Next Article in Journal
Dynamics of Zooplankton along the Romanian Black Sea Coastline: Temporal Variation, Community Structure, and Environmental Drivers
Next Article in Special Issue
Naturally Occurring Simple Oxygenated Benzophenones: Structural Diversity, Distribution, and Biological Properties
Previous Article in Journal
Active Coral Restoration to Preserve the Biodiversity of a Highly Impacted Reef in the Maldives
Previous Article in Special Issue
Essential Oil Composition of Ten Species from Sect. Serpyllum of Genus Thymus Growing in Bulgaria
 
 
Search for Articles:
Title / Keyword
Author / Affiliation / Email
Journal
Article Type
 
 
Advanced Search
 
Section
Special Issue
Volume
Issue
Number
Page
 
Journals
Diversity
Volume 15
Issue 9
10.3390/d15091023
diversity-logo
Submit to this Journal Review for this Journal Propose a Special Issue
► Article Menu

Article Menu

share Share announcement Help format_quote Cite question_answer Discuss in SciProfiles thumb_up
...
Endorse textsms
...
Comment
first_page
settings
Order Article Reprints
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:
Background:
Review

Hypecoum spp.—Chemistry and Biological Activity of Alkaloids

by
Nadezhda Kostova
and
Tsvetelina Doncheva
*
Institute of Organic Chemistry with Centre of Phytochemistry, Bulgarian Academy of Sciences, 9 Acad. G. Bonchev Str., 1113 Sofia, Bulgaria
*
Author to whom correspondence should be addressed.
Diversity 2023, 15(9), 1023; https://doi.org/10.3390/d15091023
Submission received: 18 July 2023 / Revised: 1 September 2023 / Accepted: 17 September 2023 / Published: 19 September 2023
(This article belongs to the Special Issue Chemistry and Biology of Medicinal and Aromatic Plants)
Browse Figure
Review Reports Versions Notes

Abstract

:
Genus Hypecoum Tourn. ex L. belongs to the poppy family Papaveraceae and comprises about 19 species occurring in Europe, Northern Africa and Asia. Hypecoum species have been widely used in traditional medicine as antipyretic, analgesic and anti-inflammatory remedies. Their effects are associated with the biologically and pharmacologically active isoquinoline alkaloids in them, such as protopines, protoberberines, benzophenanthridines, aporphines, simple isoquinolines, secoberbines, spirobenzylisoquinolines and others. In this study, we aimed to review and organize information on ethnomedicinal, phytochemical, chemotaxonomical and pharmacological studies of alkaloids and extracts obtained from Hypecoum plants, and to suggest opportunities for further research.

1. Introduction

The flowering plants of the genus Hypecoum, belonging to the family Papaveraceae, subfamily Fumarioideae, are widely distributed in temperate areas from Europe to Africa to Southwestern Asia. It is represented by 19 species (23 synonyms), with 2 accepted subspecies and 1 ambiguous name [1]. These plants have recognized medicinal value and are used in different forms of traditional medicine in the treatment and prevention of many diseases—colds, pneumonia, pharyngitis, inflamed red eyes, hepatitis, cholecystitis and other [2,3,4,5,6]. Scientific investigations of the Hypecoum species show that many of the therapeutic effects of the plants are primarily related to the bioactive isoquinoline alkaloids found in them. The known alkaloids in the genus belong to the various classes of isoquinolines—protopines, protoberberines, benzophenanthridines, aporphines, simple isoquinolines, secoberbines, spirobenzylisoquinolines and others. Protopine is a predominant alkaloid isolated from all investigated plants of the genus [2,7,8,9,10,11,12,13,14,15,16,17,18,19,20,21,22,23,24]. Besides being biologically active compounds, isoquinoline alkaloids are characteristic secondary metabolites in the family Papaveraceae and can be used for chemotaxonomic purposes [25].
In recent years, more than 40 alkaloids have been identified in Hypecoum species, and new alkaloid structures, along with their pharmacological activities, are reported every year, enriching the diversity of natural compounds. Some of them have promising properties for the treatment of important diseases such as inflammation, cancer and microbial infections [18,19,22,23,26,27,28,29].
In this review, the chemical structures and biological activities of the isoquinoline alkaloids that have been reported for the genus Hypecoum over the past fifty years are systematically summarized. For this purpose, the relevant data were collected through the scientific databases “SCOPUS”, “Google Scholar”, “ISI Web of Knowledge”, “ScienceDirect”, “PubMed”, “SciFinder Scholar” and “Wiley Online Library”.

2. Botany

The plant family Papaveraceae includes two subfamilies—Fumarioideae and Papaveroidae [1]. The genus Hypecoum Tourn. ex L. belongs to the subfamily Fumarioideae and consists of 19 accepted species, 2 accepted subspecies and 1 ambiguous name of flowering plants found in warm temperate areas of the Mediterranean, Europe and Southwest and Central Asia. In these geographic regions, 21 other Hypecoum species and 2 varieties of the genus have been reported from morphological data. According to World Flora Online, these 23 plant names have taxonomic status—synonyms of the respective species (Table 1) [1].

3. Ethnopharmacological Relevance

The plants of the genus Hypecoum are used extensively in various ethnic communities in China, Mongolia and India as antipyretic, analgesic and anti-inflammatory remedies [2,30,31]. A literature survey of ethnobotanical data shows that the most commonly reported species used in traditional medicine are H. leptocarpum and H. erectum.
H. leptocarpum, namely “Ba Er Wa Da”, “Ba Er Ba Da”, etc., is a traditional Tibetan herb with a specific use in the treatment of colds, pneumonia, hepatitis, cholecystitis and other diseases [2,3,30]. Extracts from this plant have been reported to have antipyretic and detoxifying effects, as well as antioxidant, antiviral, antibacterial, anticancer and other activities [22,32,33]. Chinese scientists have registered patents for obtaining antiviral and antibacterial preparations based on thinfruit Hypecoum herb extract [34,35].
H. erectum is mainly used in China and Mongolia for traditional treatments for inflammation, fever and pain relief [2,4,5,36,37]. The whole plant and its root are used for acute pharyngitis, relief from cough and inflamed red eyes [6]. In Mongolian medicine, H. erectum is included in various herbal formulations such as Deva-5, which is used to treat acute infectious diseases [36]. The plant H. erectum, along with 20 other herbs, is used as a Tibetan medicine—Liu Gan Pills (LGP)—to treat flu, headache, cough, body aches and fever [38]. In the past few years, LGP has been widely used in the prevention and treatment of COVID-19 in the Tibetan areas of China [39,40].

4. Chemistry of Hypecoum Alkaloids

Alkaloids are a large group of N-containing natural compounds with diverse structures and a wide spectrum of pharmacological effects on human health. The Hypecoum species are recognized as important medicinal plants, biosynthesizing isoquinoline alkaloids as major active ingredients.
This section summarizes the alkaloid compounds that have been identified in the Hypecoum spp. since 1972 (Table 2) [2,7,8,9,10,11,12,13,14,15,16,17,18,19,20,21,22,23,24,27,40,41,42,43,44,45,46,47,48,49,50]. So far, a total of 86 naturally occurring alkaloids have been reported for ten plant species—H. procumbens, H. procumbens var. glaucescens, H. imberbe, H. lactiflorum, H. pendulum, H. trilobum, H. leptocarpum, H. erectum, H. ponticum and H. parviflorum. Based on their structures, the Hypecoum alkaloids can be divided into eight major groups: protopines (1–11), protoberberines (12–17), benzophenantridines (18–28), aporphines (29–33), simple isoquinolines (34–38), secoberbines (39–66), spirobenzilisoquinolines (67–73) and others (74–86). Two chemical structures have been detected in the literature with the name leptocarpine—protopine alkaloid 8 and alkaloid 82. Both compounds have been identified in H. leptocarpum [10,22,42]. On the other hand, the structure of alkaloid 41 has been published in the literature under two different names, dihydroleptopine and coryximine, isolated from H. leptocarpum [22,23,43]. Similarly, the newly found in H. erectum 2-(1,3-dioxolo [4,5-h]isoquinolin-7-yl)-4,5-dimethoxy-N-methyl-benzenethanamine has the same structure as the alkaloid leptocarmine (62), isolated from H. leptocarpum [19,23,24].

