	triterpenoidesters and glycosides showed anti-inflammatory activity	In vivo	(Sultana et al., 2020)
	Lupeol acetate	triterpenoidesters and glycosides showed anti-inflammatory activity	In vivo	(Sultana et al., 2020)

pharmacological activities	Name	Description	In vivo/In vitro	Reference
	3β-hydroxy-24-nor-urs-4,12,28-triene triterpene	triterpenoidesters and glycosides showed anti-inflammatory activity	In vivo	(Sultana et al., 2020)
	(±)-scholarisine II	(±)-scholarisine II selectivelyinhibited the inducible COX-2 but not COX-1, also significantly inhibited 5-LOX, comparable to positive controls	In vivo	(Cao et al., 2012)
	The methanol extract of the stem bark of A. boonei	extract showed significant inhibition of carrageenan-induced paw edema and cotton ball granuloma in rats, and exhibited anti-arthritic activity (P < 0.05). Acetic acid-induced peritoneal vascular permeability in mice was also inhibited.	In vivo	(Olajide et al., 2000)
	The ethanolic bark extract of ASE	ASE exerted a powerful anti-inflammatory activity, with ASE-treated cells showing MCP-1 levels 928.8 ± 64.0 pg/mL (at 100 ppm) and 1074.0 ± 82.2 pg/mL (at 500 ppm) lower than control cells	In vitro	(Chandrashekar et al., 2012)
	ScholarisinⅥ	exhibited inhibition of Cox-2 selectively (>90%) comparable to the standard drug NS-398	In vitro	(Wang et al., 2013)
	(E)-16-formyl-5α-methoxystrictamine	exhibited inhibition of Cox-2 selectively (>90%) comparable to the standard drug NS-398	In vitro	(Wang et al., 2013)
α-glucosidase inhibitory activity	Quercetin 3-O-β-D-xylopyranosyl (1″’ → 2″)-β-D-galactopyranoside	showed the high inhibitory activity only against maltase at an IC₅₀ value of 1.96 mM	In vitro	(Nilubon et al., 2007)
	(-)-lyoniresinol 3α-O-β-D-glucopyranoside	exhibited inhibitory activity against not only sucrase but also maltase as well with IC₅₀ values of 1.95 and 1.43 mM, respectively	In vitro	(Nilubon et al., 2007)
	(+)-lyoniresinol 3α-O-β-D-glucopyranoside	showed far lower inhibition against sucrase and maltase	In vitro	(Nilubon et al., 2007)
Anti-melanogenesis activity	Alpneumine E	showed anti-melanogenesis in B16 mousemelanoma cells with IC₅₀ values of 71.4 µM	In vitro	(Koyama et al., 2010a)
	AlpneumineG Vincamine Apovincamine	demonstrated an anti-melanogenic activity in B16 mouse melanoma cells at IC50 values of 58.3, 68.9 and 49.8 µM.	In vitro	(Koyama et al., 2010a)
Antidiabetic and antihyperlipidemic activities	EEAS	streptozotocin-induced diabetic rats were treated orally with EEAS (100, 200 and 400 mg/kg). Moreover, EEAS not only significantly reduced blood glucose levels, glycated hemoglobin and lipid peroxidation (P <0.001)	In vivo	(Arulmozhi et al., 2010)
DRAK2 inhibitory activity	Alstonlarsine A	demonstrated DRAK2 inhibitory activity at an IC₅₀ value of 11.65 ± 0.63 μΜ	In vitro	(Zhu et al., 2019)

