CC BY
17Received by the Editor 06.10.2020
IRSTI 76.31.31
UDC 615.322:582.711.31
THE MAIN GROUPS OF BIOLOGICALLY ACTIVE SUBSTANCES OF PLANTSGENUS CROCUS L.
Z. Allambergenova, S. Sakipova, N. Aliev, N. Omarkulova
«S.D. Asfendiyarov Kazakh National Medical University» NJSC, Almaty city, Kazakhstan
This review provides data on the chemical components of plants of the genus Crocus L. and discusses the main classes of biologically active substances (carotenoids, flavonoids, terpenoids, phenolcarboxylic acids, and vitamins), as well as general and individual structural formulas of compounds isolated from some species of Crocus L and identified. Key words: Crocus L., crocin, apocarotenoids, flavonoids, phenolic acids.
ОСНОВНЫЕ ГРУППЫ БИОЛОГИЧЕСКИ АКТИВНЫХ ВЕЩЕСТВ РАСТЕНИЙРОДА CROCUS L.
Алламбергенова З. Б., Сакипова З.Б., Алиев Н.У., Омаркулова Н.С.
НАО «Казахский Национальный медицинский университет им. С. Д. Асфендиярова», Алматы, Казахстан
В настоящем обзоре приведены данные о химических составляющих растений рода CrocusL. и обсуждаются основные классы биологически активных веществ (каротиноиды, флавоноиды, терпеноиды, фенолкарбоновые кислоты и витамины), а такжеприведены общие и индивидуальные структурные формулы соединений, выделенных и идентифицированных из некоторых видов CrocusL. Ключевые слова: CrocusL., кроцин, апокаротиноиды, флавоноиды, фенолокислоты.
0С1МД1КТЕРДЩ БИОЛОГИЯЛЬЩ БЕЛСЕНД1 ЗАТТАРЫНЬЩ НЕГ1ЗГ1 ТОПТАРЫ L.
Алламбергенова З.Б., Сакипова З.Б., Алиев Н.У., Омаркулова Н.С.
"С.Д. Асфендияров атындагы ^азак улттьщ медициналык университет^' КеА^, Алматы К, ^азакстан
Б^л шолуда Crocus L т^кымдасына жататын еамдактердщ химиялык к¥рамы туралы мэлiметтер келтiрiлген. жэне биологиялык белсендi заттардын непзп кластары (каротиноидтар, флавоноидтар, терпеноидтар, фенолкарбоксил кышкылдары жэне витаминдер), сонымен катар CrocusL кейбiр тYрлерiнен окшауланган жэне аныкталган косылыстардыц жалпы жэне жеке к¥рылымдык формулалары талкыланады.
ТYЙiндi сездер: Crocus L., крокин, апокаротеноидтар, флавоноидтар, фенол кышкылдары.
Introduction
The genus Crocus L. belongs to the large family Iridaceae Juss. The history and taxonomy of Crocus L. have been reviewed in two monographs, Maw (1886) and Mathew (1982). In the monograph of Mathew (1982), 80 species are listed in the genus Crocus L., and since then several more species and subspecies have been described. Currently, this number has reached 83 species. The genus Crocus L. is divided into two subgenera, namely the subgenus Crocus, including all species but one, C. banaticus, which is the only member of the subgenus Crociris. Today more than 100 varieties of crocuses are known. They are obtained from a selection within and hybridization between relatively few species [1].
Two species grow on the territory of Kazakhstan: Crocus alatavicus Regel et Semen. and Korolkov's crocus Crocuskorolkowii Regel et Maw.
C.alatavicus L. is endemic to the Tien Shan, found in the Dzhungarsky andZailiysky Alatau, the Ketmen, Kungei and the Terskey Alatau, the Karatau and the Western Tien Shan. It grows on gravel and clay slopes, meadow and steppe areas, in thickets of shrubs from foothills to the upper border of
the forest belt.