4.1. Protopine Alkaloids

The protopine alkaloids (1–11) represent the major class of alkaloids in the Hypecoum species (Table 2). Their structure includes a tricyclic frame with a carbonyl group at C-14 and methoxy- or methylendioxy- groups at C-2, C-3, C-9 and C-10. Alkaloids 3, 6 and 7 are further oxygenated at C-13. Although only eleven protopines have been identified in the genus, protopine (1) has been found in all studied Hypecoum species [2,7,8,9,10,11,12,13,14,15,16,17,18,19,20,21,22,23,24]. Alkaloid 1 together with cryptopine (4) and allocryptopine (5) are the most pharmacologically studied and biologically active protopines in the genus. It has been established that these alkaloids possess potent anti-inflammatory, analgesic and antibacterial effect [13,19].

4.2. Protoberberine Alkaloids

The protoberberine alkaloids (12–17) are a small group of Hypecoum isoquinolines containing only six representatives (Table 2). Most of them are of the tetrahydroprotoberberine type (12, 13, 15–17), and only coptisine (14) is a typical protoberberine with a three aromatic ring system. Alkaloid 14 has shown significant cytotoxic activity against different cancer cell lines, which is probably related to the positive N-ion in its molecule [23].

4.3. Benzophenantridine Alkaloids

Eleven benzophenantridine alkaloids (18–28) have been identified in six Hypecoum species—H. procumbens, H. leptocarpum, H. trilobum, H. ponticum, H. imberbe and H. erectum (Table 2). Their structure includes a tetracyclic skeleton with an aromatic (18, 19, 21 and 28) or nonaromatic (20, 22–27) ring B. The alkaloids with three aromatic ring systems are usually in the form of quaternary ammonium salts (18, 19, 21), and those with non-aromatic ring B are usually C-8-substituted (23–27). Benzophenanthridine alkaloids are known to have diverse and significant biological properties, but so far, only 8-hydroxymethyldihydrosanguinarine (24), isolated from H. erectum, has been found to possess in vitro anti-inflammatory activity [19,51].

4.4. Aporphine Alkaloids

The alkaloids in this group (29–33) contain an aporphine skeleton with two aromatic rings and N-methyl function. Five aporphines have been isolated from four plant species—H. procumbens, H. procumbens var. glaucescens, H. leptocarpum and H. imberbe (Table 2). Alkaloids 29–32 are tertiary and only one—magnoflorine—(33) is a quaternary ammonium salt. Although alkaloids of this type are of great research interest due to their important biological properties such as cytotoxicity, antioxidation, immunoregulation, etc., the isolated Hypecoum aporphines have not been studied pharmacologically [52].

4.5. Simple Isoquinoline Alkaloids

The simple isoquinoline group includes five alkaloids (34–38) present in three Hypecoum species—H. imberbe, H. leptocarpum and H. erectum (Table 2). These alkaloids have the simplest structure, involving an isoquinoline nucleus which is C-6- and/or C-7-substituted. Compound 38 is, unusually, 1,3,6,6-tetramethylated and oxygenated at C-8. Several biological activities have been established for alkaloids 34, 36 and 38, including anti-inflammatory, antibacterial, anticancer and analgesic effects [13,19,27].

4.6. Secoberbine Alkaloids

The secoberbine alkaloids (39–66) are the largest group of isoquinoline alkaloids, consisting of 28 members, which have been identified in seven Hypecoum species—H. procumbens, H. procumbens var. glaucescens, H. leptocarpum, H. erectum, H. lactiflorum, H. erectum, H. ponticum and H. parviflorum (Table 2).
According to the chemical structure, the alkaloids are divided into three subgroups: 7,8-secoberbines—tricyclic (39–49) and tetracyclic (50–58); 7,8-14,7-bissecoberbine—peshawarine (59) and 6,7-secoberbines (60–66) [53]. All tricyclic 7,8-secoberbines in the Hypecoum species have substitutions at C-8 with -CH2OH or -COOH groups. Structure–activity relationship studies on these compounds have shown that the presence of the carboxyl group in coryximine (41), leptopidine (46) and hendersine B (49) is the probable reason for the low cytotoxicity against different tumor cell lines [23,27]. Furthermore, the quaternary alkaloid hypepontine 47,and -CH2OH substituted at C-8, has demonstrated good in vitro antibacterial and antifungal activity [18]. Among the tetracyclic 7,8-secoberbines, hypecorinine (55) and 2,3-dimethoxyhypecorinine (58) have been found to possess good antimicrobial and anti-inflammatory properties, respectively [13,19]. The alkaloids 60 and 62 of the 6,7-secoberbine subgroup have moderate cytotoxicity against different cancer cell lines, probably due to possessing the most electron-donating groups in their structures [23,24]. Moreover, 60 possesses potent anticancer activity, and its acidified form can be used as a potential regulator of diabetes mellitus [28,54].

4.7. Spirobenzylisoquinoline Alkaloids

Spirobenzylisoquinolines (67–73) are a small group isoquinolines with a “spiro” structure identified in two Hypecoum species—H. leptocarpum and H. erectum (Table 2). In these species, most of the spirobenzylisoquinoline alkaloids are C-8 linked via a C–C bond to an amide carbonyl group (67, 68) or 3-aminomaleimide group (69–71). Alkaloid 73 is spirobenzylisoquinoline with a unique 6/6/5/6/6 skeleton. Some of the isolated alkaloids, such as 68–70 and 72, have shown good anti-inflammatory activity via selective inhibition of inflammatory mediators [19].

4.8. Other Alkaloids

This group summarizes the Hypecoum alkaloids of various structural types (74–86) such as the benzylisoquinoline—N-methylcoclaurine (74), the phenantrene—N-methylsecoglaucine (75), the indenobenzazepines (80, 81), the phthalideisoquinoline—hypecoumine (83), the C19-benzylisoquinoline—hyperectumine (84) and alkaloids with unusual structures that cannot be assigned to any of the established groups (76–79, 82, 85, 86) (Table 2). The alkaloids 80, 81 and 84 have shown significant anti-inflammatory properties in different in vitro models [19].

5. Biosynthesis and Chemotaxonomical Relevance of Isoquinoline Alkaloids

The isoquinoline alkaloids are characteristic secondary metabolites in the Papaveraceae family and their structural types have been used as chemotaxonomical markers to determine relationships between genera [25]. However, for a correct chemotaxonomic classification, it is important to understand the biosynthetic pathways of isoquinoline alkaloids in the plant species.
The biosynthetic pathways of the different types of isoquinoline alkaloids identified in Hypecoum species are presented in Figure 1.
The first step in the process is the condensation and cyclization of two tyrosine derivatives, dopamine and 4-hydroxyphenylacetaldehyde, to yield the benzylisoquinoline alkaloid (S)-norcoclaurine, which is the central precursor of all isoquinoline alkaloids. (Figure 1) [55]. (S)-Norcoclaurine is sequentially hydroxylated, O-methylated and N-methylated to give (S)-reticuline. It can subsequently undergo stereochemical inversion to (R)-reticuline, a precursor of the morphinane alkaloids. This inversion is not characteristic of Hypecoum plants, as this type of alkaloid has not been found in the genus [56].
As shown in Figure 1, the transformation of (S)-reticuline via C–C or C–O coupling enzymatic reactions is the branch point that drives the formation of protoberberine and aporphine subclasses [56].
The protoberberine alkaloid N-methylstylopine (15) is the central intermediate in branch pathways that lead to protopines and benzophenantridines, secoberbines, spirobenzylisoquinolines and the phtalideisoquinoline alkaloid hypecoumine (86) [56,57].
Afterward, the main scaffold of each type undergoes different enzyme reactions such as oxidations, N- and O-methylations or methylenedioxy bridge formation, yielding the structural diversity of alkaloids identified in Hypecoum species (Table 2). Yuan et al. presented a possible biosynthetic pathway of spirobenzylisoquinolines (69–71) C-8 linked via a C–C bond to a 3-aminomaleimide group, in which sibiricine (72) is further attacked by asparagine to hyperectine (70) (Figure 1) [19].
The protopine biosynthesis pathway is predominant in the Hypecoum plants, as protopine (1) is the main alkaloid isolated from all investigated species [2,7,8,9,10,11,12,13,14,15,16,17,18,19,20,21,22,23,24]. On the other hand, Hypecoum species contain great variety of secoberbine alkaloids in addition to protopines, protoberberines and benzophenatridines. Secoberbines are characteristic metabolites in the genus, and the presence of these alkaloids distinguishes Hypecoum plants chemotaxonomically from other genera of the subfamily Papaveroidae and is indicative of a close relationship between genus Hypecoum and some species of subfamily Fumariaidae [25].
Based on the chemotaxonomic significance of the isoquinoline alkaloids, attempts have been made to improve the species rank of some Hypecoum synonyms. Doncheva et al. found that H. ponticum (synonym of H. procumbens) is well separated from the species -H. procumbens and H. imberbe due to the presence of a greater number of quaternary isoquinoline alkaloids [17]. However, the application of individual isoquinoline alkaloids for chemotaxonomical purpose has to be approached cautiously, as the alkaloid biosynthesis depends on many environmental factors such as geographic location, altitude, soils and others [25].

