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TaylorFrancisTaylorFrancisGroupRCheckforupdates2-PyronesfromendophyticfungusDiaporthefoeniculinaBZM-15ZhonghuaYuabbzXiuxiangLuae*zJaehyuckChoibShulinDengaBinghongXiong WengeZhangaeHuanWangaczSasaWangandHaiboTan*[2:CONTACTHaiboTan卤tanhaibo@scbg.ac.cn;SasaWang@wgsasa@
163.com][3:Theauthorscontributedequally.QSupplementaldataforthisarticlecanbeaccessedathttps://d0i.0rg/l
0.1080/
14786419.
2021.
1904400.©2021InformaUKLimitedtradingasTaylorFrancisGroup]aKeyLaboratoryofPlantResourcesConservationandSustainableUtilizationKeyLaboratoryofSouthChinaAgriculturalPlantMolecularAnalysisGuangdongProvincialKeyLaboratoryofAppliedBotanySouthChinaBotanicalGardenChineseAcademyofSciencesGuangzhouChina;bDepartmentofLandscapeArchitecturePaiChaiUniversityDeajeonSouthKorea;cNationalEngineeringResearchCenterofNavelOrangeGannanNormalUniversityGanzhouPeopleurmalUniversitynt;dGuangxiKeyLaboratoryofChemistryandEngineeringofForestProductsGuangxiUniversityforNationalitiesNanningChina;eUniversityofChineseAcademyofSciencesBeijingChinaABSTRACTFoeniculinsA-C1-3togetherwithapairofenantiomers土-foe-niculinD4wereisolatedfromendophyticfungusDiaporthefoeniculinaBZM-
15.TheirstructuresincludingabsoluteconfigurationswereunambiguouslyestablishedbyextensiveinterpretationoftheNMRandHR-ESI-MSdataECDmeasurementspoweredbymolecularcalculationsaswellasMo2OAc4mediatedCDmethodology.Thecytotoxicactivityassaydisclosedthatthesecompoundsdidntshowanynoticeablecytotoxicactivity.KIntroductionChemically2-pyronefeaturingacharacteristicsix-memberedunsaturatedcycliclactonesystemsharesfascinatingchemicalandphysicalpropertieswhichwerereminiscentofbothofthealkeneandaromaticcompoundsMcGIackenandFairlamb
2005.ThischemicalscaffoldrepresentedoneofthemostcharacteristicfamilyofsecondarymetabolitesoftenencounteredinbacteriaandmicrobialsystemswithhighlyabundanceFuetaL2011;GeiseleretaL2012;ZhangetaL
2017.Moreoverthe2-pyronenaturalproductsusuallyshowaplethoraofdifferentbiologicalmeaningfulactivitiessuchasantibacterialantifungalMcGIackenandFairlamb2005;Caietal.2017;Bhatetal.2017antitumourSuzukietal.1997;Kondohetal.1998neroprotectiveHongetal.2009;Walkeretal.2007cytotoxicCalderon-Montanoetal.2013;Zhangetal.2013;Guoetal.2020immunomodulatoryFujimotoetal.2005HIVproteaseinhibitorySteinbaughetaL1996;Thaisrivongsetal.1996;HeetaL2011andselectiveCOX-2inhibitoryactivitiesChuetal.2013;Yehetal.
2014.OnthecontinuingprogramtoexplorethestructurallydiverseandpharmaceuticallysignificantnaturalleadcompoundsfromtheendophyticfungiofthemedicinalplantsandendophyticmicrobialLiuetal.2019a2019bz2019c2019d;Zhangetal.2020theinitiallychemicalconstitutesevaluationthroughHPLC-MSanalysisofthesecondarymetabolitesfromDiaporthefoeniculinaanBZM-15disclosedtheabundanceofa-pyronederivatives.Thusthefurtherefforttowardtheinspectionandisolationofnovela-pyronesfromD.foeniculinaBZM-15wasconductedwhichresultedintheisolationoffoura-pyronederivativesfoeniculinsA-D1-
4.NotablythefoeniculinCexistedasadiastereoisomerwithfoeniculinDwhereasfoeniculinDwereapairofenantiomers.HereinwereportthedetailsofisolationstructuralelucidationbyNMRspectralinterpretationandbiologicalevaluationofthesepreviousundescribedisolates.ResultsanddiscussionCompound1waspurifiedasawhitesolid.ItsmolecularformulawassuccessfullydeterminedtobeC13H16O5withsixdegreesofunsaturationbytheHRESIMSspectrumwithanobviousprotonatedpeakatm/z
253.1075[M+H]+G3H17O5calcd
253.