C.alatavicus L. is a herbaceous perennial (10-20 cm high) with a rounded-spherical corm (1.52 cm in diameter). The leaves are narrow, linear (from 8 to 16 pcs.), collected in a near-ground bundle, surrounded by long membranous sheaths. Flowers (from 1 to 5) are funnel-shaped, regular. Tepals (up to 4-5 cm long) are snow-white, gray-violet on the outside along the back, grow together below into a long tube. The crocus stem is underdeveloped, so the tube carries the flower above the soil surface. It blooms in early spring, from February to late mid-March. Fruits (three-nested capsules) are located in the upper layers of the soil, and only after ripening (April-May) their tops are visible above the surface.This little-studied decorative species belongs to the group of obligate ephemeroids, that is, after fruiting the aerial part of the plant completely dies off, while the underground part (corm) remains. With the onset of favorable conditions, dormant corms wake up, using for that the reserves of starch and nutrients accumulated during the growing season [3]. According to the results of research of Russian scientists, it has been noted that the dynamics of accumulation of reserve substances in C.alatavicus L. corms gradually increases from May to October. By the end of October, the accumulation of nutrients was as follows: sugar - 4,1%, starch - 17.8%, saponins - 4,14%, ascorbic acid - 38,85 mg%, catechins - 18,54 mg%, pectins - 0, 89%, propectins - 2,6%, tannins -0,25%. The high content of these nutrients contributes to the stability of the Alatau crocus during their overwintering in the open field in harsh conditions [4].
Materials and methods
This review summarizes the data on the chemical components of some species of the genus Crocus L. The corresponding data were obtained as a result of a computer search in the main known scientific databases: Scopus and PubMed. According to the search results (03/25/2020) conducted in the NCBI-PubMed database (http://www.ncbi.nlm.nih.gov/pubmed) for the keywords: "Crocus L.", "Saffron", "Crocin", "Safranal"1109 scientific articles were found on several species of the genus Crocus L. The first entry quoted with the keywords "saffron + crocus + crocin + safranal" in NCBI-PubMed is from apublication of the year 1977. The number of such articles increased between 2010 and 2019 (from 50 to 129 articles respectively). We believe that a literature review based on the latest research in the field of phytochemical analysis and biological activity of the main components of plants of the genus Crocus L. will help to reveal the phytochemical composition and pharmacological activity of the little-studied species C. alatavicus L.
Chemical constituents of plants of the genus Crocus L.
The search results showed that about 85% of scientific works are devoted to Crocus sativus L. C.sativus L. (commonly known as saffron, the most expensive herbal spice in the world, it is obtained from the stigma of the corresponding flower) is a perennial plant from the family Iridaceae, which is mainly cultivated in Iran and several other countries including Spain, India, Greece, China, Azerbaijan, Turkey, Israel, Egypt, Morocco, Italy, France, and Mexico. More than 80% of the world's saffron is produced in Iran, mainly in the South Khorasan province [2]. Saffron as a medicinal plant has many medicinal effects. Important pharmacologically active substances of Crocus L. plants are
carotenoids (crocetin, crocins, a-carotene, lycopene, zeaxanthin), monoterpene aldehydes (picrocrocin and safranal), monoterpenoids (crocusatins), flavonoids, phenolic acids. Phytochemical studies have shown that saffron is composed of at least four active ingredients, which include crocin (a monoglycosyl or diglycosyl ester of crocetin), crocetin (a natural carotenoid precursor of crocin dicarboxylic acid), picrocrocin (a monoterpene glycosidic precursor of safranal) and safranal (the main organoleptic precursor of stigmas) (fig. 1). Saffron carotenoids are sensitive to oxygen, light, heat and enzymatic oxidation. However, regulation of these factors is necessary to ensure the quality of the saffron. Among more than 150 chemicals in saffron, the most biologically active components are two carotenoids, including crocin and crocetin. Most pharmacokinetic studies are related to these compounds [5].
O
-0R2
R1O'
Crocin
O
O
HO
OH
O
H3<X .,CH3
CH3
Safranal
H H
Picrocrocin
HO
Figure 1 - Chemical structure of the four main biologically active ingredients of Crocus sativus L: crocin, crocetin, picrocrocin, safranal.