6. Biological Activities

Based on the long-standing use of Hypecoum species in traditional medicine, different solvent extracts and isolated alkaloids have been evaluated for their effects in the treatment of inflammation, microbial and viral infections, as well as for their analgesic, antitumor, anti-lipase and antioxidant properties.

6.1. Anti-Inflammatory Activity

H. erectum is widely used in Tibetan medicine to treat various inflammations, relieve pain and reduce fever [4,5].
In 2021, Yuan et al. [19] verified the traditional use of H. erectum by assessing its anti-inflammatory effect. The authors studied the in vivo anti-inflammatory activity of the methanolic (MeOH) extract, total alkaloid and non-alkaloid fractions of H. erectum at doses of 200, 100 and 50 mg/kg using a carrageenan-induced paw edema model. It was found that the alkaloid fraction showed significant anti-inflammatory activity at all tested doses with inhibition percentages of 60.5%, 54.3% and 47.4%, while the MeOH extract and non-alkaloid fractions showed good effects only at the dose of 200 mg/kg, with inhibition of 53.0% and 43.2%, respectively.
To determine the compounds responsible for the bioactivity of H. erectum, four individual isoquinoline alkaloids—protopine (1), cryptopine (4), allocryptopine (5) and oxohydrastinine (34)—at doses of 100 and 50 mg/kg were assessed for their in vivo anti-inflammatory activity using the same carrageenan-induced paw edema animal model [19]. The results indicated that compounds 4, 5 and 34 in both doses used possessed significant anti-inflammatory activity equivalent to that of the positive control (aspirin). Therefore, the authors suggest that these isoquinoline alkaloids are the main anti-inflammatory substances in the species.
To further elucidate the possible contributions of these alkaloids to the anti-inflammatory effects of H. erectum, all isolated compounds were evaluated for their in vitro inhibitory effects on the production of inflammatory mediators—cyclooxygenase-2 (COX-2), interleukin-1β (IL-1β) and tumor necrosis factor-α (TNF-α)—in lipopolysaccharide (LPS)-stimulated RAW 264.7 macrophages. It was found that alkaloids 1, 24, 34, 36, 38, 62, 70, 80 and 81, with a treatment concentration of 5 μg/mL, showed anti-inflammatory activity via selectively inhibiting the release of inflammatory mediators—COX-2, IL-1β and TNF-α. The compounds protopine (1), 1,3,6,6-tetramethyl-5,6,7,8-tetrahydroisoquinolin-8-one (38) and trans-benzindenoazepines (80) showed anti-inflammatory activity against IL-1β comparable to the control, dextromethorphan (DXM) [19]. Also, the C19-benzylisoquinoline alkaloid hyperectumine (84), isolated from H. erectum, exhibited moderate anti-inflammatory activity via suppressing the response in LPS-induced RAW 264.7 macrophages [26].
Other authors also found that the ethanolic extract of H. erectum may reduce LPS-induced inflammation [58]. Protopine (1) reduces nitric oxide (NO) production and inhibits the levels of prostaglandin E2 (PGE2) and COX-2 in LPS-stimulated RAW 264.7 murine cell lines in a dose-dependent manner [59]. The mechanism of action of 1 involved the suppression of phosphorylation of mitogen-activated protein kinases (MAPKs) and blocking of the activation of nuclear factor kappa-light chain-enhancer of activated B cells (NF-κB) [59].

6.2. Anticancer Activitiy

The anticancer properties of H. leptocarpum are well known in traditional Tibetan medicine. Therefore, Luo et al. [28], in 2022, evaluated the anticancer activity of the isoquinoline alkaloid corydamine (60). It was found that the alkaloid significantly reduced hepatocellular carcinoma (HCC) growth both in vitro and in vivo. Corydamine (60) dose-dependently suppressed HuH7 and LM9 cell proliferation and metastasis in vitro via arresting the cell cycle in the G1/G0 phase and inducing cell apoptosis of the mitochondrial pathway. In vivo studies in LM9 xenografted nude mice showed that a 21 day therapy with 60 at a dose 50 mg/kg/day significantly inhibited tumor growth. These findings suggest that 60 may be used as a natural therapeutic agent for the treatment of HCC.
In 2015, Zang et al. [27] evaluated the cytotoxicity of hypecocarpine (43) and leptopidine (46) isolated from H. leptocarpum in human breast cancer cells (MDA-MB-231) with different concentrations (0, 2, 4, 6, 8, 10 g/mL) of the alkaloids for 24 and 48 h, followed by a cell viability assay. The results showed that only 46 exerted a cytotoxic effect on the growth of MDA-MB-231 cells in a dose- and time-dependent manner. In addition, this alkaloid affected intracellular fatty acid biosynthesis in breast cancer cells via downregulating fatty acid synthase expression.
An anticancer screening of the isolated alkaloids from H. leptocarpum was conducted using a MTT assay by Wen et al. [24] in 2022. The compounds oxohydrastinine (34), corydamine (60) and leptocaramine (62) had moderate cytotoxicity against human lung cancer (A549) and human gastric carcinoma (MGC-803) cell lines.
Other authors in the same year evaluated the cytotoxic activity of the 15 isolated alkaloids from H. leptocarpum against three tumor cell lines—human ovarian cancer cell lines (A2780), human cervical cancer cell lines (HeLa) and human hepatocellular carcinoma cell lines (HepG2) [23]. This study established that coptisine (14) exhibited significant cytotoxic activity against the A2780 and HeLa tumor cell lines with IC50 values of 31.49 and 30.72 µM, respectively, while leptocaramine (62) exhibited moderate cytotoxicity against HepG2 cell lines with an IC50 value of 22.16 µM. The cytotoxicity of 14 against A2780 and HeLa tumor cell lines is due to the presence of a positive N-ion in the alkaloid molecule. The moderate cytotoxicity of 62 against the HepG2 cancer cell line is related to the number of electron-donating groups in its structure. The presence of the carboxyl group in the alkaloids coryximine (41), leptopidine (46), hendersine B (49), corydamic acid (61) and leptocarpinine B (79) is the probable reason for their low cytotoxicity against the three tumor cell lines [23].

6.3. Antibacterial and Antifungal Activity

An in vitro study of the antimicrobial activity of 306 Iranian plants against Escherichia coli, Klebsiella pneumoniae, Salmonella typhi, Pseudomonas aeruginosa, Morganella morganii (Gram-negative bacteria), Bacillus subtilis and Staphylococcus aureus (Gram-positive bacteria) and Candida albicans, established that the methanolic extract of H. pendulum L. exhibited a significant effect against E. coli, M. morganii and S. aureus [60].
In 2022, a group of Turkish scientists found that the methanolic extract of H. trullatum Å.E.Dahl, which is an endemic species in Turkey, inhibited the in vitro growth of Salmonella infantis, Listeria innocua, Enterococcus durans, Staphylococcus epidermidis (DSMZ 20044), E. coli (ATCC 25922) and Saratia marrescens (ATCC 13048) [29].
The antimicrobial activity of tertiary and quaternary alkaloid mixtures from H. ponticum was screened against Gram-positive bacteria (S. aureus 209), Gram-negative bacteria (E. coli and P. aeruginosa) and C. albicans [18]. The quaternary alkaloid mixture containing N-methylstylopine (15), N-methylcanadine (16) and hypepontine (47) showed potent in vitro antibacterial activity against Gram-negative and Gram-positive bacteria, with MIC values of 0.036 mg/mL and 0.072 mg/mL, respectively. Furthermore, the mixture of quaternary alkaloids had remarkable antifungal activity (MIC 0.018 mg/mL), higher than the reference antibiotic, and may be a good candidate for future pharmacological tests. It was noticed that the activity of the isolated alkaloids against all tested microorganisms was lower than the activity of the quaternary alkaloid mixture. This effect is probably induced by a synergistic interaction among the quaternary alkaloids. Only alkaloid 47 demonstrated a good inhibitory effect against Gram-negative bacteria P. aeruginosa, with an MIC value of 0.064 mg/mL.
Seven alkaloids isolated from H. erectum were evaluated for their antibacterial activity against six microorganisms—Bacillus cereus, B. subtilis and S. aureus (Gram-positive bacteria), and E. coli, P. aeruginosa and Erwinia carotovora (Gram-negative bacteria) [13]. It was established that the alkaloids protopine (1), cryptopine (4), allocryptopine (5), oxohydrastinine (34) and hypecorinine (55) possessed in vitro antibacterial activity, among which alkaloids 1, 5 and 55 showed more obvious properties than others against E. coli and P. aeruginosa, with an MIC value of 125 µg/mL.