1071.MoreovertheIRspectrumshowedthepresenceofaseriesofcharacteristicfunctionalitiesinvolvingcarbonyl1739cm-1andalkenylgroups1681cm-
1.The1HNMRspectrumof1displayedsixteenprotonsignalsresponsiveforseventypeswhichwereattributabletofourmethylsincludinganoxygenatedone5H
4.01soneoxygenatedmethyleneandtwoolefinichydrogens.The13CNMRdataTableS1couplingwithHSQCspectrumdisclosedthepresenceof13carbonsignalsascribedtofourmethylsonemethylenesixolefiniccarbonsandtwoestercarbonylgroups.Bothofthe1Hand13CNMRdatawereconsistentwiththemolecularformulaestablishedbytheHRESIMSandstronglyindicatedthatcompound1shouldbeatypicala-pyronederivative.Theplanarstructureof1wasestablishedbytheconclusive2DNMRanalyses.Firstlythe1H-1HCOSYspectrumshowedtheexistenceofaspincouplingfragmentaCH-CH2asshowninFigureS48seesupportinginformation.ThecriticalHMBCcorrelationsfromtheH3-10toC-2C-3ZandC-4inconjugationwithH-5toC-3C-4andC-6couldrevealtheexistenceofthekeya-pyronecorewithamethylfunctionalgrouplocatedatC-3position.Moreoverthemethoxylmoietywasdeducedtobelinkedtothea-pyronecoreatC-4positionbecauseoftheobviousHMBCcorrelationformH3-12toC-
4.Figure
1.Chemicalstructuresofnewcompounds1-
4.OnthebasisofspincouplingfragmentaztheHMBCcorrelationsfromH3-2ZandH2-9totheestercarbonylcarbonC-VlogicallyassignedanacetoxymoietyattachedatC-9position.ThefurtherHMBCcorrelationsfromH3-11toC-6C-7ZandC-8H2-9toC-7C-8H-8toC-6ZC-7andC-11ztogetherwiththe-COSYcorrelationsH2-9/H-8col-lectivelypointedtothatcompound1possessanoxygenated3-butenesidechainanditshouldbeconnectedtothea-pyronecoreskeletonatC-6positionthroughtheC-6-C-7singlebond.Thedoublebondconfigurationofcompound1wasdeterminedtobethetransconfigurationbecauseitsNMRdatawerecloselysimilartothoseoftheknowncompoundtrans-8-acetoxypestalopyroneLiaoetaL2020;CaoandClardy
2011.Thusthecompletestructureof1wasfinallyestablishedasdepictedinFigure1andgiventhetrivialnameasfoeniculinA.Compound2wasisolatedasawhiteoil.TheHRESIMSspectrumof2showedaclearmolecularionpeakatm/z
255.1233[M+H]+calcd
255.1227whichwellagreedwiththemolecularformulaC13H18O5thusnecessitatingfivedegreesofunsaturation.TheIRspectrumshowedthepresenceofacarbonyl1734cm-1andalkenylgroups1681cm-
1.Compound2couldbereadilyconcludedtobeahydrogenatedderivativeof1basedonitsHRMSandNMRdatawhichshowedveryclosesimilarityinmostprofiles.Differentfromcompound1theNMRdataTableS1of2showedthepresenceofanadditionalmethine5H
2.68z
35.9andamethylene5H
1.81and
2.05dc
33.0insteadofadoublebond5C
131.
2128.2in
1.Theaforementionedinformativeresultssuggestivelyimpliedthattheoxygenated3-buteneunitin1wasreplacedbyanoxygenated3-butaneone.ThisconclusioncouldbefurtherevidencedbythecontinuousspincouplingfragmentCH3-CH-CH2-CH2baseontheiHCOSYspectrumFigureS
48.Theabsoluteconfigurationof2wasdeterminedbythecalculatedCDspectrummethodasexpecteditshowedasatisfyingagreementbetweenthecalculatedCDspectrumofthe7SisomerandtheexperimentaloneFigureS
49.Thusthestructureofcompound2wasfinallydeterminedtobeana-pyronederivativeasdepictedinFigure1andgiventhetrivialnameasfoeniculinB.Compound3waspurifiedasawhitesolid.TheHRESIMSof3assigneditsmolecularformulatobeCnH16O5withfourindicesofhydrogendeficiencyattributabletotheprotonatedmolecularionpeakobservedatm/z
229.1077[M+H]+calcd
229.