pharmacological activities	Name	Description	In vivo/In vitro	Reference
	Alstoscholarisine K	alstoscholarisine K had superior antibacterial activity than berberine (37.50 μg/mL), indicating an MIC value of 18.75 µg/mL againstis Escherichia coli	In vitro	(Yu et al., 2021)
Reversed multidrug resistance	Alstolucine A Alstolucine B	were found to reverse multidrug resistance in vincristine-resistant KB (VJ300) cells	In vitro	(Tan et al., 2010)
	Alstolobine A Alstolucine F	were found to reverse multidrug resistance in vincristine-resistant KB (VJ300) cells	In vitro	(Tan et al., 2010)
	N₄-demethylalstogustine 19-epi-N₄-demethylalstogustine	were found to reverse multidrug resistance in vincristine-resistant KB (VJ300) cells	In vitro	(Tan et al., 2010)
	Scholaricine	were found to reverse multidrug resistance in vincristine-resistant KB (VJ300) cells	In vitro	(Tan et al., 2010)
Analgesic activity	Scholarisine I (±)-scholarisine II	at 10, 20, 40 and 80 mg/kg, scholarisine I and (±)-scholarisine II reduced the writhing reflex in mice by 48.4, 40.1, 36.6 and 49.5%, respectively, comparable to aspirin at 200 mg/kg (57.2%). At doses of 50 and 100mg/kg, scholarisine I and (±)-scholarisine II decreased xylene-induced ear edemain mice by 46.0 and 41.2%, comparable to aspirin at 200 mg/kg (45.7%)	In vitro	(Cao et al., 2012)
	The methanol extract of the Stem bark of A. boonei	the extract of A. boonei produced significant analgesic effect in non-inflammatory pain and inflammatory pain	In vivo	(Olajide et al., 2000)
	methanol extract of A. macrophylla leaves (MEAML)	MEAML also exhibited significant dose-dependent analgesic activity, with a significant increase in response time for all doses tested in both tests	In vitro	(Chattopadhyay et al., 2004)
Antioxidant activity	EEAS	significantly reduced the levels of lipid peroxidation and bone marrow peroxidation in joint tissues and increasing the levels of superoxide dismutase, glutathione peroxidase and antioxidant enzymes glutathione	In vivo	(Arulmozhi et al., 2011)
	AM	AM crude extracts were found to be effective free radical scavengers given that the IC₅₀ value was low at 0.71 mg/mL	In vivo	(Tan et al., 2019)
	The root bark extract of A. boonei	ethyl acetate fraction displayed superior antioxidant activity with an IC₅₀ of 54.25 μg/mL compared to 121.79 and 141.67 μg/mL for acetone and methanol fractions, respectively. The crude precipitate and isolated compound revealed IC₅₀ of 364.39 and 354.94 μg/mL, respectively	In vivo	(Obiagwu et al., 2014)
Antipyretic activity	The methanol extract of the stem bark of A. boonei	the extract also significantly reduced hyperthermia in mice.	In vivo	(Olajide et al., 2000)
Anti-HBV activity	The crude extract of A. venenata bark	shows activity against HBV in HepG2.2.15 cell line	In vitro	(Bagheri et al., 2020)

pharmacological activities	Name	Description	In vivo/In vitro	Reference
CNS activity	MEAML	it was confirmed by spontaneous activity, touch, pain and vocal responses that the methanolic extract of MEAML at doses not<100 mg/kg affects the general behavioral characteristics of the treated animals. The same effect was observed for its fractions, such as fraction B	In vivo	(Chattopadhyay et al., 2004)
Anti-HSV and Anti-HDV activity	17-nor-excelsinidine	strictamine was found to possess better activity against HSV and adenovirus than those of 17-nor-excelsinidine, with EC₅₀ values of 0.36 and 0.28 l g/mL and CC₅₀ values of 5.01 and 3.31 l g/mL, which led to SI values of 13.93 and 11.82, respectively	In vitro	(Zhang et al., 2014)
Anti-HSV and Anti-HDV activity	Strictamine		In vitro	(Zhang et al., 2014)
Antidiarrhoeal activity	ASE	at doses of 100–1000 mg/kg, it exerted 31–84% protection against castor oil-induced diarrhea in mice, similar to that of loperamide	In vivo	(Shah et al., 2010)
Antidiarrhoeal activity		regarding both the 100 and 200 mg/kg bw at all oral doses, significant dose-dependent antidiarrheal activity was shown for all A. congensis samples, with a significant increase in time to onset and varying decreases in all other diarrheal parameters in both models compared to the untreated group	In vitro	(Lumpu et al., 2012)
Radioprotective activity	The hydro-alcoholic extracted material from the bark of ASE	the results showed more favorable postirradiation changes in the number of peripheral blood constituents in animals treated with ASE before irradiation in comparison with irradiated control mice	In vivo	(Gupta et al., 2008)
	The bark of ASE	the extract was found to re store the total leucocytes and differential leucocytes (lymphocytes, monocytes, neutrophils, and non-neutrophilic granulocytes) count in the A. scholaris extract pretreated animals as compared to the irradiated control group. The data clearly indicate that the A. scholaris extract significantly reduced the deleterious bioeffects of radiation on peripheral blood	In vivo	(Gupta et al., 2011)
Anti-pulmonary fibrosis	TA	the administration of TA significantly improved pathological changes in the lungs, reducing levels of Krebs von den Lungen-6, lactate dehydrogenase, transforming growth factor-β, hydroxyproline, type I collagen, and malondialdehyde, and increasing superoxide dismutase activity in serum and lung tissue	In vivo	(Zhao et al., 2020c; Zhao et al., 2020a)

The proportions of the different types with alkaloids in the genus Alstonia.

