Sesquiterpene Lactones and Flavonoids from Psephellus Pyrrhoblepharus with Antiproliferative Activity on Human Gynecological Cancer Cell Lines
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molecules Article Sesquiterpene Lactones and Flavonoids from Psephellus pyrrhoblepharus with Antiproliferative Activity on Human Gynecological Cancer Cell Lines Pelin Tastan 1, Zsuzsanna Hajdú 2, Norbert Kúsz 2 , István Zupkó 3,4 , Izabella Sinka 3, Bijen Kivcak 1 and Judit Hohmann 2,4,* 1 Department of Pharmacognosy, Faculty of Pharmacy, Ege University, 35040 Bornova/Izmir,˙ Turkey 2 Institute of Pharmacognosy, Interdisciplinary Excellence Centre, University of Szeged, 6720 Szeged, Hungary 3 Institute of Pharmacodynamics and Biopharmacy, Interdisciplinary Excellence Centre, University of Szeged, 6720 Szeged, Hungary 4 Interdisciplinary Centre of Natural Products, University of Szeged, 6720 Szeged, Hungary * Correspondence: [email protected]; Tel.: +36-62-545-558 Received: 30 July 2019; Accepted: 29 August 2019; Published: 30 August 2019 Abstract: Multistep chromatographic separations of the chloroform extract of the Turkish endemic plant Psephellus pyrrhoblepharus (Boiss.) Wagenitz (syn. Centaurea pyrrhoblephara Boiss.) resulted in the isolation of six guaianolid-type sesquiterpenes, chlorojanerin (1), 19-deoxychlorojanerin (2), 15-hydroxyjanerin (3), aguerin B (4), cynaropicrin (5), eleganin (6); three flavonoids, apigenin, 6-methoxyluteolin and jaceosidine; two glycosides, benzyl-1-O-β-d-glucoside and 3(Z)-hexenyl-1-O-β-d-glucoside; and the coumarin scopoletin. The structures were established by the interpretation of their ESI-MS and 1D and 2D NMR data including 1H-NMR, JMOD, 1H,1H-COSY, HSQC, HMBC, and NOESY experiments. All compounds were isolated for the first time from P. pyrrhoblepharus. Compounds 1–6, the isolated flavonoids and scopoletin were evaluated for their antiproliferative activities on human gynecological cancer cell lines (SiHa, HeLa, and MDA-MB-231 cells) using the MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay. Chlorojanerin (1), 19-deoxychlorojanerin (2), aguerin B (4), cynaropicrin (5), eleganin (6) were shown to have noteworthy effects on all of the tested cell lines, while apigenin, jaceosidine, and 6-methoxyluteolin were moderately active on HeLa cells. The highest activities were demonstrated by the chlorine-containing derivatives chlorojanerin (1) and 19-deoxychlorojanerin (2) with IC50 values of 2.21 and 2.88 µM, respectively, against the triple negative breast cancer model MDA-MB-231 cells. Keywords: Psephellus pyrrhoblepharus; Asteraceae; sesquiterpene lactones; chlorojanerin; 19-deoxychlorojanerin; gynecological cancer cells; antiproliferative activity 1. Introduction The genus Psephellus Cass., belonging to the Asteraceae family, tribe Cynareae, includes approximately 80 species. In Turkey, this genus is represented by 32 species. Some of these are new members of the genus as some sections of the genus Centaurea have been transferred into the genus Psephellus in recent years. Psephellus pyrrhoblepharus (Boiss.) Wagenitz (syn. Centaurea pyrrhoblephara Boiss.) is an endemic plant of Turkey, and grows in the Middle and East Black Sea Region, Upper Red River Area, and Upper Fırat Area of the country [1–3]. Psephellus species such as P. appendicigerus, P. erzincani, and P. karduchorum have been used in traditional medicine as wound healing agents and in the treatment of abscesses [4–7]. Basal leaves of P. karduchorum have been used as foodstuff and eaten in fresh form [6]. Molecules 2019, 24, 3165; doi:10.3390/molecules24173165 www.mdpi.com/journal/molecules Molecules 2019, 24, 3165 2 of 9 Molecules 2019, 24, x 2 of 9 A systematicsystematic survey of plants used against cancer by J.J. HartwellHartwell reportedreported thatthat somesome speciesspecies ofof thethe tribetribe CynareaeCynareae (Carduu(Carduus acanthoidesacanthoides, Cynara scolymus, Cirsium acarna. C. C. ferox, ferox, Arctium lappa ,, A. A. minus, Centaurea acaulis, acaulis, C. C. calcitrapa calcitrapa, C., C. centaurium centaurium, C., C.cyanus cyanus, C., monanthaC. monantha, C. ,nigraC. nigra, C. salonitana, C. salonitana, and, andC. scabiosaC. scabiosa) were) were applied applied against against cold cold tumors, tumors, carcinomas, carcinomas, tumors tumors of of the the eye eye and and throat, uterineuterine fibroids,fibroids, andand indurationinduration of of spleen spleen and and liver liver in in the the form form of of decoctions, decoctions, plasters, plasters, liniments, liniments, and and pastes pastes [8]. Ethnopharmacological[8]. Ethnopharmacological studies studies have have revealed revealed that thatCentaurea Centaurea ornata ornataand andC. C. repens repenshave have beenbeen usedused inin the treatment treatment of of cancer-related cancer-related diseases diseases [9,10]. [9,10 A]. wide A