1071.TheIRspectrumshowedthepresenceofhydroxygroups3365and1020cm-1carbonylgroup1683cm-1alkenylgroups1558and669cm-
1.TheNMRdataTableS2displayscharacteristicsignalsoffourmethylgroups[anoxygenatedmethyl5h
3.99]oneoxygenatedmethylene5H
4.01andanolefinproton5H
6.
75.The13CNMRdatacouplingwithHSQCspectrumof3indicated11carbonsignalswhichwerecorrespondingtofourmethylfunctionalgroupstwodoublebonds5C
93.
699.
7167.
7168.6anestercarbonylmoiety0c
164.5twooxygenatedcarbonsincludingamethyne5C
70.8andonequaternarycarbon5C
75.
7.Theseprotonsignalscollectivelyconfirmedtheexistenceofana-pyroneskeleton.AccordingtotheHMBCanalysesof3FigureS48thepresenceofthecorrelationsfromH3-10toC-2C-3andC-4readilyevidencedthelocationofC-10methylatC-3positionina-pyronescaffold.MoreoverthemethoxylmoietywasverifiedtobeconnectedatC-4positionreferringtotheinformativeHMBCcorrelationfromH3-12toC-
4.TheobviousHMBCcorrelationsformH3-9andH3-11toC-7andC-8togetherwiththeiH」HCOSYspinsystemCH-CH3suggestedtheexistenceof23-butanediolsidechain.FurthermorethesidechainwaschemologicallyconcludedtobeattachedatC-6inthea-pyronecorebecauseoftheHMBCcorrelationsfromH3-11toC-6andH-5toC-
7.Thereforetheplanarstructureof3wassuccessfullyestablishedandthemaindifferencebetween3and2wasattributedtotheoxygenatedstateofthesidechain.Compound4wereinitiallyisolatedasamixtureofapairofenantiomersasawhitesolid.TheHRESIMSdataofm/z
229.1073[M+H]+calcdforCnH17O5z
229.1071indicatedthattheyhavethesamemolecularformulaCnH16O5asthatof
3.InterestinglytheirNMRdatawerehighlysimilaronlyslightdifferencescouldbedistinguishedbetweenthechemicalshiftsofH-8andC-8[5H
4.01mdc
70.8for3;5H
3.92qzJ=
6.5Hz*
71.3for4]H3-9andC-9[dH
1.23dJ=
6.4Hz»
15.5for3;5H
1.11dJ=
6.5Hz3C
16.3for4]zandH3-11andC-l1[5H
1.40s5C
21.8for3;3H
1.51sz3C
21.9for4].Moreoverthe2DNMRcorrelationsFigureS48furtherstrengthenedthattheysharedthesameplanarstructurewiththatof
3.Theaforementionedinformationsuggestedthattheyshouldbethediastereoisomerof
3.ThemeasurementsoftherotateopticalvalueandCDspectrumof4suggestedthatitmightbearacemicmixture.Thensubsequentpurificationthroughsemi-preparativeHPLCwithaChiralpakICcolumnsuccessfullyresolvedtheseracematesintoapairofopticallypureenantiomers4aand4bzwhereintheexperimentalcirculardichroismECDandopticalrotationdataof+-4aand—-4bclearlyshowedtheenantiomericrelationshipFigureS43SupportingInformation.Becausecompounds3and4sharedthesamev/c-diolgroupinthemoleculeamodifieddimolybdenumtetraacetate[Mo2OAc4]mediatedCDmethodologywasappliedtodeterminetheirabsoluteconfigurationsGoreckietaL2020;DietaL2020;Politietal.2020;Caoetal.