4.1.1

4.1.1 Corynantheine-strychnine alkaloids (1–157)

Corynantheine-strychnine alkaloids mainly include akuammiline type (1–94), corynantheine type (95–112), strychnine (113–146) and yohimbine types alkaloids (147–157). Corynantheine-strychnine alkaloids are primarily detected in different parts of A. scholaris and A. macrophylla.

Among them, akuammiline type alkaloids are the most abundant. The name akuammiline alkaloids was derived from the local name for the Picralima klaineana tree growing in Ghana (formerly called as the Gold Coast) - Akuamma (Henry et al., 1952). These compounds were characterized by a bridging ring framework having a rigid structure (Duan, 2018). Then, most corynantheine alkaloids possess characteristic 6/5/6/6 ring systems. In addition to A. scholaris and A. macrophylla, corynantheine alkaloids were also available from Alstonia angustifolia A. DC. and A. mairei. The core structure of strychnine alkaloids was extraordinarily compact with its twenty-four skeletal elements (21 radical, 2 nitrogens, 1 oxygen) forming seven fused and/or bridged rings (1 2 7) (Zlotos et al., 2022), in addition to contain 6 chiral centers. Yohimbine alkaloids have a less complex structure, possessing characteristic 6/5/6/6/6 ring systems (147–157) containing 5 chiral centers; the C-3 and C-16 sites are mostly cis-type structures in the genus Alstonia (147–149 and 156). In Table 2, the structure of corynantheine-strychnine alkaloids. are listed.

4.1.2

4.1.2 Sarpagine, macroline, and ajmaline alkaloids (158–240)

Sarpagine (158–174), ajmaline (175–201) and macroline alkaloids (202–240) are three structurally related indole alkaloids. Sarpagine alkaloids were mostly produced in the stem bark and leaves of Alstonia penangiana Sidiy. (Yeap et al., 2020). Most of the ajmaline alkaloids were in the leaves of A. macrophylla and the whole plant of Alstonia yunnanensis Diels (Arai et al., 2010; Cao et al., 2012). The macroline alkaloids were also detected in A. yunnanensis, A. macrophylla, A. penangiana and A. angustifolia (Kam and Choo, 2004a; Yeap et al., 2018; Kam et al., 2004; Kam and Choo, 2004a ). Most of them had four stereocenters, which are C-3, C-5, C-15, and C-16 (158–166 and 203–240) (Lewis, 2006). In Table 3, the relevant structures of the compounds in the sarpagine macroline, and ajmaline alkaloids are shown.

4.1.3

4.1.3 Eburnamine and kopsifoline alkaloids (241–261)

These alkaloids include primarily eburnamine and kopsifoline types, possessing characteristic 6/5/6/5/6 ring systems in the genus Alstonia. Eburnamine alkaloids were mainly obtained from the trunk of Alstonia rostrata C.E.C. Fisch. and the leaves of Alstonia pneumatophora Backer ex Den Berger (241–244) (Koyama et al., 2010a, 2010b; Zhong et al., 2017 ). Kopsifoline type alkaloids (245–261) were mainly present in different parts of A. angustifolia, A. mairei and A. yunnanensis (Goh et al., 1989; Cao et al., 2012; Li et al., 2022a, 2022b; Tan et al., 2010 ). A summary of the structures relevant to the compounds in the eburnamine and kopsifoline types alkaloids is given in Table 2.

4.1.4

4.1.4 Bisindole alkaloids (262–287)

Bisindole alkaloids are polymerized from the same or different two monoterpene indole alkaloids, which are complicated in structure. The main bisindole alkaloids contained in the genus Alstonia were the macroline‐ajmaline type (262–264), macroline‐pleiocarpamine type (265) (Lim et al., 2013), macroline‐macroline type (266–277) (Lim, et al., 2012), macroline‐akuammiline type (278–281) (Yeap et al., 2018), macroline‐corynantheine type (282–284) and akuammiline-ajmaline type (2 8 1), etc. A recently conducted study (Wang et al., 2021) showed that rupestrisines A and B (285–287) were an unprecedented yohimbine-kopsinine type dimeric indole alkaloid. In Table 3, the structures of relevant compounds in bisindole alkaloids are shown.