6.4. Antiviral Activity

The plant H. erectum, along with four other Asian plants (Terminalia chebula, Polygonum bistorta, Momordica cochinchinensis and Gentiana decumbens), is included in the herbal formulation Deva-5, used in traditional Mongolian medicine to treat acute infectious diseases [61]. The aqueous extracts of these plants were investigated for inhibitory activity against influenza A virus subtype H3N8 [3]. The in vitro study revealed that H. erectum extract had strong antiviral activity at concentrations of 0.5–1%, but further research is needed to identify the biologically active components with direct activity.

6.5. Analgesic Effect

The analgesic effect of three different fractions (methanolic, alkaloidal and non-alkaloidal) and four major isoquinoline alkaloids (protopine (1), cryptopine (4), allcryptopine (5) and oxyhydrastinin (34)) from H. erectum was evaluated using the acetic acid-induced writhing test [19]. The alkaloidal fraction exhibited significant analgesic activity at a dose of 100 mg/kg. At the same dose, only compounds 1 and 34 significantly decreased the amount of stretching or twisting in the acetic acid-induced writhing animal model. These findings support the traditional application of H. erectum for the treatment of inflammatory and pain disorders.

6.6. Anti-Lipase Activity

Bustanji et al. [62] studied 29 medicinal plants, including H. dimidiatum Delile, to evaluate their inhibitory potential against hormone sensitive lipase (HSL), which is involved in the regulation of lipid metabolism in the treatment of insulin resistance. In this study, the methanolic extract of H. dimidiatum showed weak antilipase activity, with an inhibitory effect of only 25.0%, compared to the plants Malva nicaeensis All., Haplophyllum buxbaumii (Poir.) G. Donand and Anchusa italica Retz., whose inhibitory potential was over 55% [62].

6.7. Antioxidant Activity

The antioxidant activity of Hypecoum species is associated with phenolic compounds [63,64,65]. However, there is one study in which the free radical scavenging ability of the alkaloids—protopine (1), cryptopine (4) and coptisine (14)—and the new nonalkaloid compound—hypecoumic acid, isolated from H. erectum—was examined [20]. The antioxidant activity was assessed using the DPPH-scavenging assay and the determination of IC50 values related to the amount of sample required to reduce 50% of free radicals. The most effective antioxidant was found to be hypecoumic acid, with an IC50 of 86.3 µM, followed by the alkaloids 14, 1 and 4 with IC50 values 252.6, 345.2 and 430.1 µM, respectively.

6.8. Hepatoprotective Effect

The H. erectum aqueous extract had a marked hepatoprotective effect characterized by inhibition of the disturbances in the cholate-synthetic functions of the liver, increase of the bile secretion rate and preservation of the cholate concentration in the bile. The significant increase of the total concentration of secreted bile, as well as the amount of the main constituents in the bile—bilirubin, bile acids and cholesterol—indicated that the choleretic properties of the extract are in the dose range of 50–200 mg/kg [66,67]. Also, the H. erectum extract, at an experimental dose of 50 mg/kg, limited liver degeneration in tetracycline-induced hepatitis [68].

6.9. Anti-Hyperglycemic Activity

The dipeptidyl peptidase-4 (DPP 4) is essential in the regulation of diabetes mellitus (DM), and DPP4 inhibitors can be used as potential drugs for this disease. Gong and collaborators implemented a new artificial intelligence protocol to test and validate potential inhibitors from the Traditional Chinese Medicine Database, among which was an acidified form of corydamine (60) from H. leptocarpum [54]. Combining the constructed models and algorithms, the authors reported that 60 was a potent inhibitor and that H. leptocarpum can be used as a potential and effective medicinal herb for the treatment of DM.

6.10. Insecticidal Activity

H. leptocarpum extracts obtained via two extraction methods (constant temperature oscillation method and Soxhlet extraction method) with different polarity solvents (ethanol, methanol, hexane and dichloromethane) were tested for insecticidal activity against Mythimna seperata, a pest of a number of agricultural plants [69]. The extracts were found to show a strong growth inhibitory effect on the third instar larvae of M. seperata, and, after 24 to 48 h of feeding, the inhibition rate was over 70%, while with the ethanol extract it was the highest—over 90%. All types of extracts had low gastric and contact toxicity. In another study, acetone extract of H. leptocarpum also showed clear insecticidal activity against M. seperata [70].

7. Conclusions and Future Perspectives

This review is a summary of the traditional Chinese, Tibetan and Mongolian medicines produced by plants of the genus Hypecoum. To date, the isoquinoline alkaloids are the most-studied natural compounds isolated from the Hypecoum spp., and a total of 86 of them have been identified and classified by structural type. The structural type of isoquinolines are used for chemotaxonomic purposes to determine the relationships between Hypecoum species and other genera in the Papaveraceae family. Pharmacological studies of the isolated alkaloids, as well as some Hypecoum extracts, show that they have anti-inflammatory, antitumor, antibacterial, antiviral, hepatoprotective and antioxidant properties, among others. The alkaloids protopine (1), cryptopine (4), allcryptopine (5), oxyhydrastinin (34) and corydamine (60) have shown multiple potent biological activities and could be good candidates for future pharmacological tests.
Although recent years have seen an increase in the interest of researchers in the plants of the genus, they are still relatively poorly studied. Phytochemical research has only focused on ten Hypecoum species, and data on the composition and biological activity of the remaining species and subspecies belonging to the genus are still lacking. Future studies on the alkaloid profile of these plants would contribute to enriching the diversity of biologically active natural compounds with the potential to improve human health. Furthermore, studies of the chemical composition should include not only the determination of the structural type of compounds but also the study of biosynthesis and metabolic processes, which are essential for the discovery of new medicinal resources. In addition, pharmacological studies of the genus are insufficient and most of the active studies remain only at the level of in vitro experiments of extracts or individual compounds, which hinders their future applications to some extent. Further assessments and in vitro and in vivo studies should be performed to confirm the bioactive compounds, as well as their toxicity, mechanisms of action and the safety of effective doses in humans. Therefore, in the next stage of research, the alkaloids of the Hypecoum species should be subjected to wider phytochemical and pharmacological analyses that will improve the knowledge of the genus.

Author Contributions

Conceptualization, T.D. and N.K.; investigation, T.D. and N.K.; revising, T.D. and N.K.; writing—original draft preparation, T.D. and N.K.; writing—review and editing, T.D. and N.K.; supervision, T.D.; project administration, N.K. All authors have read and agreed to the published version of the manuscript.

Funding

This research received no external funding.

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

All the data are available in the manuscript.

Conflicts of Interest

The authors declare no conflict of interest.