2020.Accordingtothemethodologythediolmoietyofcompound4couldbeconfirmedasthreoconfigurationandofcompound3wasidentifiedaserythrononeCaoetaL
2020.ThenasshowinFiguresS45-S47supportinginformationtheMo2-complexof3inDMSOshowedanegativeCottoneffectatapproximately310nmindicatingthattheabsoluteconfigurationof3wasof7R8R.SimilarlyMo2-complexof4ashowedapositiveCottoneffectandof4bshowedanegativeCottoneffectsatapproximately318nmsuggestedthattheabsoluteconfigurationof4ashouldbe7R8Sand4bshouldbe7S8R.Inadditiontheanti-tumoractivitiesofthesecompoundswereevaluatedagainstSF-268MCF-7andHepG-2tumorcelllinesandallisolatedcompoundswereexhibitednoanti-tumoractivityevenattheconcentration100jllM.ExperimentalGeneralexperimentalproceduresOpticalrotationwasmeasuredwithanAntonPaarMCP-500spectropolarimeterAntonPaarGrazAustria.UVspectrawereobtainedusingaShimadzuUV-2600spectrophotometerShimadzuKyotoJapan.IRspectrawereacquiredonaShimadzuIRAffinity-1spectrometerShimadzuKyotoJapan.The旧500MHz13C125MHzand2D1H-1HCOSYHSQCHMBCandNOESYNMRspectrawererecordedonaBrukerAvance-500spectrometerBrukerCorporationFallandenSwitzerlandwithTMSasinternalreference.ExperimentalECDspectrainMeOHwereacquiredinaquartzcuvetteof1mmopticalpathlengthonanAppliedPhotophysisChirascan.HR-ESI-MSspectrawereobtainedinaThermoMAT95XPhighresolutionmassspectrometerThermoFisherScientificBremenGermany.PreparativeHPLCwasperformedonanAgilent1260infinitysystemequippedwithaDAD-UVdetectorusingapreparativeYMCODSC18column20x250mm5im.Columnchromatographywasperformedusingsilicagel200-300meshQingdaoMarineChemicalInc.QingdaoChinaandSephadexLH-20gelPharmaciaFineChemicalCo.Ltd.Sweden.Thin-layerchromatographyTLCwascarriedoutonsilicagelplatesMerckKGaADarmstadtGermanyusingvarioussolventsystems.AllsolventswerepurchasedfromGuangzhouChemicalRegentsCompanyLtd.GuangzhouChina.FungusandfermentationThefungusDiaporthefoeniculinaBZM-15wasisolatedfromtheplantofLeptospermumbrachyandrumwhichwascollectedfromSouthChinaBotanicalGardenSCBGChineseAcademyofSciencesChinainSeptember
2016.ThestrainwasidentifiedasD.foeniculinaaccordingtothesequenceanalysisofrDNAITSinternaltranscribedspacerregionwhichhasbeensubmittedtoGenBankwiththeaccessionnumberofMN
788609.ThestrainwasdepositedintheLaboratoryofNaturalProductMedicinalChemistrySCBG.ThefungusD.foeniculinawasincubatedin200mLofpotatodextrosebrothat30°Conarotaryshaker120rpmfor7daystoacquiretheseedbroth.Large-scalefermentationwascarriedoutinErlenmeyerflasks16x3Leachcontainedrice200ganddistilledwater300mLwhichwereautoclavingat121°Cfor25min.AftercoolingatroomtemperaturethoseErlenmeyerflaskswereaddedseedbrothrespectivelyfurthermorewhichwerefermentedfor30daysat28°C.
33.ExtractionandisolationAftercultivationtheobtainedmycelialsolidmediumwasextractedwithEtOAc3times24hforeverytimeatroomtemperatureandtheextractsolutionwasconcentratedinvacuotoreceiveacrudeextract50gwhichwasfractionatedbysilicagelcolumnchromatographyCCpetroleumether-EtOAcv/v100:1—50:50andCH2CI2-MeOHv/v5:1—2:1toaffordsixmainfractionsFr.1-Fr.
6.Fr.