At present, a phytochemical study of more than 20 species of the genus Crocus L. has been carried out, as a result, more than 150 volatile, nonvolatile and aromatic natural compounds related to lipophilic and hydrophilic carbohydrates, proteins, amino acids, minerals, vitamins, etc. have been isolated and identified [5].A review article by P. Van et al. [6] 19 flavonoids, 38 terpenoids (4 tetraterpenes, 2 triterpenoids, 12 diterpenoids) and 19 monoterpenes per stigma of Crocus sativus L. were reported. Tetra - and diterpenoids were identified in the stigma of saffron, triterpenes were found in corms, monoterpenes were found in stigmas, petals. Similar reviews summarizing information on the chemical components of the stigma of Crocus sativus L. have been published by B.M. Joseet al. [7], M.Vahedi et al. [8], T.K.Lim [9], A.R. Gohari [10], E.Christodoulou [11]. Apocarotenoids and their glycosides
Crocins are a group of hydrophilic carotenoids, which are mono- or di-glycosylpolyene esters of crocetin, in which D-glucose and/or D-gentiobiose occur as carbohydrate residues. The crocin group includes various glycosyl esters, of which six types have been found in saffron. The sugars associated with the two acidic groups of the crocetin aglycone are presented in table and the structural formulas are given in figure 2 [12].
RlO
OR2
Crocin
hoA^^/0
H0X bH I
Hi
Gentiobiosyl
HOx bH
Glucosyl
Figure 2 - Carbohydrate parts of crocins.
Table - Carbohydrate parts (R1 and R2) and gross formulas of six types of crocins.
OH
OH
O
HO
Compounds Carbohydrate, R1 and R2 Gross formula Isomers
Crocin 1 Ri= P-D-glucosyl; R2 = H C26H34O9 TpaHC-
Crocin2 Ri= P-D-gentiobiosil; R2 = H C32H44O14 Cis / trans
Crocin 2' Ri= R2 = P-D-glucosyl C32H44O14 Cis / trans
Crocin 3 Ri= P-D-gentiobiosil; R2 = P-D-glucosyl C38H54O19 Cis / trans
Crocin 4 Ri= R2= P-D-gentiobiosil C44H64O24 Cis / trans
Crocin 5 Ri= 3 p-D-gentiobiosil; R2 = P-D-gentiobiosil C50H24O29 Cis / trans
All crocin derivatives are reported to occur as pairs of cis- and trans- isomers, with the exception of crocin-1. Research conducted by S.H. Alavizadeh et al.[12] showed that trans-crocins undergo photoisomerization reactions and are converted into cis-crocins; this process depends on agricultural and ecological conditions in the zone of origin of the plants. Compared to other saffron carotenoids, crocin or trans-crocetin Di-P-D-gentiobiosyl ether has the highest coloring power due to its high solubility in water.
Carotenoids are vital for many organisms, not only in their intact form, but also because they are precursors of a number of other biologically active derivatives, which are usually formed as a result of oxidative degradation. These compounds are smaller than their predecessors and are collectively referred to as apocarotenoids. It has been demonstrated that chemical degradation of carotenoids can occur either by simple chemical/physical mechanisms or by enzymatic catalyzed reactions [13] (fig. 3.).
Crocin
hydrolysis
■
O
Crocetin
Figure 3 - Hydrolysis of crocin to crocetin.
The highest levels of water-soluble C20 apocarotenoids - crocetin (C20H24O4) (crocetin 1, crocetin p - D-glucosyl methyl ether, dimethyl crocetin, etc.) and its glycosidic esters crocins (C44H64O24), conjugated with one or some sugar fragments as well as fat-soluble carotenoids such as phytoene, zeaxanthin, a- and p-carotene, lycopene, phytofluene were registered in the stigma of C. sativus L. [14].
