molecules Article Constituents of Coreopsis lanceolata Flower and Their Dipeptidyl Peptidase IV Inhibitory Effects Bo-Ram Kim 1,2, Sunil Babu Paudel 3, Joo-Won Nam 3 , Chang Hyun Jin 1 , Ik-Soo Lee 2,* and Ah-Reum Han 1,* 1 Advanced Radiation Technology Institute, Korea Atomic Energy Research Institute, Jeongeup-si, Jeollabuk-do 56212, Korea; [email protected] (B.-R.K.); [email protected] (C.H.J.) 2 College of Pharmacy, Chonnam National University, Gwangju 61186, Korea 3 College of Pharmacy, Yeungnam University, Gyeongsan-si, Gyeongsangbukdo 38541, Korea; [email protected] (S.B.P.); [email protected] (J.-W.N.) * Correspondence: [email protected] (I.-S.L.); [email protected] (A.-R.H.); Tel.: +82-62-530-2932 (I.-S.L.); +82-63-570-3167 (A.-R.H.) Academic Editor: Cristina Forzato Received: 7 September 2020; Accepted: 22 September 2020; Published: 23 September 2020 Abstract: A new polyacetylene glycoside, (5R)-6E-tetradecene-8,10,12-triyne-1-ol-5-O-β-glucoside (1), was isolated from the flower of Coreopsis lanceolata (Compositae), together with two known compounds, bidenoside C (10) and (3S,4S)-5E-trideca-1,5-dien-7,9,11-triyne-3,4-diol-4-O-β-glucopyranoside (11), which were found in Coreopsis species for the first time. The other known compounds, lanceoletin (2), 3,20-dihydroxy-4-30-dimethoxychalcone-40-glucoside (3), 4-methoxylanceoletin (4), lanceolin (5), leptosidin (6), (2R)-8-methoxybutin (7), luteolin (8) and quercetin (9), were isolated in this study and reported previously from this plant. The structure of 1 was elucidated by analyzing one-dimensional and two-dimensional nuclear magnetic resonance and high resolution-electrospray ionization-mass spectrometry data. All compounds were tested for their dipeptidyl peptidase IV (DPP-IV) inhibitory activity and compounds 2-4, 6 and 7 inhibited DPP-IV activity in a concentration-dependent manner, with IC50 values from 9.6 to 64.9 µM. These results suggest that C. lanceolata flower and its active constituents show potential as therapeutic agents for diseases associated with type 2 diabetes mellitus. Keywords: Coreopsis lanceolata; polyacetylene glycoside; flavonoid; dipeptidyl peptidase IV; type 2 diabetes mellitus 1. Introduction Coreopsis is a perennial plant belonging to the Compositae family [1]. It was planted for decoration on the roadsides in North America, Asia and Oceania regions [2–4]. Typically, C. lanceolata, C. tinctoria and C. drummondii are generally Coreopsis plants distributed all around Korea [5]. Among them, C. lanceolate are ornamental plants commonly found in Korea in spring and summer. The shape of the yellow petals are split and jagged, and have a diameter 4-6 cm, which is larger than other species [5,6]. In the previous phytochemical studies on C. lanceolata, phenolics, flavonoids (aurones, chalcones, flavaons, flanavol) and acetylene compounds have been isolated from this plant [5–12]. The C. lanceolata flower has been reported to have diverse biological activities, such as anti-cancer [5], anti-inflammatory [6], antioxidant [6,8,10], anti-allerginc [9,10], antileukemic [11] and nematicidal [12] effects. Because of the good efficacy of C. lanceolata, it has been traditionally used as an ingredient in herbal medicine, such as folk remedies to control fever in China and East Asia [8]. This plant has been studied for a few chemical constituents and its pharmacological activity, but a literature review revealed that there is no anti-diabetes. Molecules 2020, 25, 4370; doi:10.3390/molecules25194370 www.mdpi.com/journal/molecules Molecules 2019, 24, x FOR PEER REVIEW 2 of 9 Asia [8]. This plant has been studied for a few chemical constituents and its pharmacological activity, Molecules 2020, 25, 4370 2 of 9 but a literature review revealed that there is no anti-diabetes. Type 2 diabetes mellitus is a chronic metabolic disorder, characterized by hyperglycemia caused by theType dysregulation 2 diabetes mellitus of blood is a chronicglucose metabolic homeostasi disorder,s, increased characterized liver glucose by hyperglycemia production, caused insulin by thesecretion, dysregulation insulin ofresistance blood glucose and β homeostasis,-cell dysfunction increased [13]. liver According glucose to production, the eighth insulin edition secretion, of the insulinInternational resistance Diabetes and βFederation-cell dysfunction (IDF) Diabetes [13]. According Atlas, there to thewere eighth 425 million edition people of the with International diabetes Diabetesworldwide Federation in 2017, and (IDF) most Diabetes of them Atlas, have there type were 2 diabetes 425 million mellitus. people This with number diabetes of worldwidepatients is inincreasing 2017, and every most year, of themand is have expected type to 2 diabetesincrease to mellitus. about 700 This million number by 2045 of patients [14]. The is five increasing factors everythat affect year, diabetes and is expected treatment to are increase dipeptidyl to about peptidase- 700 million IV (DPP-IV), by 2045 α [14-glucosidase]. The five factorsinhibitors, that aldose affect diabetesreductase treatment (ALR) inhibitors, are dipeptidyl phatase peptidase- 1B (PTP1B) IV (DPP-IV), inhibitorsα-glucosidase and peroxisome inhibitors, proliferator-activated aldose reductase (ALR)receptor- inhibitors,γ (PPAR- phataseγ) [15]. 