References

  1. WFO. World Flora Online. 2023. Available online: http://www.worldfloraonline.org/search?query=Hypecoum (accessed on 17 July 2023).
  2. Zhang, R.F.; Zha, S.; Yin, X.; Bai, R.F.; Li, Y.; Tu, P.F.; Chai, X.Y. Phytochemical and pharmacological progress on Tibetan medicine Hypecoi Erecti Herba and plants of Hypecoum L. Chin. Tradit. Herb. Drugs 2016, 47, 1217–1224. [Google Scholar] [CrossRef]
  3. Oyuntsetseg, N.; Khasnatinov, M.A.; Molor-Erdene, P.; Oyunbileg, J.; Liapunov, A.V.; Danchinova, G.A.; Oldokh, S.; Baigalmaa, J.; Chimedragchaa, C. Evaluation of direct antiviral activity of the Deva-5 herb formulation and extracts of five Asian plants against influenza A virus H3N8. BMC Complement. Altern. Med. 2014, 14, 235. [Google Scholar] [CrossRef] [PubMed]
  4. Song, P.; Xia, J.; Rezeng, C.; Tong, L.; Tang, W. Traditional, complementary, and alternative medicine: Focusing on research into traditional Tibetan medicine in China. BioSci. Trends 2016, 10, 163–170. [Google Scholar] [CrossRef] [PubMed]
  5. Zhou, J.; Xie, G.; Yan, X. Encyclopedia of Traditional Chinese Medicines—Molecular Structures, Pharmacological Activities, Natural Sources and Applications; Springer: Berlin/Heidelberg, Germany, 2011; Volume 5, p. 468. [Google Scholar]
  6. Hao, D.; Xu, L.; Zheng, Y.; Lyu, H.; Xiao, P. Mining therapeutic efficacy from treasure chest of biodiversity and chemodiversity: Pharmacophylogeny of Ranunculales medicinal plants. Chin. J. Integr. Med. 2022, 28, 1111–1126. [Google Scholar] [CrossRef]
  7. Philipov, S.; Istatkova, R.; Denkova, P.; Dangaa, S.; Samdan, J.; Krosnova, M.; Munkh-Amgalan, C. Alkaloids from Mongolian species Hypecoum lactiflorum Kar. et Kir. Pazij. Nat. Prod. Res. 2009, 23, 982–987. [Google Scholar] [CrossRef]
  8. Gözler, T.; Önür, M.A.; Minard, R.D.; Shamma, M. (−)-Corydalisol: A new secoberbine alkaloid. J. Nat. Prod. 1983, 46, 414–416. [Google Scholar] [CrossRef]
  9. Pabuççuoglu, V.; Arar, G.; Gözler, T.; Freyer, A.J.; Shamma, M. Nitrotyrasanguinarine: An unusual nitrated benzophenanthridine alkaloid from Hypecoum species. J. Nat. Prod. 1989, 52, 716–719. [Google Scholar] [CrossRef]
  10. Zhang, G.; Rücker, G.; Breitmaier, E.; Mayer, R. Alkaloids from Hypecoum leptocarpum. Phytochemistry 1995, 40, 1813–1816. [Google Scholar] [CrossRef]
  11. Saad, H.E.A. (±)-8-Oxohypecorinine from Hypecoum procumbens var. glaucescens. Phytochemistry 1995, 38, 1049–1051. [Google Scholar] [CrossRef]
  12. Zhou, Y.; Zhang, G.; Li, B. Five alkaloids from Hypecoum leptocarpum. Phytochemistry 1999, 50, 339–343. [Google Scholar] [CrossRef]
  13. Su, Y.F.; Li, S.K.; Li, N.; Chen, L.L.; Zhang, J.W.; Wang, J.R. Seven alkaloids and their antibacterial activity from Hypecoum erectum L. J. Med. Plants Res. 2011, 5, 5428–5432. [Google Scholar] [CrossRef]
  14. Yakhontova, L.D.; Komarova, M.N.; Perel’son, M.E.; Blinova, K.F.; Tolkachev, O.N. Alkaloids of Hypecoum erectum structure of hypecorine and hypecorinine. Chem. Nat. Comp. 1972, 8, 592–595. [Google Scholar] [CrossRef]
  15. Önür, M.A.; Abu Zarga, M.H.; Gözler, T. Hypecumine: A new 3-arylisoquinoline Hypecoum procumbens. Planta Med. 1986, 52, 70–71. [Google Scholar] [CrossRef]
  16. Shamma, M.; Rothenberg, A.S.; Jayatilak, G.S.; Hussain, S.F. A new group of isoquinoline alkaloids: The secoberbines. Tetrahedron 1978, 34, 635–640. [Google Scholar] [CrossRef]
  17. Doncheva, T.; Kostova, N.; Vutov, V.; Aneva, I.; Philipov, S. Comparative study of the alkaloid composition in some Bulgarian species of genus Hypecoum. Compt. Rend. Acad. Bulg. Sci. 2019, 72, 727–731. [Google Scholar] [CrossRef]
  18. Doncheva, T.; Kostova, N.; Valcheva, V.; Toshkovska, R.; Vutov, V.; Philipov, S. Hypepontine, a new quaternary alkaloid with antimicrobial properties. Nat. Prod. Res. 2020, 34, 668–674. [Google Scholar] [CrossRef]
  19. Yuan, H.L.; Zhao, Y.L.; Qin, X.J.; Liu, Y.P.; Yang, X.W.; Luo, X.D. Diverse isoquinolines with anti-inflammatory and analgesic bioactivities from Hypecoum erectum. J. Ethnopharmacol. 2021, 270, 113811. [Google Scholar] [CrossRef]
  20. Xu, N.; Bao, W.; Xin, J.; Xiao, H.; Yu, J.; Xu, L. A new 1, 3-Benzodioxole compound from Hypecoum erectum and its antioxidant activity. Molecules 2022, 27, 6657. [Google Scholar] [CrossRef]
  21. Zhang, Q.; Ma, T.; Hu, N.; Ding, C.; Liang, Y.; Li, W.; Suo, Y.; Ding, C. One step to separate five alkaloids from Hypecoum leptocarpum by High-Speed Counter-Current Chromatography. J. Chromatogr. Sci. 2016, 54, 466–471. [Google Scholar] [CrossRef]
  22. Wen, H.X.; Jiang, L.; Zhang, D.; Yuan, X.; Dang, J.; Mei, L.; Shao, Y.; Tao, Y. Anti-inflammatory activity of total alkaloids from Hypecoum leptocarpum Hook. f. et Thoms. Pharmacogn. Mag. 2018, 14, 397–403. [Google Scholar] [CrossRef]
  23. Sun, B.; Assani, I.; Wang, C.G.; Wang, M.X.; Liu, L.F.; Li, Y.; Yan, G.; Yang, Y.R.; Chen, Z.; Liao, Z.X. Two new alkaloids from Tibetan medicine of Hypecoum leptocarpum. Nat. Prod. Res. 2022, 36, 5304–5310. [Google Scholar] [CrossRef] [PubMed]
  24. Wen, H.; Yuan, X.; Li, C.; Li, J.; Yue, H. Two new isoquinoline alkaloids from Hypecoum leptocarpum Hook. f. et Thoms. Nat. Prod. Res. 2022; in press. [Google Scholar] [CrossRef] [PubMed]
  25. Preininger, V. Chemotaxonomy of Papaveraceae and Fumariaceae. In The Alkaloids; Brossi, A., Ed.; Academic Press: London, UK, 1986; Volume 29, pp. 1–98. [Google Scholar]
  26. Yuan, H.L.; Zhao, Y.L.; Hu, K.; He, Y.J.; Yang, X.W.; Luo, X.D. C19 Benzylisoquinoline alkaloid with unprecedented architecture from Hypecoum erectum. J. Org. Chem. 2021, 86, 16764–16769. [Google Scholar] [CrossRef] [PubMed]
  27. Zhang, Q.; Luan, G.; Ma, T.; Hu, N.; Suo, Y.; Wang, X.; Ma, X.; Ding, C. Application of chromatography technology in the separation of active alkaloids from Hypecoum leptocarpum and their inhibitory effect on fatty acid synthase. J. Sep. Sci. 2015, 38, 4063–4070. [Google Scholar] [CrossRef]
  28. Luo, T.; Deng, X.; Li, Z.; Liu, D.; Wen, H.; Wang, Z. Synthesis and anti-hepatocellular carcinoma effects of corydamine from Hypecoum leptocarpum. Phytochem. Lett. 2022, 51, 119–126. [Google Scholar] [CrossRef]
  29. Baskan, S.; Bulbul, A.S. Investigation of antimicrobial properties of endemic Hypecoum trullatum Å.E.Dahl plant in in-vitro conditions. Res. J. Biol. Sci. 2022, 15, 143–148. [Google Scholar]
  30. How, F.C.; Wu, T.L. A Dictionary of the Families and Genera of Chinese Seed Plants; Kexue Chubanshe: Beijing, China, 1982. [Google Scholar]