Crocetin and its glycoside esters crocins are represented by diterpenes and triterpenes. Five derivatives of crocetin (Crocetin-Di-(2,3,4,8,9,10,12-hepta-0-acetyl-P-D-gentiobiosyl) - ether; Crocetin-Di-(2,3,4,6-tetra-0-acetyl-P-D-glucosyl) ether; trans-/cis-crocetin Di-(P-D-gentiobiosyl) ether; trans / cis-crocetin (P-D-gentiobiosyl) ether; trans / cis-crocetin Di-(P-D-glucosyl) ester) were first isolated from the stigma of C. sativus and identified in 1982 [15]. 8 cis- and trans-isomers of crocetin were identified from stigmas and petals of C. sativus using HPLC and UV-visible spectrophotometry: trans- /cis-crocetin (tri-P-D-glucosyl) - (P-D-gentiobioz) ester ( trans- / cis-5-tG); trans- / cis-crocetin (P-D-neolithanosyl) - (P-D-gentiobiose) ester (trans- / cis-5-nG); trans- / cis-crocetin (P-D-neolithanosyl) - (P-D-glucosyl) ester (trans- /cis-4-nG); trans- / cis-crocetin Di- (P-D-gentiobiose) ester (trans- / cis-4-GG); trans- / cis-crocetin (P-D-glucosyl) - (P-D-gentiobiose) ester (trans- / cis-3-GG); trans- / cis-crocetin (P-D-gentiobiosyl) ether (trans- / cis-2-G); trans- / cis-crocetin di- (P-D-glucosyl) ester (trans / cis-2-GG); trans- / cis-crocetin (P-D-glucosyl) ester (trans-/ cis-1-G) [16-22], as well as 2 cis- and trans-isomers of crocetin were isolated from the stigma of C. neapolitanus: trans- / cis-crocetin (P-D-neolithanosyl) - (P-D-gentiobiose) ester (trans- / cis-5-nG); Crocetin-Di- (P-D-neolithanosyl) ether [23].
In addition to crocins and crocetins, a number of carotenoid compounds have been identified in saffron, including minor amounts of lycopene, alpha- and beta-carotene, zeaxanthin, phytoene, which are tetraterpenes by chemical structure and are classified as oil-soluble saffron color pigments [6,7,15] (fig. 4.).
C40H64 Phytoene
C40H56 Lycopene
Figure 4 - Fat-soluble carotenoids of saffron: phytoene, zeaxanthin, a- and ft-carotene, lycopene.
Picrocrocin and safranal are the other two major phytochemicals of saffron, derived from carotenoid oxidation products, and are responsible for its tart taste and aroma [18]. Picrocrocin (C16H26O7) is a precursor to safranal (C10H14O), a monoterpene aldehyde that is the main essential oil component responsible for the saffron aroma. The safranal content is up to 1% [21,24]. According to the results of Maggi L. and her colleagues [25] safranal is more than 60% of the essential oil. The total yield of essential oil from saffron stigmas is 0.4-1.3% [18,26,27]. a-pinene, 1,8-cineole (eucalyptol), [18, 24] are also the main monoterpenoids of the essential oil from the stigma of C. sativus. Japanese scientists [28] isolated a new safranal glycoside, 4-O- [P-D-glucopyranosyl (1 ^ 3) -b-D-glucopyranoside] from the ethanol extract of saffron (fig. 5.).
CH3
CH3
H3C ^CH3
a - Pinene
1,8-Cineole
4-O-[p-D-glucopyranosyl(1-3)-p-D-glucopyranoside]
Figure 5 - Structural formula of monoterpenoids: a-pinene, 1,8-cineole, 4-O- [fi-D-glucopyranosyl (1^3) -fi-D-glucopyranoside]. Flavonoids
In plants of the Crocus L. genus, flavonoid derivatives are the second BAS in terms of percentage. The dominant flavonoids in native Crocus L. taxa are kaempferol and quercetin (fig.6.). Flavonoidsaremainlyrepresentedbyglycosidicderivativesofkaempferol [18, 20, 30-43].
0R5
OH O
OH O
Kaempferol and its derivatives
Quercetin
Figure 6 - The main flavonoids of the genus Crocus L .: kaempferol and quercetin.
