In Search of High-Yielding and Single-Compound-Yielding Plants: New Sources of Pharmaceutically Important Saponins from the Primulaceae Family
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biomolecules Communication In Search of High-Yielding and Single-Compound-Yielding Plants: New Sources of Pharmaceutically Important Saponins from the Primulaceae Family Maciej Włodarczyk 1,* , Paweł Pasikowski 2 , Kinga Osiewała 3, Aleksandra Frankiewicz 3, Andrzej Dry´s 4 and Michał Gle ´nsk 1 1 Department of Pharmacognosy and Herbal Drugs, Wroclaw Medical University, Borowska 211 A, 50-556 Wrocław, Poland 2 Mass Spectrometry Laboratory, Polish Center for Technology Development, Stabłowicka 147, 54-066 Wrocław, Poland 3 Students Scientific Cooperation on Pharmacognosy, Wroclaw Medical University, Borowska 211 A, 50-556 Wrocław, Poland 4 Department of Physical Chemistry and Biophysics, Wroclaw Medical University, Borowska 211 A, 50-556 Wrocław, Poland * Correspondence: [email protected]; Tel.: +48-71-78-40-223 Received: 30 December 2019; Accepted: 25 February 2020; Published: 29 February 2020 Abstract: So far, only a few primrose species have been analyzed regarding their saponin composition and content. Moreover, the roots of only two of them are defined by the European Union (EU) Pharmacopoeia monograph and commercially utilized by the pharmaceutical industry. Thus, this study intended to find some new sources of main triterpene saponins from Primulae radix, namely primulasaponins I and II together with the closely related sakurasosaponin. Using isolated standards, UHPLC-ESI-HRMS served to assess over 155 Primulaceae members qualitatively and quantitatively. Nine examples of plants accumulating over 5% of primulasaponin I in their roots were found. Among them, in one case, it was found as the almost sole secondary metabolite with the concentration of 15–20% (Primula grandis L.). A reasonable content of primulasaponin II was found to be typical for Primula vulgaris Huds. and P. megaseifolia Boiss. & Bal. The sakurasosaponin level was found in seven species to exceed 5%. The finding of new, single and rich sources of the abovementioned biomolecules among species that were never analyzed phytochemically is important for future research and economic benefit. The chemotaxonomic significance of the occurrence of these three saponins in Primulaceae is discussed. Keywords: primrose root; Primulae radix; primulasaponin; sakurasosaponin; 13,28-epoxyoleanane saponins; Primula; Dodecatheon; Auganthus; biodiversity 1. Introduction Primulaceae Batsch. is a large family covering many perennial and herbaceous plants. Members of this family are widely distributed in the Northern Hemisphere, particularly in the meadows and rocky valleys of the Alps, Apennines, Pyrenees, Himalayas and North American Cordillera but also in dry regions of Kazakhstan, Iran and Turkey. Today, some of the primroses are known exclusively from herbaria specimens while several exist as endangered endemics. Since the time of Charles Darwin and A. K. Bulley, primulaceous plants have been a point of interest for botanists and alpine enthusiasts as well as for the gardeners who help to maintain threatened species and discover new ones [1–5]. Biomolecules 2020, 10, 376; doi:10.3390/biom10030376 www.mdpi.com/journal/biomolecules Biomolecules 2020, 10, 376 2 of 19 Biomolecules 2020, 10, 376 2 of 19 Thanks to them, over 200 Primulaceae-related species remain in the plant trade apart from decorative varieties.decorative Due varieties. to these Due and to thethese fact and that the most fact Primulathat mostspecies Primula possess species partly possess recognized partly recognized chemical compositionchemical composition [6–8], they [6–8], provide they an provide interesting an interesting field for phytochemical field for phytochemical research. research. AccordingAccording toto thethe EuropeanEuropean Pharmacopoeia,Pharmacopoeia, thethe oofficialfficial primroseprimrose rootroot ((PrimulaePrimulae radixradix)) maymay bebe obtainedobtained fromfrom PrimulaPrimula verisveris L.L. oror P.P. elatiorelatior(L.) (L.) Hill.Hill. andand isis wellwell knownknown asas anan eefficientfficient secretolyticsecretolytic andand expectorantexpectorant drug [9–11]. [9–11]. It It was was widely widely introduced introduced to to European European academic academic medicine medicine as as a surrogate a surrogate of ofthe the American American Senega Senega root root during during WWI. WWI. ItIt is is stil stilll popular popular as as a a component of simple andand complexcomplex pharmaceuticalpharmaceutical formulationsformulations [ 9[9].]