molecules Article Constituents of Huberantha jenkinsii and Their Biological Activities Htoo Tint San 1,2 , Tanawat Chaowasku 3,4, Wanwimon Mekboonsonglarp 5, Ratchanee Rodsiri 6 , Boonchoo Sritularak 1,7, Hathairat Buraphaka 8, Waraporn Putalun 8 and Kittisak Likhitwitayawuid 1,* 1 Department of Pharmacognosy and Pharmaceutical Botany, Faculty of Pharmaceutical Sciences, Chulalongkorn University, Bangkok 10330, Thailand; [email protected] (H.T.S.); [email protected] (B.S.) 2 Department of Pharmacognosy, University of Pharmacy, Yangon 11031, Myanmar 3 Department of Biology, Faculty of Science, Chiang Mai University, 239 Huay Kaew Rd., Chiang Mai 50200, Thailand; [email protected] 4 Center of Excellence in Bioresources for Agriculture, Industry, and Medicine, Chiang Mai University, Chiang Mai 50200, Thailand 5 Scientific and Technological Research Equipment Center, Chulalongkorn University, Bangkok 10330, Thailand; [email protected] 6 Department of Pharmacology and Toxicology, Faculty of Pharmaceutical Sciences, Chulalongkorn University, Bangkok 10330, Thailand; [email protected] 7 Natural Products for Ageing and Chronic Diseases Research Unit, Faculty of Pharmaceutical Sciences, Chulalongkorn University, Bangkok 10330, Thailand 8 Faculty of Pharmaceutical Sciences, Khon Kaen University, Khon Kaen 40002, Thailand; [email protected] (H.B.); [email protected] (W.P.) * Correspondence: [email protected] Received: 4 July 2020; Accepted: 27 July 2020; Published: 2 August 2020 Abstract: The phytochemical investigation of Huberantha jenkinsii resulted in the isolation of two new and five known compounds. The new compounds were characterized as undescribed 8-oxoprotoberberine alkaloids and named huberanthines A and B, whereas the known compounds were identified as allantoin, oxylopinine, N-trans-feruloyl tyramine, N-trans-p-coumaroyl tyramine, and mangiferin. The structure determination was accomplished by spectroscopic methods. To evaluate therapeutic potential in diabetes and Parkinson’s disease, the isolates were subjected to assays for their α-glucosidase inhibitory activity, cellular glucose uptake stimulatory activity, and protective activity against neurotoxicity induced by 6-hydroxydopamine (6-OHDA). The results suggested that mangiferin was the most promising lead compound, demonstrating significant activity in all the test systems. Keywords: Huberantha jenkinsii; glucose uptake; α-glucosidase; Parkinsonism; diabetes 1. Introduction In recent years, non-communicable diseases (NCDs), such as neurodegenerative disorders, cardiovascular diseases, and metabolic syndromes, have become a major global health issue. In several parts of the world, NCDs have caused serious socioeconomic impacts, through increasing impoverishment and slowing down social and economic development [1]. Plants are a natural source of chemopreventive agents for NCDs. A large number of plant-derived products have been shown to possess protective activity against diabetes [2] and neurodegeneration [3]. Currently, our research Molecules 2020, 25, 3533; doi:10.3390/molecules25153533 www.mdpi.com/journal/molecules Molecules 2020, 25, x FOR PEER REVIEW 2 of 11 Molecules 2020, 25, 3533 2 of 11 has been focused on studying plants with potential preventive activity against NCDs, including hasneurodegenerative been focused on disorders studying and plants diabetes with [4–6]. potential preventive activity against NCDs, including neurodegenerativeThe genus Huberantha disorders Chaowasku, and diabetes a [4 –recently6]. established genus in the family Annonaceae, containsThe genus27 speciesHuberantha transferredChaowasku, from the a recently genus establishedPolyalthia [7,8]. genus Huberantha in the family jenkinsii Annonaceae, (Hook. contains f. and 27Thomson) species transferredChaowasku from is called the genus “DangPolyalthia nga khao”[7,8 in]. HuberanthaThai or “Taung-Kabut” jenkinsii (Hook. in Myanmar. f. and Thomson) It was Chaowaskuformerly known is called as “DangGuatteria nga jenkinsii khao” in Hooker Thai or and “Taung-Kabut” Thomson or in Myanmar.Polyalthia jenkinsii It was formerly (Hook. knownf. and asThomson)Guatteria Hooker jenkinsii andHooker Thomson and Thomson[7,8]. The plant or Polyalthia has no records jenkinsii of(Hook. traditional f. and medicinal Thomson) uses. Hooker A recent and Thomsonreport on [Polyalthia7,8]. The plantcinnamomea has no recordsdescribes of the traditional isolation medicinal of alkaloids uses. with A recent α-glucosidase report on inhibitoryPolyalthia cinnamomeaactivity [9], describessuggesting the the isolation possible of presence alkaloids of with compoundsα-glucosidase with inhibitory antidiabetic activity potential [9], suggesting in plants that the possibleare in or presencerelated to of the compounds genus Polyalthia with antidiabetic. In this study, potential the chemical in plants components that are in of or Huberamtha related to the jenkinsii genus Polyalthiawere isolated. In this and study, evaluated the chemical for biological components activities of Huberamtha related to jenkinsii NCDs,were including isolated neuroprotective and evaluated foractivity biological against activities Parkinson’s related disease, to NCDs, α-glucosidase including neuroprotective inhibitory potential, activity and against cellular Parkinson’s glucose disease,uptake αstimulatory-glucosidase properties. inhibitory potential, and cellular glucose uptake stimulatory properties. 