1BRecently, (PTP1B) incretin-based inhibitors and therapie peroxisomes for the proliferator-activated treatment of type receptor-2 diabetesγ (PPAR-mellitusγ )[have15]. begun Recently, to appear, incretin-based one of which therapies is DPP-IV for the inhibitors treatment [16]. of type The 2incretin diabetes system mellitus includes have begunglucagon-like to appear, peptide-1 one of which(GLP-1) is an DPP-IVd glucose-dependent inhibitors [16]. Theinsulinotropic incretin system polypeptide includes (GIP), glucagon-like which in peptide-1response to (GLP-1) high blood and glucose-dependentsugar levels induce insulinotropicthe release of insulin polypeptide from the (GIP), pancreatic which in β-cell response [13,16]. to highDPP- bloodIV is involved sugar levels in the induce quick degradation the release of and insulin inactivation from the of pancreaticGLP-1 and βGIP-cell in [the13, 16incretin]. DPP- system IV is involved[17]. As ina theresult, quick DPP-IV degradation inhibi andtion inactivationenhances the of GLP-1glucose-produc and GIP ining the effect incretin of systemGLP-1, [ 17thereby]. As a result,improving DPP-IV glucose inhibition tolerance enhances in diabetic the glucose-producing patients [18]. As eff ectDPP-IV of GLP-1, inhibitors, thereby synthetic improving chemical glucose tolerancecompounds in diabeticor natural patients product-de [18].rived As DPP-IV compounds inhibitors, recently synthetic represent chemical promising compounds drug candidates or natural product-derived[16,19–22]. compounds recently represent promising drug candidates [16,19–22]. During thethe screeningscreening procedureprocedure to to find find new new candidates candidates from from natural natural sources sources for for the the treatment treatment of typeof type 2 diabetes 2 diabetes mellitus, mellitus, the ethyl the acetateethyl acetate fraction fraction of the C.of lanceolata the C. lanceolataflower showed flower potent showed inhibitory potent activityinhibitory in aactivity DPP-IV ininhibitor a DPP-IV screening inhibitor assay,screening with assay, 100% inhibitionwith 100% at inhibition a concentration at a concentration of 100 µg/mL. of Therefore,100 μg/mL. this Therefore, active fraction this active was subjectedfraction was to detailed subjected phytochemical to detailed phytochemical investigation, andinvestigation, 11 compounds and were11 compounds isolated, includingwere isolated, a new including compound a new1 (Figure compound1). In 1 this (Figure study, 1). we In describethis study, the we isolation describe and the structuralisolation and elucidation structural of elucidation1 and the biological of 1 and the results biological of compounds results of1 –compounds11. 1–11. HO 1 OH 3 OH OR2 5 OCH3 91113 5' O 7 14 R1O OH HO 1' O R1 R2 HO 2 H H 3' OH 3 Glc CH3 4 H CH O 3 1 5 Glc H OH OH OH OH OH OCH3 OCH3 OH HO O HO O HO O R O OH O O 67 8 R = H 9 R = OH OH OH OH O O HO O HO O HO HO OH OH 11 10 Figure 1. Chemical structures of compounds isolated from the ethyl acetate-soluble fraction of Figure 1. Chemical structures of compounds isolated from the ethyl acetate-soluble fraction of Coreopsis lanceolata. Coreopsis lanceolata. Molecules 2020, 25, 4370 3 of 9 2. Results and Discussion 2.1. Structure Elucidation of Compound 1 Compound 1 was obtained as a brown solid, with a molecular ion peak at m/z 401.1575 [M+Na]+ in the high resolution electrospray ionization mass spectrum, corresponding to an elemental formula of C20H26O7Na. Its specific UV spectrum showed maximum absorptions at 254, 260, 274, 290, 310 and 330 nm, predicted to be ene-triyne chromophore [23,24]. The 1H NMR and 13C NMR spectra of 1 (Table1) exhibited signals for a trans-olefin group at δH 6.39 (1H, dd, J = 16.0, 6.0 Hz, H-6)/δC 151.4 (C-6) and δH 6.06 (1H, dd, J = 16.0, 1.5 Hz, H-7)/δC 108.6 (C-7), three methylene groups at δH 1.45 (2H, dd, J = 13.0, 6.8 Hz, H-4)/δC 35.1 (C-4), δH 1.35 (2H, dd, J = 14.0, 6.3 Hz, H-2)/δC 32.8 (C-2), and δH 1.28 (2H, dd, J = 14.0, 6.8 Hz, H-3)/δC 21.7 (C-3), an oxygenated methylene group at δH 3.33 (2H, dd, J = 12.3, 6.3 Hz, H-1)/δC 61.1 (C-1), and an oxygenated methine group at δH 4.26 (1H, ddd, J = 13.0, 6.0, 1 1 1.5 Hz, H-5)/δC 76.5 (C-5), representing a 6-heptene-1,5-diol group, which was supported by the H- H COSY correlations of H-1/H-2, H-4/H-3, H-5 and H-6/H-5, H-7, and the 1H-13C HMBC correlations of H-1/C-3, H-2/C-4 and H-4/C-6 (Figure2).