  31. Belhouala, K.; Benarba, B. Medicinal plants used by traditional healers in Algeria: A multiregional ethnobotanical study. Front. Pharmacol. 2021, 12, 760492. [Google Scholar] [CrossRef] [PubMed]
  32. Qing, Z.X.; Yang, P.; Tang, Q.; Cheng, P.; Liu, X.B.; Zheng, Y.; Liu, Y.S.; Zeng, J.G. Isoquinoline alkaloids and their antiviral, antibacterial, and antifungal activities and structure–activity relationship. Curr. Org. Chem. 2017, 21, 1920–1934. [Google Scholar] [CrossRef]
  33. Qing, Z.X.; Huang, J.L.; Yang, X.Y.; Liu, J.H.; Cao, H.L.; Xiang, F.; Cheng, P.; Zeng, J.G. Anticancer and reversing multidrug resistance activities of natural isoquinoline alkaloids and their structure-activity relationship. Curr. Med. Chem. 2018, 25, 5088–5114. [Google Scholar] [CrossRef]
  34. Wen, H.; Shao, Y.; Mei, L.; Tao, Y.; Wang, Q. Application of the Thinfruit Hypecoum Herb Extract in Preparation Antiviral Drugs. CN Patent 105168374B, 8 January 2019. [Google Scholar]
  35. Wen, H.; Shao, Y.; Mei, L.; Tao, Y.; Yuan, X. Application of Slender-Fruited Hypecoum Extract in Preparation of Antibacterial Medicines. CN Patent 105168375A, 8 January 2019. [Google Scholar]
  36. He, S.Y.; Xing, Q.H.; Yin, Z.T.; Jiang, X.P. Beijing Flora (Revision); Beijing Press: Beijing, China, 1984; pp. 270–271. (In Chinese) [Google Scholar]
  37. World Health Organization. Medicinal plants in Mongolia; WHO Regional Office for the Western Pacific: Manila, Philippines, 2013; Available online: https://www.who.int/publications/i/item/9789290616320 (accessed on 17 July 2023).
  38. Chinese Pharmacopoeia Commission. Drug Standards of Tibetan Medicines; Ministry of Health of the People’s Republic of China: Beijing, China, 1995. (In Chinese)
  39. Zhang, K.; Wang, L.; Peng, J.; Sangji, K.; Luo, Y.; Zeng, Y.; Zeweng, Y.; Fan, G. Traditional Tibetan medicine to fight against COVID-19: Basic theory and therapeutic drugs. Front. Pharmacol. 2023, 14, 1098253. [Google Scholar] [CrossRef]
  40. Taborska, E.; Mikesova, M.; Veznik, F.; Slavik, J. Alkaloids of the two Hypecoum L. species. Coll. Czech. Chem. Commun. 1987, 52, 508–513. [Google Scholar] [CrossRef]
  41. Yakhontova, L.D.; Tolkachev, O.N.; Komarova, M.N.; Shreter, A.I. The alkaloid compositions of Hypecoum erectum and H. lactiflorum. Chem. Nat. Comp. 1984, 20, 645–646. [Google Scholar] [CrossRef]
  42. Taborska, E.; Bochorakova, H.; Sedmera, P.; Valka, I.; Simanek, V. Leptocarpine, a new protopine alkaloid. Heterocycles 1995, 41, 799–805. [Google Scholar] [CrossRef]
  43. Li, B.G.; Zhou, M.; Zhang, G. Four alkaloids from Hypecoum leptocarpum Hook. f. et Thoms. Indian J. Chem. 2001, 40B, 1215–1218. [Google Scholar] [CrossRef]
  44. Mete, E.; Kayalar, H. A novel quaternary alkaloid N-methylcoryximine from Hypecoum pendulum L. Univ. J. Pharm. Res. 2022, 7, 40–47. [Google Scholar] [CrossRef]
  45. Taborska, E.; Veznik, F.; Slavik, J.; Sedmera, P.; Simanek, V. Procumbine, a new secoberbine alkaloid. Heterocycles 1988, 27, 39–44. [Google Scholar] [CrossRef]
  46. Perel’son, M.E.; Aleksandrov, G.G.; Yakhontova, L.D.; Tolkachev, O.N.; Fesenko, D.A.; Komarova, M.N.; Esipov, S.E. Alkaloids of Hypecoum erectum, the structure of hyperectine. Chem. Nat. Comp. 1984, 20, 592–598. [Google Scholar] [CrossRef]
  47. Yakhontova, L.D.; Yartseva, I.V.; Klyuev, N.A.; Tolkachev, O.N. Structure of isohyperectine—An alkaloid from Hypecoum erectum. Chem. Nat. Comp. 1993, 29, 744–747. [Google Scholar] [CrossRef]
  48. Sun, P.T.; Cao, Y.G.; Xue, G.M.; Li, M.; Zhang, C.L.; Zhao, F.; Cao, Z.Y.; Wang, D.; Gustafson, K.R.; Zheng, X.K.; et al. Hypeisoxazole A, a racemic pair of tetrahydroisoxazole-fused benzylisoquinoline alkaloids from Hypecoum erectum and structural revision of hypecoleptopine. Org. Lett. 2022, 24, 1476–1480. [Google Scholar] [CrossRef]
  49. Mete, I.E.; Gözler, T. (+)-Oxoturkiyenine: An isoquinoline-derived alkaloid from Hypecoum pendulum. J. Nat. Prod. 1988, 51, 272–274. [Google Scholar] [CrossRef]
  50. Gözler, T.; Gözler, B.; Weiss, I.; Freyer, A.J.; Shamma, M. (+)-Turkiyenine: An unusual extension of the biogenetic sequence for isoquinoline alkaloids. J. Am. Chem. Soc. 1984, 106, 6101–6102. [Google Scholar] [CrossRef]
  51. Han, N.; Yang, Z.; Liu, Z.; Liu, H.; Yin, J. Research progress on natural benzophenanthridine alkaloids and their pharmacological functions: A Review. Nat. Prod. Commun. 2016, 11, 1181–1188. [Google Scholar] [CrossRef]
  52. Chen, J.; Gao, K.; Liu, T.; Zhao, H.; Wang, J.; Wu, H.; Wang, W. Aporphine alkaloids: A kind of alkaloids’ extract source, chemical constitution and pharmacological actions in different botany. Asian J. Chem. 2013, 18, 10015–10027. [Google Scholar] [CrossRef]
  53. Rozwadowska, M.D. Secoisoquinoline alkaloids. In The Alkaloids; Brossi, A., Ed.; Academic Press: New York, NY, USA, 1988; Volume 33, pp. 231–306. [Google Scholar]
  54. Gong, J.N.; Zhao, L.; Chen, G.; Chen, X.; Chen, Z.D.; Chen, C.Y.C. A novel artificial intelligence protocol to investigate potential leads for diabetes mellitus. Mol. Divers. 2021, 25, 1375–1393. [Google Scholar] [CrossRef] [PubMed]
  55. Facchini, P.J. Alkaloid biosynthesis in plants: Biochemistry, cell biology, molecular regulation, and metabolic engineering applications. Ann. Rev. Plant Physiol. Plant Mol. Biol. 2001, 52, 29–56. [Google Scholar] [CrossRef]
  56. Beaudoin, G.A.; Facchini, P.J. Benzylisoquinoline alkaloid biosynthesis in opium poppy. Planta 2014, 240, 19–32. [Google Scholar] [CrossRef]
  57. Fossati, E.; Ekins, A.; Narcross, L.; Zhu, Y.; Falgueyret, J.P.; Beaudoin, G.A.W.; Facchini, P.J.; Martin, V.J.J. Reconstitution of a 10-gene pathway for synthesis of the plant alkaloid dihydrosanguinarine in Saccharomyces cerevisiae. Nat. Commun. 2014, 5, 3283–3294. [Google Scholar] [CrossRef]
  58. Liu, X.J.; Wei, H.; Yang, J. Protection effect of herb of thinfruit hypecoum (Xì Guǒ Jiǎo Huí Xiānɡ) alcohol extract on endotoxin induced inflammatory mice. J. Soochow Univ. 2012, 32, 754–759. [Google Scholar]
  59. Bae, D.S.; Kim, Y.H.; Pan, C.H.; Nho, C.W.; Samdan, J.; Yansan, J.; Lee, J.K. Protopine reduces the inflammatory activity of lipopolysaccharide-stimulated murine macrophages. BMB Rep. 2012, 45, 108–113. [Google Scholar] [CrossRef]
  60. Bazzaz, B.S.; Haririzadeh, G. Screening of Iranian plants for antimicrobial activity. Pharm. Biol. 2003, 41, 573–583. [Google Scholar] [CrossRef]
  61. Tumurbaatar, N. Hot-Natured Disorders in Traditional Mongolian Medicine; Eruul Enkh Press: Ulaanbaatar, Mongolia, 1998; Volume 19, p. 92. [Google Scholar]