4.1.5

4.1.5 Other structural alkaloids (288–319)

In addition, there are several other types of indole alkaloids (288–304). For example, alstrostines A and B derived from the leaves of A. rostrata with a 6/5/5/6 tetracyclic system (288–289) (Cai et al., 2011). Recently two vobasinyl-type alkaloids, alstolarine A (2 9 2), alstolarine B (2 9 3), were yielded from the A. scholaris leaves (Zhang et al., 2020).

In addition to indole alkaloids, there are some non-indole alkaloids (305–325). For example, Yeap et al. discovered the first quinolone alkaloids isolated from Alstonia (316–317) (Yeap et al., 2020). The relevant structures of the compounds in other types of alkaloids are shown in Table 4.

4.2

4.2 Terpenoids (320–366)

Terpenoids refer to different saturated derivatives that satisfy the (C₅H₈) _n-pass formula and its oxygen content. It can be considered as a class of natural compounds consisting of isoprene or isopentane linked in different ways. The skeletons of the terpenoids in the genus Alstonia are predominantly iridoids (320–330) and triterpenes (331–362). Iridoids are mainly distributed in the stem bark of A. macrophylla and A. scholaris. Iridoids usually form iridoid glycosides with sugars (320–321 and 330), most of which are glucose, with a variety of physiological activities, such as stimulating gallbladder, strengthening abdomen, and anti-inflammatory. Apart from that, some triterpenoids were isolated in the genus Alstonia. These compounds may exist in nature with free form or with glycosides or esters. C-3 position combined with glucose to form triterpene saponins or glucopyranoside esters (Sultana et al., 2020). Such as, lanosta 5ene, 24-ethyl-3-O-D-glucopyranoside (3 5 8) was triterpene saponin; lanosta 5ene 24-ethyl-3-O-β-D-glucopyranosideester (3 5 9) was glucopyranoside ester. Triterpenoidesters and glycosides had anti-inflammatory activities (Sultana et al., 2020).

4.3

4.3 Flavonoids (363–379)

Flavonoids are widely distributed in nature with common C6-C3-C6 parent nucleus. The C-2, C-3 or C-4′ of flavonoids could be combined with sugars to form flavonoid glycosides (363–366 and 368–369) (Parveen et al., 2010; Nilubon et al., 2007; El-Askary et al., 2013 ). At present, 16 flavonoids have been collected from the genus Alstonia.

4.4

4.4 Other compounds (380–392)

In addition to the aforementioned compounds, the genus has also obtained fatty acids (3 8 0), phenolic acids (381–389), lignans (390–391), and esters (3 9 2). The C-3 position of lignan was linked to glucose to form a glycoside with strong α-glucosidase inhibitory activity (Nilubon et al., 2007).

5 Pharmacological activities

Through extensive modern pharmacological experimental researchs indicated that Alstonia played an essential part in the cytotoxicity, anticancer, vasodilatory, β₂-adrenergic receptor (β₂AR) activity, antiplasmodial, anti-inflammatory, antibacterial, antifungal, antioxidant, analgesic and radioprotective activities, etc. The pharmacological activities of genus Alstonia can be found in Table 5. Fig. 2 shows the different pharmacological activities of Alstonia plants.

The different pharmacological activities of Alstonia plants.

5.1

5.1 Cytotoxicity and anticancer activities

In 2017, cancer was the second most common cause of mortality worldwide and a major load on wellness systems. Several researches reported that in laboratory animal models, compounds possessing antioxidant or anti-inflammatory properties, sunch as certain phytochemicals, had been found to inhibit tumorigenesis, promotion and development (Chesson and Collins, 1997; Hocman, 1989). According to the statistics of literature, the crude extracts and compounds of Alstonia plants had anti-cancer effects in numerous in vivo and in vitro experiments. ASERS (the alkaloid fraction of A. scholaris) was considered the most efficientt doses of 210 mg/kg (Jagetia and Baliga, 2006). This opens the way for the genus Alstonia to be an anti-tumor, attracting the attention of many scholars. Moreover, Baliga reported that echitamine (35) had cytotoxic effects on HeLa, HepG2, HL60 and other models (Baliga, 2010). Moreover, one recent study (Spiegler et al., 2021) further demonstrated that A. boonei extracts were effective for common pediatric tumor types (leukemias and Ewing sarcoma). 15-hydroxyglutathione A (78) was identified as the effective ingredient of A. boonei extract using bioassay-guided approach. The IC₅₀ value for MCF-7 cells was 26 μM. This is the first time that compounds of A. boonei are mentioned. Preliminary mechanistic studies demonstrated that in G2/M phase, apoptosis increased and cell cycle arrested.

