w ww . e l s e v i e r . c o m / l o c a t e / b j p
Review
Vouacapane
diterpenoids
isolated
from
Pterodon
and
their
biological
activities
Leandra
A.R.
Oliveira
a,b,
Gerlon
A.R.
Oliveira
c,
Leonardo
L.
Borges
d,e,
Maria
Teresa
F.
Bara
b,∗,
Dâmaris
Silveira
aaFaculdadedeCiênciasdaSaúde,UniversidadedeBrasília,CampusDarcyRibeiro,Brasília,DF,Brazil bFaculdadedeFarmácia,UniversidadeFederaldeGoiás,Goiânia,GO,Brazil
cInstitutodeQuímica,UniversidadeFederaldeGoiás,CampusSamambaia,Goiânia,GO,Brazil
dEscoladeCiênciasMédicas,FarmacêuticaseBiomédicas,PontifíciaUniversidadeCatólicadeGoiás,Goiânia,GO,Brazil eCampusAnápolisdeCiênciasExataseTecnológicasHenriqueSantillo,UniversidadeEstadualdeGoiás,Anápolis,GO,Brazil
a
r
t
i
c
l
e
i
n
f
o
Articlehistory: Received7April2017 Accepted30May2017 Availableonline30August2017
Keywords: Biologicalactivity Phytochemistry Sucupira
Vouacapanediterpenoids
a
b
s
t
r
a
c
t
ThePterodongenuscomprisestwonativespeciesinBrazil,knownas“sucupira-branca”or“faveira”. TheirfruitshavelongbeenusedinBraziliannaturalmedicine,mainlyforthetreatmentofinfections andinflammations.Thepharmacologicalpropertiesofthesefruitshaveoftenbeenlinkedwith vouaca-panediterpenoids.Thisreviewevaluatedthescientificresearchintheperiodfrom1973toFebruary 2017,aimingtoanswerhowdifficult itstill istodevelopascientificallysupportedproductbased onPterodonvouacapanes.Therefore,thispaperreviewspurification,identification,andquantification methodsappliedtovouacapanediterpenoidsfromPterodon,aswellastheperformanceofthese phyto-chemicalsinpharmacologicaltestsdescribedintheliterature.Dataanalysisresultssupportconventional notionsthatsuggestvouacapanediterpenoidsfromPterodonhaveanti-inflammatoryproperties. How-ever,thestudiescarriedoutsofarstillrepresentpartialassessmentofthevouacapaneactivitiesand furtherstudiesneedtobecompleted.Pterodonditerpenoidshavealsobeenassociatedwithlarvicidal, leishmanicidal,cardiovascular,andantitumoractivities,whichreinforcesthegenus’potentialasasource ofphytomedicines.Someremaininggapsaboutthereviewedactivitieswerementioned,whiletrends andperspectivesforfutureresearchwereproposed.
©2017SociedadeBrasileiradeFarmacognosia.PublishedbyElsevierEditoraLtda.Thisisanopen accessarticleundertheCCBY-NC-NDlicense(http://creativecommons.org/licenses/by-nc-nd/4.0/).
Introduction
Theuseofmedicinalplantshasbeencommonsince ancient
times;theearliestreferencescanbefoundinEgyptianpapyruses,
Chinese scriptures, and Sumerian clay tablets (Hamburger and
Hostettmann,1991).Amongthemedicinalplantsused inmany countries,theFabaceaefamilypresentsthesecondlargestgroup ofspecies,withapproximately490membersdescribedinthe lit-erature(Gaoetal.,2010).ThisfamilyincludesthePterodongenus, whichcomprisesimportantmedicinalplants,particularlyinSouth America.
AccordingtothewebsiteThePlantList(2013),Pterodonhastwo nativeBrazilianspecies,knownas“sucupira-branca”or“faveira”: Pterodonabruptus(Moric.)Benth.(synonym:Commilobium
abrup-tum Moric.) and P. emarginatus Vogel [synonyms: Acosmium
∗ Correspondingauthor. E-mail:mbara@ufg.br(M.T.Bara).
inornatum (Mohlenbr.) Yakovlev; C. polygalaeflorus Benth.; C. pubescensBenth.;P.apparicioiPedersoli.;P.polygalaeflorus(Benth.) Benth.; P. polygaliflorus (Benth.) Benth.; P. pubescens (Benth.) Benth.;andSweetiainornataMohlenbr.].