  62. Bustanji, Y.; Issa, A.; Moulay, A.; Hudaib, M.; Tawaha, K.; Mohammad, M.; Hamed, S.; Masri, I.; Alali, F.Q. Hormone sensitive lipase inhibition by selected medicinal plants. J. Med. Plants Res. 2011, 5, 4405–4410. [Google Scholar] [CrossRef]
  63. Toropova, A.A.; Razuvayeva, Y.G.; Nikolayev, S.M.; Flodorov, A.V.; Sambuyeva, Z.G. In vitro antioxidant and membrane stability activities of extracts from Lomatogonium carinthiacum (Wulf.) Reichenb. and Hypecoum erectum L. Acta Biomed. Sci. 2012, 6, 94–97. (In Russian) [Google Scholar]
  64. Tawaha, K.; Alali, F.Q.; Gharaibeh, M.; Mohammad, M.; El-Elimat, T. Antioxidant activity and total phenolic content of selected Jordanian plant species. Food Chem. 2007, 104, 1372–1378. [Google Scholar] [CrossRef]
  65. Yeshi, K.; Kashyap, S.; Yangdon, P.; Wangchuk, P. Taxonomical identification of Himalayan edible medicinal plants in Bhutan and the phenolic contents and antioxidant activity of selected plants. J. Biol. Act. Prod. Nat. 2017, 7, 89–106. [Google Scholar] [CrossRef]
  66. Nikolaev, S.M.; Fedorov, A.V.; Toropova, A.A.; Razuvaeva, I.G.; Sambueva, Z.G.; Lubsandorzhieva, P.B. Hepatoprotective effect of Hypecoum erectum extract on experimental D-galactosamine-induced damage of rat liver. Eksp. Klin. Farmakol. 2014, 77, 18–22. (In Russian) [Google Scholar] [PubMed]
  67. Nikolaev, S.M.; Fedorov, A.V.; Razuvaeva, I.G.; Sambueva, Z.G.; Toropova, A.A. The choleretic and hepatoprotective effect of Hypecoum erectum extract. Eksp. Klin. Gastroenterol. 2014, 10, 59–63. (In Russian) [Google Scholar]
  68. Toropova, A.A.; Nikolaev, S.M.; Razuvaeva, Y.G.; Fedorov, A.V.; Sambueva, Z.G.; Ubeeva, I.P. Effect of Hypecoum erectum extract on morphofunctional state of the liver in rats with tetracycline-associated hepatitis. Antibiot. Khimioter. 2014, 59, 25–28. (In Russian) [Google Scholar]
  69. Zhang, J.X.; Yang, X.H.; Yang, S.Y.; Zhang, X.H.; Shen, H.M. A study on the mode of action against Mythimna seperata of Hypecoum leptocarpum extracts obtained with different solvents. Acta Pratacult. Sin. 2013, 22, 167–172. (In Chinese) [Google Scholar] [CrossRef]
  70. Gang, L.; Huimin, S.; Xinhu, Z. Preliminary research of insecticidal activity of acetone extracts from sixteen species of poisonous plants in the Tianzhu Grassland of Gansu Province to Mythimna seperata. J. Gansu Agr. Univ. 2010, 44, 101–104. (In Chinese) [Google Scholar]
Diversity 15 01023 g001
Figure 1. Possible biosynthesis pathways of isoquinoline alkaloids in Hypecoum species. TYDC: tyrosine/dopadecarboxylase; NCS: norcoclaurine synthase; 6OMT: norcoclaurine 6-O-methyltransferase; CNMT: coclaurine N-methyltransferase; 4′OMT: 4′-O-methyltransferase; BBE: berberine bridgeenzyme; MSH: N-methylstylopine-14-hydroxylase; P6H: protopine 6-hydroxylase; DBOX: dihydrobezophenanthridine oxidase.
Figure 1. Possible biosynthesis pathways of isoquinoline alkaloids in Hypecoum species. TYDC: tyrosine/dopadecarboxylase; NCS: norcoclaurine synthase; 6OMT: norcoclaurine 6-O-methyltransferase; CNMT: coclaurine N-methyltransferase; 4′OMT: 4′-O-methyltransferase; BBE: berberine bridgeenzyme; MSH: N-methylstylopine-14-hydroxylase; P6H: protopine 6-hydroxylase; DBOX: dihydrobezophenanthridine oxidase.
Diversity 15 01023 g001
Table 1. Hypecoum species and synonyms accepted by World Flora Online.
Table 1. Hypecoum species and synonyms accepted by World Flora Online.
Accepted Name
Species/Subspecies/Ambiguous		Synonym
Species/Subspecies/Varieties
H. aegypitacum (Forssk.) Asch. & Schweinf.
H. aegyptiacum (Forssk.) Asch. & Schweinf.H. patens Willd.
H. refractum Mart. ex Fedde
H. aequilobum Viv
H. angustilobum Å.E.Dahl
H. dimidiatum Delile
H. duriaei Pomel
H. erectum L.H. millefolium H.Lév. & Vaniot
H. imberbe Sibth. & Sm.
H. imberbe SmH. procumbens subsp. imberbe (Sm.) Malag.
H. glaucescens Guss.
H. grandiflorum Benth.
H. procumbens subsp. grandiflorum (Benth.) Pau
H. lactiflorum (Kar. & Kir.) Pazij
H. leptocarpum Hook.f. & ThomsonH. chinense Franch.
H. alpinum Z.X.An
H. littorale WulfenH. deuteroparviflorum Fedde
H. geslini Coss. & Kralik
H. pendulum L.H. tetragonum Bertol.
H. caucasicum Koch ex Ledeb.
H. ferrugineomaculatum Z.X.An
H. pendulum var. parviflorum (Kar. & Kir.) Cullen
H. parviflorum Kar. & Kir.
H. procumbens L.H. gracile Benth Cat.
H. nodosum Lam.
H. armatum Steud.
H. ponticum Velen
H. procumbens subsp. atropunctatum Å.E.Dahl
H. procumbens subsp. fragrantissimum Å.E.Dahl
H. pseudograndiflorum PetrovicH. imberbe subsp. pseudograndiflorum (Petrovic) E.Mayer & Nikolic
H. torulosum Å.E.Dahl
H. trilobum Trautv. 1H. pendulum var. trilobum Cullen
H. trullatum Å.E.Dahl
H. zhukanum Lidén
1 Ambiguous name.
Table 2. Alkaloid structures reported for Hypecoum spp.
Table 2. Alkaloid structures reported for Hypecoum spp.
Alkaloids/TypesStructureSpeciesReferences
Protopines
Protopine (1)Diversity 15 01023 i001H. procumbens
H. procumbens var. glaucescens
H. imberbe
H. lactiflorum
H. pendulum
H. trilobum
H. leptocarpum
H. erectum
H. ponticum
H. parviflorum		[2,7,8,9,10,11,12,13,14,15,16,17,18,19,20,21,22,23,24]
Dihydroprotopine (2)Diversity 15 01023 i002 H. procumbens
H. imberbe
H. leptocarpum 		[17,24]
13-Oxoprotopine (3)Diversity 15 01023 i003 H. procumbens
H. erectum 		[15,19]
Cryptopine (4)Diversity 15 01023 i004H. procumbens var. glaucescens
H. erectum
H. leptocarpum		[2,11,13,19,20,21,22,23,40]
Allocryptopine (5)Diversity 15 01023 i005H. lactiflorum
H. leptocarpum
H. procumbens
H. procumbens var. glaucescens
H. erectum		[7,8,10,11,13,14,19,21,40,41]
13-Oxocryptopine (6)Diversity 15 01023 i006 H. erectum [19]
13-Oxoallocryptopine (7)Diversity 15 01023 i007 H. erectum [19]
Leptocarpine (8) *Diversity 15 01023 i008 H. leptocarpum [42]
Hunnemanine (9)Diversity 15 01023 i009 H. procumbens [15]
Bis[1,3]benzodioxolo[4,5-c:5′,6′-g]azecin-14(4H)-one, 5,6,7,13-tetrahydro-5-methyl-one (10)Diversity 15 01023 i010 H. erectum [19]
6,7,8,14-Tetrahydro-3,4-dimethoxy-6-methylbenzo
[c][1,3]benzodioxolo [5,6-g]azecin-15(5H)-one (11)		Diversity 15 01023 i011 H. erectum [19]
Protoberberines
(S)-Stylopine (12)Diversity 15 01023 i012 H. procumbens [17]
(S)-Scoulerine (13)Diversity 15 01023 i013 H. procumbens [8,15]
Coptisine (14)Diversity 15 01023 i014 H. procumbens
H. leptocarpum
H. erectum 		[8,14,20,23,40,41]
(S)-N-Methylstylopine (15)Diversity 15 01023 i015 H. lactiflorum
H. procumbens
H. ponticum 		[7,17,18]
(S)-N-Methylcanadine (16)Diversity 15 01023 i016 H. lactiflorum
H. erectum
H. procumbens
H. ponticum
H. leptocarpum 		[7,13,17,18,21]
Hydroprotopine (17)Diversity 15 01023 i017 H. leptocarpum [27]
Benzophenanthridines
Chelerythrine (18)Diversity 15 01023 i018 H. procumbens