5.2

5.2 Vasodilatory activity

Vasodilators help treat cerebral vasospasm and hypertension as well as improve peripheral circulation. More and more species of genus Alstonia are being identified to have vasorelaxant activities. Arai et al. found that vincamedine (1 8 5) showed potent vasodilatory activity. The mechanism of vincamedine (1 8 5) might be the inhibition of Ca²⁺ influx through volte-dependent Ca²⁺ channels (VDCs) and/or receptor-operated Ca²⁺ channels (ROCs) (Arai et al., 2012). In addition to the above, they observed the presence of two substituents at the N-1 and C-17 positions, which may be critical in showing vasodilatory activity (Arai et al., 2012)(). Obviously, the activity of compounds varies with their structure.

5.3

5.3 Antibacterial and antifungal activities

Multidrug resistance is a leading challenge in both developed and developing countries. There is an urgent need to tackle multi-drug resistance. Through many experiments, some scholars found that Alstonia species had antibacterial and antifungal activity. Khan et al. found that there was excellent antimicrobial activity and broad antimicrobial spectrum in crude methanolic extracts made from leaves, stems and root barks of A. scholaris, in particular the butanol part of A. scholaris. However, all fractions were inactive against the tested moulds (Khan et al., 2003). Singh et al. demonstrated that Δ³-alstovenine (1 5 5) was a quaternary alkaloid. At concentrations of 250–1000 mg/L, spore germination of the tested fungi was mostly inhibited (Singh et al., 1999). In addition to alkaloids with antifungal activity, flavonoid glycosides had the same activity. For example, a compound with antibacterial activity named tricin-4′-O-β-L-arabinoside (3 6 3) was obtained from the leaves of A. macrophylla (Parveen et al., 2010).

5.4

5.4 β₂AR and spasmolytic activities

β₂AR agonist is one of the most commonly used drugs for asthma and chronic obstructive pulmonary disease. Hou et al. used a liquid chromatography with ion trap time-of-flight mass spectrometry (LCMS-IT-TOF) system to isolate alkaloids with β₂AR agonists activity from A. scholaris. In addition, the alkaloids were identified to have a synergistic effect in an isolated guinea pig model (Hou et al., 2012a). In vitro experiments proved that akuammidine (1 6 1) and Z-alstoscholarine (2 9 9) were new indole alkaloid-type β₂AR agonists. Shah et al. showed that the A. scholaris extract (ASE) possessed spasmolytic effect. This mechanism might be mediated by calcium channel block (CCB) (Shah et al., 2010).

5.5

5.5 Anti-inflammatory activity

Alkaloids are potent anti-inflammatory compounds found in the genus Alstonia. Cao et al. obtained eight compounds from A. yunnanensis, including raucaffrinoline N₄-oxide (1 8 1), vinorine N₁, N₄-dioxide (1 8 2), and vinorine N₄-oxide (1 8 3) exhibited selective inhibition of Cox-2 with 94.77%, 88.09% and 94.05% inhibition, respectively (Cao et al., 2012). Wang et al. obtained three monoterpene indole alkaloids from 70% ethanol extract of Alstonia rupestris Kerr leaves. Scholarisin I (1), scholarisinVI (26) and E-16-formyl-5α-methoxystrictamine (39) had elective inhibition of Cox-2 with inhibition rates of 96.4%, 95.5%, and 92.0% (Wang et al., 2013). A recent study (Zhao et al., 2020a, 2020c) suggested that TA obtained from A. scholaris leaves had the potential to be an effective new drug to treat emphysema. TA not only inhibited airway wall inflammation and airflow resistance, as well as improved pulmonary elasticity and protease/antiprotease balance.

5.6

5.6 Antioxidant and analgesic activities

Oxidative damage can lead to various diseases. Therefore, the study of antioxidant drugs has attracted the attention of medical workers. Studies demonstrated (Arulmozhi et al., 2011) that the ethanol extract of A. scholaris leaves (EEAS) significantly decreased lipid peroxidation and myeloperoxidase levels in the joint tissue. The bark of the Philippine A. macrophylla (AM) and the root bark extract of A. boonei demonstrated antioxidant activity against DPPH radical (Tan et al., 2019; Obiagwu et al., 2014). Similarly, the analgesic activity of Alstonia plants has also been identified through a large number of experiments. Compared to aspirin, alkaloids from A. scholaris leaves, especially scholarisine I (1) and (±)-scholarisine II (2), had the same analgesic efficacy at 200 mg/kg (Cai et al., 2010). Acetic acid-induced writhing and early and late paw licking in mice were observed to be reduced, indicating that the methanolic extract of A. boonei stem bark produced significant analgesic activity (Olajide et al., 2000).