. It It has has been been proven proven that that the the main main saponins saponins and and active active components components of theof the offi cialofficial drug drug are primulasaponins: are primulasaponins: I (=primulasaponin I (=primulasaponin A, PSI) andA, PSI II (PSII) and), sometimesII (PSII), mentionedsometimes asmentioned primula acidsas primula due to acids the acidic due to character the acidic of character their glycone of their part glycone [9,12]. part [9,12]. PrimulaPrimula sieboldii E.E. Morren Morren is is common common in in the the Far Far East East region region (Japan, (Japan, Amurland, Amurland, Manchuria Manchuria and andKorea). Korea). The phytochemical The phytochemical value valueof this of plant this is plant connected is connected with the with triterpenoid the triterpenoid biosynthesis biosynthesis yielding yieldingalmost a almostsingle saponin, a single saponin, sakurasosaponin sakurasosaponin (SSI) [13], (SSI a close)[13], structural a close structural relative relativeof PSI and of PSI PSIIand (FigurePSII (Figure1). However,1). However, ethnomedicinal ethnomedicinal applications applications of P. sieboldii of P.sieboldii to treat tocough treat and cough bronchitis and bronchitis are not arewidely not widelyknown known[14]. [14]. FigureFigure 1.1. Structures of primulasaponins I,I, IIII andand sakurasosaponinsakurasosaponin ((PSIPSI,, PSIIPSII andand SSISSI,, respectively).respectively). BesidesBesides thethe well-known well-known activities activiti ofes saponins of saponins such assuch expectorant as expe orctorant vasoprotectant, or vasoprotectant, an increasing an numberincreasing of researchersnumber of are researchers interested inare the interested evaluation in of the their evaluation promising positiveof their interactionspromising with,positive for example,interactions chemotherapeutics with, for example, [15 –chemotherapeutic17]. Their usage ins pharmacy,[15–17]. Their cosmetology usage in andpharmacy, the food cosmetology industry as naturaland the andfood e ffiindustrycient emulsifiers as natural or and foaming efficient agents emulsifiers is also desirableor foaming [18 agents–20]. is also desirable [18–20]. TheThe glycosidesglycosides andand glycoside-estersglycoside-esters ofof oleananeoleanane typetype areare amongamong thethe mostmost widelywidely distributeddistributed groupsgroups ofof saponins.saponins. Despite theirtheir widewide occurrence,occurrence, primulasaponinsprimulasaponins I,I, IIII andand sakurasosaponinsakurasosaponin werewere previouslypreviously notnot the the object object of anyof any clinical clinical study. study. However, However, they belong they tobelong 13,28-epoxyoleanane to 13,28-epoxyoleanane saponins thatsaponins are of that particular are of particular medical interest. medical Epoxidized interest. Epoxidized oleanane derivativesoleanane derivatives were found were to befound active to asbe enzymeactive as inhibitors enzyme [inhibitors21], anti-mycobacterial [21], anti-mycobac and anti-protozoanterial and anti-protozoan compounds compounds [22,23] and [22,23] selectively and cytotoxicselectively molecules cytotoxic [ 24molecules,25]. It was [24,25]. demonstrated It was demonstrated that the partially that deglycosylated the partially deglycosylated metabolites of long-chainmetabolites 13,28-epoxyoleanane of long-chain 13,28-epoxyoleanane saponins also display saponins antitumor also display activities antitumor at a level activities similar at to a theirlevel prodrugsimilar to digested their prodrug by intestinal digested flora by [ 26intestinal]. flora [26]. PrimulasaponinsPrimulasaponins I andand II,II, asas wellwell asas sakurasosaponin,sakurasosaponin, maymay serveserve asas aa readilyreadily availableavailable modelmodel compoundcompound forfor researchresearch (including(including structuralstructural modifications)modifications) in the mentionedmentioned areas of medicine. ParticularlyParticularly interestinginteresting areare aldehydesaldehydes suchsuch asas ardisiacrispinardisiacrispin BB thatthat can display, forfor example,example, cytotoxiccytotoxic eeffectsffects inin multi-factorial multi-factorial drug-resistant drug-resistant cancer cancer cells cells [25 [25,27].,27]. The The researchers researchers know know that that the the problem problem of the of unavailabilitythe unavailability of large of large amounts amounts of a single of a specializedsingle specialized metabolite metabolite is usually is ausually hurdle a in hurdle semi-synthesis. in semi- synthesis. The number of unwanted by-products increases dramatically with a decrease in the purity of the substrate. Herewith, the use of single-metabolite yielding plants could be a strategy to work around this problem. Biomolecules 2020, 10, 376 3 of 19 The number of unwanted by-products increases dramatically with a decrease in the purity of the substrate. Herewith, the use of single-metabolite yielding plants could be a strategy to work around this problem. High-yielding sources of specialized natural compounds are not very frequent. The primary phytochemical education teaches that such compounds are