57.22gwassubjectedintoODScolumnchromatographyCandelutedwithMeOH-H2Ov/vz40%—100%togivesixsubfractionsFr.5-1toFr.5-
6.Fr.5-
21.94gwasseparatedbySephadexLH-20CCelutingwithCHCI3-MeOHv/v1:1toprovidefivesubfractionsFr.5-2-1toFr.5-2-
5.Fr.5-2-
1311.4mgwasisolatedbyflashcolumnchromatographyonsilicagelandelutedwithn-hexane-EtOAcgradientv/v5:1一1:5togetthreesub-fractionsFr.5-2-1-1toFr.5-2-1-
3.Fr.5-2-1-
1208.0mgwasthensubjectedtopreparativeHPLCwithCH3CN-H2Ov/vz50:50andfurtherpurifiedbysemi-preparativeHPLCequippedwithachiralcolumnwashedwithCH3CN-H2Ov/v
1.38:
1.62toafford
28.0mgztR=
12.6min.EquallyFr.5-2-
21.23gwaschromatographedusingsilicagelflashcolumnchromatographyelutedwithCHCI3-MeOHv/v40%—100%toaffordsixsub-fractionsFr.5-2-2-1toFr.5-2-2-
6.Fr.5-2-2-
2113.3mgwasseparatedbypreparativeHPLCwithCH3CN-H2Ov/v10:90andfurtherpurifiedbysemi-preparativeHPLCsystemwithachiralcolumnwashedwithisopropanol-hex-anev/v9:1toafford
31.0mg=
34.0minz4a
2.0mgS=
36.0minand4b
1.5mgztR=
39.0min.Fr.5-2-2-
4520.5mgwasfurtherisolatedbypreparativeHPLCwithCH3CN-H2Ov/v40:60toobtain
15.2mgztR=
15.0min.Physio-chemicalpropertiesofcompounds7・4FoeniculinA1:whitesolid;UVMeOH:2maxlog£:
2283.
393252.82nm;IRKBr:34463001292928681739168116161556154114561373135125112341224117010311008927871z798746675634cm-1;HRESIMS:m/z
253.1075[M+H]+calcdforC13H17O
5253.
1071.H500MHzand13C125MHzNMRdataseeTableSI.FoeniculinB2:whiteoil;[a]+
33.4c
0.08MeOH;UVMeOH:Amaxlogs:
2053.
272982.64nm;IRKBr:3525z29702943287717341681z16451568z146313651238115110411028898810756605cm-1;HRESIMS:m/z
255.1233[M+H]+calcdforC13H19O5z
255.
1227.1H500MHzand13C125MHzNMRdataseeTableS
1.FoeniculinC3:whitesolid;[a]—
2.6c
0.05MeOH;UVMeOH:Amaxlogs:
2053.08nmz
2982.48nm;IRKBr:336529452916283516831653155815411506145613861249116311091020669599z551cm-1;HRESIMS:m/z
229.1077[M+H]+calcdforCnH17O5z
229.
1071.1H500MHzand13C125MHzNMRdataseeTableS
2.FoeniculinD4a:whitesolid;[a]+
5.1c
0.05MeOH;UVMeOH:2maxlog8:205nmz
2982.75nm;IRKBr:33312945283316531456125111121020678z605cm-1;HRESIMS:m/z
229.1073[M+H]+calcdforCnH17O5z
229.
1071.旧500MHzand13C125MHzNMRdataseeTableS
2.FoeniculinD4b:whitesolid;[a]—
4.4c
0.1MeOH;UVMeOH:2maxloga:205nm
2992.76nm;IRKBr:332129472918283516471396125111611111Z1020669601557cm-1;HRESIMS:m/z
229.1075[M+H]+calcdforCnH17O
5229.
1071.1H500MHzand13C125MHzNMRdataseeTableS
2.CytotoxicactivityCompounds1-4weretestedfortheircytotoxicactivitiesagainstthreetumorcelllinesSF-268MCF-7andHepG-2bytheSRBSulforhodamineBmethodSkehanetal.
1990.ConclusionsInthisstudyfivenovela-pyronesfoeniculinsA-D1-4withdiverseoxygenatedstateswereisolatedfromtheEtOAcextractofendophyticfungusD.foeniculinaanBZM-
15.TheirstructuresweredefinitelyelucidatedonthebasisofextensiveanalysisofNMRspectroscopicdataanddimolybdenumtetraacetateCDspectra.AmongthemthefoeniculinCexistedasadiastereoisomerwithfoeniculinDwhereasfoeniculinDwereapairofenantiomers.TheinvestigationnotonlyrevealedthechemicalconstituteoffungusD.foeniculinaanbutalsoenrichedthestructuraldiversityofa-pyrones.DisclosurestatementNopotentialconflictofinterestwasreportedbytheauthors.FundingThisresearchwasfundedbytheNationalNaturalScienceFoundationofChinaNo.81773602NaturalScienceFoundationofGuangdongProvince2019A1515011694GuangdongSpecialSupportProgram2017TQ04R599YouthInnovationPromotionAssociationofCAS2020342andtheFoundationofKeyLaboratoryofPlantResourcesConservationandSustainableUtilizationSouthChinaBotanicalGardenChineseAcademyofSciences.ReferencesBhatZSRatherMAMaqboolMUlLahHYousufSKAhmadZ.
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