5.7

5.7 Antiplasmodial activity

Malaria remains a stubborn disease, ravishing communities in about 100 countries. The cause of this disease‐Plasmodium parasites transmitted by Anopheles mosquitoes‐had been widely understood since the late 19th century (Cox, 2010). Consequently, it is exceptionally critical to recognize a new drug against the malaria parasite. In many African countries, Alstonia congensis Engl. is a medicinal plant. Crude extracts and single compounds obtained from the root bark of A. congensis displayed antimalarial activity when tested in vitro and in vivo (Kanyanga et al., 2019). In addition, the combination of the genus Alstonia with other traditional Chinese medicines were identified to exhibit antiplasmodial activity. Tepongning et al. reported that the stem bark combination of the K. ivorensis and A. boonei showed antiplasmodial activity with large dose intervals between therapeutic and toxic doses in the murine malaria model, which was used as an antimalarial prophylactic (Tepongning et al., 2011).

5.8

5.8 Other pharmacological activities

Other than those listed above, Alstonia had been proved to possess a variety of other pharmacological activities. Alstiphyllanines E (20) and F (12) showed moderate Na⁺-glucose cotransporter (SGLT) inhibitory activity. 10-methoxy-N₁-methylburnamine-17-O-veratrate (15) exhibited potent inhibitory activity (Arai et al., 2010). Compound alstonlarsine A (1 2 8) was isolated from A. scholaris and had death associated protein related apoptotic kinase (DPAK2) inhibitory activity (Zhu et al., 2019). A. scholaris bark aqueous extracts in the 50 and 100 mg/kg body weight were able to stimulate non-specific immune response inhibitory activity (Iwo et al., 2000). Weiming et al. found that the crude alkaloidal extracts from A. yunnanensis root exhibited marginal activity against experimental tumour U₁₄ in mice (Weiming et al., 1983). Hirasawa et al. found that isolated constituents of A. pneumatophora showed antimelanogenesis in B16 mouse melanoma cells, specifically alpneumine E (1 2 5), alpneumine G (2 4 2), vincamine (2 4 3) and apovincamine (2 4 4) (Hirasawa et al., 2009).

In addition, extracts with α-glucosidase inhibitory activity were acquired by drying the methanolic water of A. scholaris (Nilubon et al., 2007). Antidiabetic and antihyperlipidemic activities of A. scholaris leaves were also reported (Arulmozhi et al., 2010). Chattopadhyay et al. revealed CNS activity of A. macrophylla leaf extracts (Chattopadhyay et al., 2004). Alstolarine B (2 9 2) showed moderate acetylcholinesterase (AChE) inhibitory activity (Zhang et al., 2020). 17-nor-excelsinidine (1 0 9) and strictamine (43) were isolated from A. scholaris and showed significant inhibitory activity against herpes simplex virus (HSV) and adenovirus (ADV) (Zhang et al., 2014). A recent research (Bagheri et al., 2020) demonstrated that Alstonia venenata R. Br. bark was effective against hepatitis B virus (HBV) in benzene, isopropanol and methanol fractions. ASE also showed significant radioprotective activity. Compared with irradiated animals, ASE pretreatment significantly increased glutathione levels in the serum and liver (Gupta et al., 2008).

6 Toxicity

In recent years, some diseases, such as cancer, bacterial infections, etc., have developed multi-drug resistance to the drugs used, which makes it more difficult to treat these diseases. The excellent pharmacological activity of genus Alstonia, particularly A. scholaris, can be used as a natural drug treasure trove for clinical use. However, there is limited knowledge of its potential toxicity and therefore toxicity studies are essential.