O
C
OH
26 kaempferol derivatives were identified: Kaempferol (3,5,7,4 '- tetrahydroxyflavone) was isolated from the stigmas of C. sativus and the leaves of C. asturicus, C. speciosus, C. aureus, C. candidus, C. olivieri, C. stellaris; Kaempferol 3-0-sophoroside-7-0-P-D-glucopyranoside (from stigmas of C. sativus, C. carwrightianus); Kaempferol-3-O-P-D-sophoroside (from the aerial parts of C.aureus,C.corsicus, C.etruscus, C.korolkowi, C.laevigatus, C.minimus, C.versicolor, C.sativus, C.carwrightianus , C. chroleucus, C. carwrightianus); Kaempferol 7-O-P-D-sophoroside (from the leaves of C.aureus, from the stigma of C.sativus); Kaempferol 3,7,4 '- tri-o-P-glucopyranoside (from the stigma of C.sativus); Kempferoltetrahexoside (from stigmas of C.speciosus, C.cancellatus); Kaempferol-3-dihexoside (from C.sativus stigma); Astragalin (kaempferol-3-O-P-D-glucopyranoside) (from the stigmas of C. sativus, C. antalyensis, C.speciosus); Populin (kaempferol 7-O-P-D-glucopyranoside) (from stigmas of C.sativus, C.carwrightianus); Dihydrokempferol-7-O-P-D-glucopyranoside (from aerial parts of C.chrysanthusbiforus, C.sativus); Dihydrokempferol-3-O-hexoside (aerial part of C.sativus); Kaempferol 3-O-P-D-glucopyranosyl-(1^2)-O-P-D-glucopyranoside-7-O-P-D-glucopyranoside (C. sativus); Kaempferol 3-O-a-L-(2-O-P-D-glucopyranosyl)rhamnopyranoside-7-O-P-D-glucopyranoside (petals of C.sativus; C.speciosus; C.pulchellus, C.chrysanthus); Kaempferol 3-O-P-D-(2-O-P-D-glucopyranosyl)glucopyranoside (petals of C.speciosus, C.antalyensis); Kaempferol 3-O-P-D-(2-O-P-D-6-o-acetylglucosyl)glucopyranoside; Kaempferol 3-O-a-L - (2-O-P-D-glucopyranosyl) rhamnopranoside-7-O-P-D- (6-O-acetyl) glucopyranoside (aerial part of C.sativus); Kaempferol 3,4 '- di-o-P-D-glucopyranoside (petals of C.antalyensis, C.speciosus); Kaempferol 3,7-di-o-P-D-glucopyranoside (C.sativus); Kempferol 3-O-rutinoside-7-O-P-D-glucopyranoside (petal C.chrysanthus, C.fleischeri, C.etruscus, C.minimus); Kaempferol 3-O-a-L-(2-O-P-D-glucopyranosyl)rhamnopyranosides (petals of C.sativus, C.speciosus, C.antalyensis);Kaempferol 3-O-P-D-(2-O-a-L-rhamnopyranosyl)glucopyranoside (perianths of C.speciosus, C.antalyensis); Kaempferol 3-O-a-L-(2-O-P-D-glucopyranosyl)rhamnopyranosides-7-O-P-D-(6"-O-
malonyl)glucopyranoside (flowers C.spp., C.chrysanthus); Kaempferol 3-O-a-(2,3-di-O-P-D-glucopyranosyl)rhamnopyranoside (flowers C.spp., C.speciosus, C.antalyensis); Kaempferol 3-O-P-D-sophoroside-7-O-a-L-rhamnopyranoside (stigma of C.sativus); Kaempferol-8-C-P-D-glycopyranosyl-6,3-di-O-P-D-glucopyranoside (leaves of C.sativus); Kaempferol-8-C-P-D-glycopyranosyl-6-O-P-D-glucopyranoside (leaves of C.sativus).