wide range range of pharmacological of pharmacological studies studies have havebeen beencarried carried out on out Centaurea on Centaurea, Arctium, Arctium, Cirsium, Cirsium, and, and PsephellusPsephellus speciesspecies to to examine examine their antitumorantitumor activities, and significantsignificant cell proliferation inhibitory properties have been demonstrated in many cases [[11–13].11–13]. Bioactivity-guided phytochemical investigations onon the active extracts revealed that,that, in general, thethe presencepresence of of sesquiterpene sesquiterpene lactones, lactones, flavonoids, flavonoids, and and lignans lignans as compoundsas compounds responsible responsible for thefor the antiproliferative antiproliferative effects effects [14– [14–16].16]. The genus genus PsephellusPsephellus waswas previously previously reported reported to be to a berich a source rich source of sesquiterpenes of sesquiterpenes and lignans and lignans[17,18]; [17moreover,18]; moreover P. pyrrhoblepharusP. pyrrhoblepharus was waspublished published to toaccumulate accumulate essential essential oil, oil, containingcontaining monoterpene andand sesquiterpene sesquiterpene hydrocarbons, hydrocarbons, and and carbonylic carbonylic compounds compounds in substantial in substantial quantities quantities [19]. [19]. The present study aimed at the phytochemical profiling of the Turkish endemic plant P. pyrrhoblepharusThe present, withstudy special aimed focus at onthe the phytochemica non-volatilel compounds profiling of with the antitumor Turkish potency.endemic Multistep plant P. chromatographicpyrrhoblepharus, with separation specialof focus the chloroformon the non-volatile extract of co thempounds aerial plant with parts antitumor was carried potency. out, Multistep resulting inchromatographic the isolation of separation six guaianolid-type of the chloroform sesquiterpenes, extract chlorojanerin of the aerial (1plant), 19-deoxychlorojanerin parts was carried out, (2), 15-hydroxyjanerinresulting in the (3isolation), aguerin of B (six4), cynaropicringuaianolid-type (5), eleganinsesquiterpenes, (6) (Figure chlorojanerin1); three flavonoids, (1), 19- apigenin,deoxychlorojanerin 6-methoxyluteolin (2), 15-hydroxyjanerin and jaceosidine; (3), aguerin two B glycosides, (4), cynaropicrin benzyl-1- (5), eleganinO-β-d-glucoside (6) (Figure and 1); 3(threeZ)-hexenyl-1- flavonoids,O-β apigenin,-d-glucoside; 6-methoxyluteolin and the coumarin and scopoletin. jaceosidine; Compounds two glycosides,1–6, the isolated benzyl-1- flavonoidsO-β-D- andglucoside scopoletin and 3( wereZ)-hexenyl-1- evaluatedO- forβ-D their-glucoside; antiproliferative and the coumar activitiesin scopoletin. using the Compounds MTT assay. Human1–6, the gynecologicalisolated flavonoids malignant and scopoletin cell lines were isolated evaluated from cervicalfor their (SiHa,antiproliferative HeLa) and activities female using breast the cancers MTT (MDA-MB-231)assay. Human gynecological were utilized malignant with regard cell to lines previous isolated investigations from cervical where (SiHa, they HeLa) were foundand female to be sensitivebreast cancers against (MDA-MB-231) metabolites of were Cynareae utilized plants with regard [11,20– 23to ].previous In the presentinvestigations assay, chlorojanerinwhere they were (1), 19-deoxychlorojanerinfound to be sensitive (against2), aguerin metabolites B (4), cynaropicrin of Cynareae (5 ),plants and eleganin[11,20–23]. (6 )In were the shownpresent to assay, have noteworthychlorojanerin e ff(ects1), 19-deoxychlorojanerin on all of the tested cell (2 lines,), aguerin while B apigenin, (4), cynaropicrin jaceosidine, (5), andand 6-methoxyluteolin eleganin (6) were wereshown moderately to have noteworthy active on HeLa effects cells. on all of the tested cell lines, while apigenin, jaceosidine, and 6- methoxyluteolin were moderately active on HeLa cells. R1 R2 R 1 Cl OH 4 H 6 2 Cl H 5 OH 3 OH OH Figure 1. Structure of the isolated sesquiterpene lactones 1–6. Figure 1. Structure of the isolated sesquiterpene lactones 1–6. 2. Results and Discussion 2. ResultsAntiproliferative and Discussion testing of species belonging to tribe Cynareae [11] and previous screening resultsAntiproliferative on P. pyrrhoblepharus testing[12 of] initiated species thebelonging present work,to tribe aiming Cynareae at the [11] identification and previous of compounds screening ofresultsP. pyrrhoblepharus on P. pyrrhoblepharuswith tumor [12] initiated cell growth the present inhibitory work, e ffaimingect. The at the aerial identification parts of the of compounds plant were extractedof P. pyrrhoblepharus with MeOH with at room tumor temperature cell growth and, inhibitory after concentration, effect. The aerial the extractparts of was the partitionedplant were extracted with MeOH at room temperature and, after concentration, the extract was partitioned