Baliga et al. administered different doses of hydroalcoholic extracts of A. scholaris to rats and observed the acute and subacute toxic effects of the extracts on rats. They found that oral administration of the hydroalcoholic extracts of A. scholaris were not toxic to mice at a dose of 2000 mg/kg body weight. However, the highest number of animals died after intraperitoneal injection at a dose of 1100 mg/kg body weight. Interestingly, they also observed that the acute toxicity of the mice depended on the season in which the plants were collected. The acute toxicity was highest for plants collected in summer, followed by those collected in winter (Baliga et al., 2004). Baliga and Shrinath further studied A. scholaris. It was demonstrated that extracts of A. scholaris stem bark and leaves did not cause death or adverse effects at a dose of 2000 mg/kg body weight. However, when injected intraperitoneally at high concentrations, mice demonstrated systemic and developmental toxicity (Baliga and Shrinath, 2012). The alkaloids isolated from the leaves of A. scholaris were also proved to be non-toxic (Zhao et al., 2020b, 2020d). While the safety of A. scholaris stem bark has been evaluated, the lack of rigorous toxicological studies and the diversity of experimental animals are necessary to further demonstrate the pharmacology and safety of high concentrations of A. scholaris stem bark extracts prior to clinical use. Zhao et al. conducted a comprehensive preclinical program including acute and subchronic studies with beagle dogs as a model. Research revealed that indole alkaloids at 20, 60 and 120 mg/kg body weight showed no signs of toxicity except for vomiting and drooling in most dogs. Alkaloid extracts of A. scholaris leaves did not cause adverse effects or death in beagle dogs (Zhao et al., 2020e). In addition, indole alkaloids are not genotoxic in the Ames test, mammalian chromosome aberration test, as well as in the micronucleus test (Zhao et al., 2020d).

Therefore, the current study indicates that the stem and leaves extract of A. scholaris are safe and provides toxicological data for conducting clinical trials.

7 Clinical research

On the basis of these findings, together with a series of preclinical studies and safety assessments, the genus Alstonia, with special reference to A. scholaris, has been developed as a new botanical drug and further approved by the Chinese Food and Drug Administration for Phase I/II clinical trials (Shang et al., 2010a, 2010b).

Li et al. evaluated the safety of A. scholaris leaves alkaloids capsule (CALAS) (No. 2011L01436), when administered orally at different doses. The clinical study was conducted in 40 healthy volunteers who were divided into four groups (n = 10 per group) and received different doses of CALAS ranging from 20 mg, 40 mg, 80 mg to 120 mg. On August 26, 2015, the trial was registered (https://www.chictr.org.cn/showproj.aspx?proj=11736) with the number ChiCTR-IPR-15006976 (Li et al., 2019). During the trial, two minor adverse events were observed, although both were related to individual physiological variability and were safe for volunteers at the current dosing regimen (Li et al., 2019). Gou et al. further assessed the clinical safety and tolerability of CALAS. In distinction to Li et al., subjects were randomized to receive either CALAS or then placebo in one of single ascending dose of 8, 40, 120, 240, 360, 480, or in one of multiple ascending dose of 40 or 120 mg, three times daily for 7 days. The results showed that in healthy Chinese volunteers, CALAS from the Alstonia scholaris leaves proved to be safe and tolerated with no unexpected or clinically relevant safety concerns at a single dose of 360 mg and up to 120 mg three times daily (Gou et al., 2021). In addition, clinical population pharmacokinetic, metabolomic and therapeutic data are also crucial to provide guidance on patient dosing. Li et al. performed a metabolomic analysis to determine biomarkers associated with treatment efficacy in CALAS from the Alstonia scholaris leaves and to assess efficacy and safety depending on symptoms and adverse events in the clinic (Li et al., 2022a, 2022b). This study identified changes in lysophosphatidylcholine, lysophosphatidylethanolamine, and amino acids as possible indirect markers in the treatment of acute bronchitis, and there were no serious adverse effects in clinical trials (Li et al., 2022a, 2022b). Pharmacokinetic, metabolomic, and therapeutic data as well as clinical safety and tolerability evaluations of CALAS from the Alstonia scholaris leaves in clinical populations have demonstrated a reliable safety profile, only showing minor, transient adverse reactions.

In conclusion, the excellent pharmacological activity and clinical Phase I data of A. scholaris further support the Phase II clinical trial. A. scholaris can be further developed into products used to treat patients who have respiratory diseases.

8 Conclusion and future perspectives

Alstonia genus is traditionally used to heal human diseases. Because of its remarkable pharmacological activity, it has attracted the attention of many scholars. In the current work, we comprehensively review the composition and pharmacological activities of genus Alstonia and discussed its toxicity for further study and clinical application. So far, over 400 chemical compounds have been obtained from genus Alstonia, such as alkaloids, triterpenes, flavonoids, fatty acids, phenolic acids, lignans, and volatile oils. Alkaloids are considered to be the main effective components, with the most widespread being MIAs among Alstonia plants. Nonetheless, compared with alkaloids, non-alkaloid components such as flavonoids and triterpenes have not been studied in depth. And some species have been less studied, such as A. pneumatophora and Alstonia balansae Guillaumin, etc. It is promising to deploy a bioactivity-oriented isolation strategy to locate additional bioactive components. Because the diversity of chemical structures determines the difference in biological activity and determines the clinical application, phytochemical research focuses on chemical components with fewer studies or better efficacy.