The authors [20,31,39,40] isolated quercetin and 9 of its derivatives from native taxa of the genus Crocus L.: Quercetin (from the leaves of C. aureus, C. corsicus, C. etruscus, C. korolkowii, C. laevigatus, C.minimus, C.versicolor, C.baytopiorum, C.alatavicus, C.sativus); Quercetin 3-O-glucopyranoside; 4'-Methoxyquercetin; Dihydroquercetin 7-glucoside; Quercetin-3,7-di-o-P-D-glucopyranoside (stigmas and petals of C. sativus); Quercetin 3,4 '- di-o-P-D-glucopyranoside (flowers of C.spp., C.sativus, C.speciosus, C.antalyensis); Quercetin 3-O-P-D-sophoroside (flowers of C.spp. C.sativus, C.alatavicus, C.speciosus); Quercetin 3-O-a-L-rhamnopyranoside-7-O-P-D-glucopyranoside (flowers of C.spp., C.speciosus, C.pulchellus, C.chrysanthus, C.chrysanthusbiforus); Quercetin 3-O-P-D-glucopyranoside; Quercetin 3-O-P-D-rhamnopyranoside-7-O-P-D-glucopyranoside (flowers C.spp., C.sativus).
Derivatives of one-, two-, triatomic phenols and phenolcarboxylic acids
Among all crocus species, aromatic compounds have been deeply studied only in the stigma of saffron. Benzene derivatives in C.sativus stigmas were represented by compounds with substituents —OH, —COOH, —COOCH3, and other substituents; in some glycosides, hydroxy and carboxyl groups were additionally linked to condensed sugar fragments [6,29]. Among hydroxycinnamic acids, chlorogenic acid [41], caffeic acid, pyrogallol, gallic acid [41, 43], and methylparaben [29] were found in the stigma of C. sativus.
Hydroxybenzoic acids are precursors in the biosynthesis of flavonoids and are often found in Crocus L.C.Y. Li et al. [29] isolated and identified several hydroxycinnamic acids from the petals of C. sativus, namely n-coumaric acid, protocatechuic acid, the methyl ester of protocatechuic acid, methylparaben, vanillic acid, n-hydroxybenzoic acid, 3-hydroxy-4-methoxybenzoic acid, as well as
a new natural (3S), 4-dihydroxybutyric acid. Using the LC-DAD-MS (ESI +) and LC-ESI-IT / MS methods, synapic acid [44] and synapic acid derivatives [20] were identified in C. sativus petals. Caffeic acid and ferulic acid have been identified in the stigma of C. cancellatus [45]. Known compounds - polysubstituted benzene derivatives, 1-O- (4-hydroxybenzoyl) -P-D-glucopyranoside, p-hydroxybenzoic acid, benzoic acid - were isolated from the stigma of C. sativus [29].
HPLC analysis revealed n-coumaric acid and rosmarinic acid in a methanol extract of C. baytopiorum leaves [33].Several phenolic acids, including caffeic acid, cinnamic acid, ferulic acid, n-coumaric acid, gallic acid, n-hydroxybenzoic acid, gentisic acid, salicylic acid [42], synapic acid [38] and vanillic acid [29] were detected by LC-MS in C. sativus corms. There is no information on phenol carboxylic acids in other Crocus L. Vitamins
In the diversity of Crocus L. species, nitrogen-containing compounds have been studied only in the stigmas of C. sativus. These compounds are represented by vitamin B2 (riboflavin), vitamin Bi (thiamine), vitamin Вб (pyridoxal), vitamin C (ascorbic acid), vitamin A (retinol) [9] and vitamin E (a-tocopherol acetate) [43]. Thymine, uracil, adenosine, harman, nicotinamide and tribusterine were also found in the stigma of C. sativus [29]. Conclusions
In this review, we have compiled the available information on the results of research work on the main biologically active groups of the genus Crocus L. In the course of our research, we reviewed and studied 45 scientific articles on the main biologically active groups. That will contribute to further in-depth study of the chemical composition of the domestic species C. alatavicus L.
A review of scientific articles shows that Crocus L. includes many valuable, therapeutically useful plants, promising and interesting species with ever-increasing populations through species conservation and cultivar breeding. However, the results show that many species from the genus Crocus L., including C. alatavicus L., are still insufficiently studied. The study of the possibility of using modern technologies to create pharmaceutical and parapharmaceutical products seems promising.
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