H. leptocarpum 		[8,14,40]
Chelirubine (19)Diversity 15 01023 i019 H. procumbens [8,14]
Dihydrochelirubine (20)Diversity 15 01023 i020 H. procumbens [17]
Sanguinarine (21)Diversity 15 01023 i021 H. procumbens
H. leptocarpum
H. trilobum
H. ponticum ,
H. imberbe		[14,17,18,21,40]
Dihydrosanguinarine (22)Diversity 15 01023 i022 H. imberbe
H. leptocarpum
H. procumbens 		[9,10,15]
(R,S)-8-Methoxydihydrosanguinarine (23)Diversity 15 01023 i023 H. procumbens
H. leptocarpum
H. imberbe 		[8,9,10]
(S)-8-Hydroxymethyldihydrosanguinarine (24)Diversity 15 01023 i024 H. erectum [19]
8-Acetonyldihydrosanguinarine (25)Diversity 15 01023 i025 H. procumbens
H. leptocarpum 		[8,10]
(R,S)-Nitrotyrasanguinarine (26)Diversity 15 01023 i026 H. imberbe
H. pendulum
H. procumbens 		[9]
Oxysanguinarine (27)Diversity 15 01023 i027 H. procumbens [8,15]
Norsanguinarine (28)Diversity 15 01023 i028 H. procumbens
H. leptocarpum 		[8,15,23]
Aporphines
(S)-Corydine (29)Diversity 15 01023 i029 H. procumbens
H. leptocarpum 		[40]
(S)-Isocorydine (30)Diversity 15 01023 i030H. procumbens
H. procumbens var. glaucescens
H. leptocarpum		[8,11,40]
(S)-Bulbocapnine (31)Diversity 15 01023 i031 H. imberbe [9]
(S)-Glaucine (32)Diversity 15 01023 i032 H. procumbens [8]
(S)-Magnoflorine (33)Diversity 15 01023 i033 H. procumbens
H. leptocarpum 		[40]
Simple isoquinolines
Oxohydrastinine (34)Diversity 15 01023 i034 H. imberbe
H. leptocarpum
H. erectum 		[2,9,10,12,13,19,21,22,23,24,27]
Doryanine (35)Diversity 15 01023 i035 H. erectum [19]
N-Methylcorydaldine (36)Diversity 15 01023 i036 H. erectum
H. leptocarpum 		[13,19,23]
2-Methyl-1,2,3,4-tetrahydro
isoquinoline-7-carboxylic acid methyl ester (37)		Diversity 15 01023 i037 H. erectum [19]
1,3,6,6-Tetramethyl-5,6,7,8-
tetrahydroisoquiolin-8-one (38)		Diversity 15 01023 i038 H. erectum [19]
Secoberbines
(S)-Corydalisol (39)Diversity 15 01023 i039 H. procumbens [8]
(S)-N-Methylcorydalisol (40)Diversity 15 01023 i040 H. lactiflorum [7]
(S)-Dihydroleptopine (41)
(Coryximine)		Diversity 15 01023 i041 H. leptocarpum [22,23,43]
Hypecocarpinine (42)Diversity 15 01023 i042 H. leptocarpum [24]
Hypecocarpine (43)Diversity 15 01023 i043 H. leptocarpum [27]
Leptopinine (44)Diversity 15 01023 i044 H. leptocarpum [12]
Leptopine (45)Diversity 15 01023 i045 H. leptocarpum [12,21]
Leptopidine (46)Diversity 15 01023 i046 H. leptocarpum [12,21,22,23,24,27]
Hypepontine (47)Diversity 15 01023 i047 H. ponticum [17,18]
N-Methylcoryximine (48)Diversity 15 01023 i048 H. pendulum [44]
Hendersine B (49)Diversity 15 01023 i049 H. leptocarpum [23]
Procumbine (50)Diversity 15 01023 i050 H. procumbens
H. leptocarpum 		[40,45]
Leptopidinine (51)Diversity 15 01023 i051 H. leptocarpum [12,21,22]
Torulosine (52)Diversity 15 01023 i052 H. leptocarpum [23,43]
8-Oxohypecorinine N-oxide (53)Diversity 15 01023 i053 H. leptocarpum [43]
N-Methyldemethyltorulosine (54)Diversity 15 01023 i054 H. leptocarpum [23,43]
(R,S)-Hypecorinine (55)Diversity 15 01023 i055H. procumbens
H. procumbens var. glaucescens
H. erectum		[8,11,13,14,19,41,46]
(R,S)-8-Oxohypecorinine (56)Diversity 15 01023 i056H. procumbens var. glaucescens[11]
Hypecorine (57)Diversity 15 01023 i057 H. erectum [14,41,46]
2,3-Dimethoxyhypecorinine (58)Diversity 15 01023 i058 H. erectum [19]
(S)-Peshawarine (59)Diversity 15 01023 i059 H. parviflorum [8,16]
Corydamine (60)Diversity 15 01023 i060 H. leptocarpum
H. erectum 		[10,19,22,23,24,41]
Corydamine acid (61)Diversity 15 01023 i061 H. leptocarpum [23]
Leptocaramine (62)
(2-(1,3-dioxolo [4,5-h]
isoquinolin-7-yl)-4,5-dimethoxy-N-methyl-benzeneethanamine)		Diversity 15 01023 i062 H. leptocarpum
H. erectum 		[19,23,24]
N-Formylcorydamine (63)Diversity 15 01023 i063 H. erectum
H. procumbens 		[15,19]
2,3-Dimethoxy-N-formyl
corydamine (64)		Diversity 15 01023 i064 H. erectum [19]
Hypecumine (65)Diversity 15 01023 i065 H. procumbens [15]
7-N-Methyl-7-N-oxide-2,3-di-
methoxycorydamine (66)		Diversity 15 01023 i066 H. erectum [19]
Spirobenzylisoquinolines
(S,S)-Hyperectumine B (67)Diversity 15 01023 i067 H. erectum [19]
(S,S)-2,3-Dimethoxyhyperectumine B (68)Diversity 15 01023 i068 H. erectum [19]
(R,S) and (S,R)-2,3-Dimethoxyhyperectine (69)Diversity 15 01023 i069 H. erectum [19]
(R,S) and (S,R)-Hyperectine (70)Diversity 15 01023 i070 H. leptocarpum
H. erectum 		[10,19,41,46,47]
(S,S) and (R,R)-Isohyperectine (71)Diversity 15 01023 i071 H. leptocarpum
H. erectum 		[10,12,47]
(R,R)-Sibiricine (72)Diversity 15 01023 i072 H. erectum [19]
(R,S)-Hypecoleptopine (73)Diversity 15 01023 i073 H. erectum
H. leptocarpum 		[21,43,48]
Other alkaloids
(S)-N-Methylcoclaurine (74)Diversity 15 01023 i074 H. procumbens [17]
N-Methylsecoglaucine (75)Diversity 15 01023 i075 H. ponticum [17,18]
(R)-Turkiyenine (76)Diversity 15 01023 i076 H. procumbens
H. pendulum
H. imberbe 		[9,15,49,50]
(S)-Oxoturkiyenine (77)Diversity 15 01023 i077 H. pendulum [49]
Leptocarpinine (78)Diversity 15 01023 i078 H. leptocarpum [12]
Leptocarpinine B (79)Diversity 15 01023 i079 H. leptocarpum [23]
(S,S)-Trans-benzindenoazepines (80)Diversity 15 01023 i080 H. erectum [19]
(S,S)-O-Methylfumarostelline (81)Diversity 15 01023 i081 H. erectum [19]
Leptocarpine (82) *Diversity 15 01023 i082 H. leptocarpum [10,22]
Hypecoumine (83)Diversity 15 01023 i083 H. procumbens [2]
Hyperectumine (84)
(8S, 9R, 15R)
(8R, 9S, 15S)		Diversity 15 01023 i084 H. erectum [25]
Dibenzooxazacycloundecine (85)Diversity 15 01023 i085 H. erectum [19]
Hypeisoxazole A (86)
(6S, 8R, 14R)
(6R, 8S, 14S)		Diversity 15 01023 i086 H. erectum [48]
* Two chemical structures with the name leptocarpine (8, 82).
Disclaimer/Publisher’s Note: The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content.

Share and Cite

MDPI and ACS Style

Kostova, N.; Doncheva, T. Hypecoum spp.—Chemistry and Biological Activity of Alkaloids. Diversity 2023, 15, 1023. https://doi.org/10.3390/d15091023

AMA Style

Kostova N, Doncheva T. Hypecoum spp.—Chemistry and Biological Activity of Alkaloids. Diversity. 2023; 15(9):1023. https://doi.org/10.3390/d15091023

Chicago/Turabian Style

Kostova, Nadezhda, and Tsvetelina Doncheva. 2023. "Hypecoum spp.—Chemistry and Biological Activity of Alkaloids" Diversity 15, no. 9: 1023. https://doi.org/10.3390/d15091023

APA Style

Kostova, N., & Doncheva, T. (2023). Hypecoum spp.—Chemistry and Biological Activity of Alkaloids. Diversity, 15(9), 1023. https://doi.org/10.3390/d15091023

Note that from the first issue of 2016, this journal uses article numbers instead of page numbers. See further details here.

Article Metrics

Back to TopTop