The exploration of bioactive molecules and multi-component interactions is important for the clinical application in Alstonia plants. For example, 15-hydroxyangustilobine A (78) is identified in A. boonei leaves as an effective constituent for the treatment of tumors. Alstonia plants have a variety of bioactivities, but their mechanism research is not in-depth, and the structure–activity relationship is not clear. In order to further make drugs from the compounds contained in Alstonia plants into drugs, the mechanisms involved in the biological activity and structure–activity relationships of chemical composition must be studied in depth.

In summary, the aim of this review is not only to contribute to a basis for analyzing the bioactive mechanisms of important natural products, but also to provide potential development value for studying new drugs. Further research on the molecular and cellular mechanisms as well as clinical applications is needed for the exploitation of Alstonia plants. Only by bridging the gap between bioactivity-related mechanisms and structure–activity relationships of chemical components can the development of Alstonia plants be further promoted.

Author contributions

Mi-xue Zhao collected the information and drafted the manuscript; Jing Cai and Ying Yang helped to modify the format of the manuscript; Wen-yuan Liu and Jian Xu were involved in the preparation of tables; Wei Li and Toshihiro Akihisa edited the pictures; Jie Zhang analyzed the manuscript. All authors approved the final submitted version of the manuscript.

Declaration of Competing Interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

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Appendix A

Supplementary material

Supplementary data to this article can be found online at https://doi.org/10.1016/j.arabjc.2023.104857.

Appendix A

Supplementary material

The following are the Supplementary data to this article:


No.	compound	R₁	R₂
255	Echitoveniline	H	OH
256	Tabersonine	H	H
257	16-methoxytabersonine	OCH₃	H
258	19-hydroxytabersonine	H	OH
259	Vandrikidine	OCH₃	OH
260	19-acetoxy‐11-methoxytabersonine	OCH₃	CH₃COO
261	Vincadifformine	H

macroline‐ajmaline and macroline‐pleiocarpamine type

No.	compound	R₁	R₂	R₃	R₄
273	Macralstonine	H	β-H	α-OH	β-CH₃
274	O-methylmacralstonine	H	α-H	OCH	CH₃
275	Lumusidine B	α-CH₃	β-H	β-OH	H
276	Lumusidine C	H	α-H	β-CH₂CH₃	CH₃
277	O-acetylmacralstonine	H	α-H	OCOCH₃	CH₃
macroline‐akuammiline type

macroline‐corynantheine type


No.	compound	R₁	R₂	R₃
310	Angustimaline	H	COCH₃	α-OH
311	Angustimaline A	CH₃	CHO	α-OH
312	Angustimaline B	CH₃	CHO	β-OH
313	Angustimaline C	H	COCH₃	β-OH

Traditional uses, chemical composition and pharmacological activities of Alstonia R. Br. (Apocynaceae): A review

Abstract

Abstract

Keywords

Alstonia R. Br. (Apocynaceae)

Chemical components

Biological activities

Traditional uses

1 Introduction

2 Distribution and botanical studies

3 Traditional uses

4 Chemical components

4.1 Alkaloids (1–319)

4.1.1 Corynantheine-strychnine alkaloids (1–157)

4.1.2 Sarpagine, macroline, and ajmaline alkaloids (158–240)

4.1.3 Eburnamine and kopsifoline alkaloids (241–261)

4.1.4 Bisindole alkaloids (262–287)

4.1.5 Other structural alkaloids (288–319)

4.2 Terpenoids (320–366)

4.3 Flavonoids (363–379)

4.4 Other compounds (380–392)

5 Pharmacological activities

5.1 Cytotoxicity and anticancer activities

5.2 Vasodilatory activity

5.3 Antibacterial and antifungal activities

5.4 β2AR and spasmolytic activities

5.5 Anti-inflammatory activity

5.6 Antioxidant and analgesic activities

5.7 Antiplasmodial activity

5.8 Other pharmacological activities

6 Toxicity

7 Clinical research

8 Conclusion and future perspectives

Author contributions

Declaration of Competing Interest

References

Appendix A

Supplementary material

Appendix A

Supplementary material

Supplementary data 1

Supplementary data 2

Supplementary data 3

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5.4 β₂AR and spasmolytic activities