2. Results and Discussion 2.1. Structural Characterization From the the stem stem of of HuberanthaHuberantha jenkinsii jenkinsii, two, two new new alkaloids alkaloids (1 and (1 2and), together2), together with five with known five knowncompounds compounds (3–7), were (3– 7isolated), were and isolated structurally and structurally characterized characterized (Figure 1). (FigureThe known1). The compounds known compoundswere identified were as identified allantoin as (3 allantoin) [10], oxylopinine (3)[10], oxylopinine (4) [11], N- (trans4)[11-feruloyl], N-trans tyramine-feruloyl tyramine(5) [12], N (5-trans)[12],- Np-coumaroyl-trans-p-coumaroyl tyramine tyramine (6) [12], and (6)[ mangiferin12], and mangiferin (7) [13] through (7)[13 the] throughcomparison the of comparison their spectroscopic of their spectroscopicdata with the literature data with values. the literature values. Figure 1. Chemical structures of compounds 1–7 isolated from Huberantha jenkinsii.. Compound 11 was obtained as a brownish white powder. The molecular formula was determined to bebe CC1919H17NONO55 fromfrom the the deprotonated molecularmolecular ionion [M-H][M-H]−− atat mm/z/z 338.1029 338.1029 (calcd. (calcd. for for C C1919HH1616NONO55 338.1028) in the the HR-ESI HR-ESI mass mass spec spectrum.trum. The The UV UV spectrum spectrum displayed displayed maximal maximal absorptions absorptions at 225, at 335, 225, 335,and and370 370nm, nm, characteristic characteristic of ofthe the 8-oxoprotoberber 8-oxoprotoberberineine skeleton skeleton [14]. [14 ].The The presence presence of of the lactamlactam 1 13 functionality waswas supportedsupported byby thethe IRIR bandband atat 16671667 cmcm−−1 andand the the 13CC NMR NMR signal signal at at δδ 159.9159.9 (Table (Table 11).). 1 The 1H NMR spectrum of 1 (Table1 1)) showed showedtwo two 2H 2H triplets triplets at at δδ 2.912.91 (2H,(2H, t,t, JJ == 6.0 Hz,Hz, HH22-5) and 4.20 (2H,(2H, t,t, JJ == 6.0 Hz,Hz, HH22-6), assignable to the methylene protons of thethe BB ringring [[15].15]. This waswas 13 supported byby theirtheir correlation correlation peak peak in in the the COSY COSY spectrum spectrum (Figure (Figure2). The 2). TheC NMR13C NMR resonances resonances for four for oxygenatedfour oxygenated quaternary quaternary carbons carbons at δ 146.7, at δ 147.0, 146.7, 149.4, 147.0, and 149.4, 149.5, and together 149.5,with together the HSQC with correlationthe HSQC peakscorrelation for five peaks aromatic for five methine aromatic carbons methine at carbonsδH 7.33 at (1H, δH s)7.33/δC (1H,111.8, s)/δδHC 111.8,7.33 (1H, δH 7.33 d, J (1H,= 8.4 d, Hz) J = /8.4δC 123.7,Hz)/δCδ H123.7,7.27 δ (1H,H 7.27 d, (1H,J = 8.4 d, Hz)J = 8.4/δC Hz)/122.6,δC δ122.6,H 6.91 δ (1H,H 6.91 s) (1H,/δC 101.5, s)/δC 101.5, and δH and6.90 δH (1H, 6.90 s) (1H,/δC 111.4,s)/δC 111.4, were suggestivewere suggestive of 2,3,9,10-tetraoxygenation of 2,3,9,10-tetraoxygenation [14]. The[14]. fourThe oxygen-containingfour oxygen-containing substituents substituents included included two two phenolic and two methoxy groups, as indicated from the HSQC cross peaks at δH 3.89 (3H, s)/δC Molecules 2020, 25, 3533 3 of 11 Molecules 2020, 25, x FOR PEER REVIEW 3 of 11 δ δ phenolic56.3 and δ andH 3.91 two (3H, methoxy s)/δC 62.2. groups, The as first indicated methoxy from group the HSQC(δ 3.89) cross should peaks be placed at H 3.89 at C-3, (3H, as s) /evidentC 56.3 fromand δ Hthe3.91 NOESY (3H, s) correlation/δC 62.2. The peak first between methoxy these group methoxy (δ 3.89) shouldprotons be and placed H-4, atwhich C-3, asalso evident showed from a NOESYthe NOESY cross correlation peak with peak H2-5 between (Figure 2). these This methoxy proposed protons structure and was H-4, corroborated which also showed by the HMBC a NOESY 3- bondcross correlations peak with H from2-5 (Figure H-4 to2 the). Thismethylene proposed carbon structure at δ 28.6 was (C-5) corroborated and the hydroxylated by the HMBC carbon 3-bond at δ 146.7correlations (C-2), and from from H-4 tothe the MeO-3 methylene protons carbon to the at carbonδ 28.6 (C-5)at δ 149.4 and the (C-3) hydroxylated (Table 1 and carbon Figure at 2).δ 146.7 The (C-2),second and methoxy from thegroup MeO-3 (δ 3.91) protons should to be the located carbon at at C-9δ 149.4 of the (C-3) D ring, (Table since1 and its protons Figure2 did). The not second display amethoxy NOESY groupcross peak (δ 3.91) with should H-11. beThis located was supported at C-9 of thefrom D the ring, 3-bond since connectivity its protons did from not the display MeO-9 a protonsNOESY to cross C-9 peak(δ 147.0) with and H-11.