Ethnobotanicalandethnopharmacologystudiesareapproaches
tofindactivecompoundstodealwithhealthproblems.Many
rele-vantmedicineswereoriginatedfromanaturalcompoundisolated
frommedicinalplants(Raietal.,2011).Anethnobotanicalstudy
conducted in southeasternBrazil indicated that hydroalcoholic
macerateofPterodonfruitshavebeenusedinpopularmedicine
asanti-inflammatory,mainlyinthetreatmentofrheumatism,sore throat,bronchitisandasthma(Grandietal.,1989).Othersurveys also attribute such properties to Pterodon fruits (Corrêa,1975; Hansenetal.,2010;Raposoetal.,2011;Faggetal.,2015).
ResearchonPterodonfruitoilandextracthasconfirmedseveral biologicalactivities,e.g.anti-inflammatory(Carvalhoetal.,1999; Hoscheidetal.,2013;Pascoaetal.,2015),antinociceptive(Silva etal.,2004;Coelhoetal.,2005;Oliveira,2012;Nuccietal.,2012; Martinsetal.,2015),effectonarthritistreatment(Sabinoetal.,
https://doi.org/10.1016/j.bjp.2017.05.014
Pereiraetal.,2011;Pereiraetal.,2012),antioxidant(Dutraetal., 2008),antimicrobial(Dutraetal.,2009;Toledoetal.,2011), larvi-cidalagainstAedesaegypti(Pimentaetal.,2006),andantiparasitic againstTrypanosoma cruzi(Barreto etal., 2008;Oliveira, 2014), Leishmaniaamazonensis(Dutraetal.,2009;Oliveiraetal.,2017) andL.braziliensis(Oliveiraetal.,2017).
Amongthecompoundsprobablyrelatedtothebiological
prop-ertiesofPterodonarevouacapanediterpenes(Euzébioetal.,2009; Spindolaet al.,2010; Galceran et al.,2011; Nucciet al., 2012). VouacapanescanbefoundinothergeneraofthefamilyFabaceae, beyondPterodon.Thesediterpenoidsarealsodistributedinthe fol-lowingspecies:Bowdichianitida(Matsunoetal.,2008),Caesalpinia bonduc(L.)Roxb(Balmainetal.,1967;Pudhometal.,2007),C.crista L.(Jadhavetal.,2003;Cheenprachaetal.,2006;Dasetal.,2010), C.echinataL. (Cotaetal.,2011;Mitsuiet al.,2015), C.minaxH. (Jiangetal.,2001;Jiangetal.,2002;Dongetal.,2015;Lianetal., 2015;Zhangetal.,2015),C.platylobaS.W.(Hurtadoetal.,2013), C.pulcherrima(L.)Sw.(Mcphersonetal.,1986;Ragasaetal.,2002; Ragasaetal.,2003;Dasetal.,2010),C.volkenssiH.(Ochiengetal., 2012),Dypteryxodorata(A)W.(Godoyetal.,1989),D.lacunifera D.(MendesandSilveira,1994),StuhlmaniamoaviV.(Odaloetal., 2009)andVouacapouaamericanaA.(Kidoetal.,2003).
Mauryaet al. (2012)reviewed the studiesinvolving natural
occurrenceofcassaneandnorcassanediterpenesuptoSeptember
2011.ThisreviewfocusedonCaesalpiniagenus,fromwhichonly12 outofits322citedstructureswerealsoreportedtoPterodongenus.
Recently, Bao et al. (2016) have reviewed thenaturally
occur-ringfuranoditerpenoids,andreportedonlysixcompoundsfrom
Pterodon. Therefore, this review summarizesthe available data
aboutvouacapanediterpenoidsisolatedfromPterodonaimingto
provideanoverviewoftheirstructuraldiversity,proceduresused intheirextraction,isolation,structuralelucidation,and quantifica-tion,aswellasthebiologicalactivitiesreportedforthesenatural
products.Theassessmentspannedtheperiodfrom1973to
Febru-ary2017.Thus,thepresentpaperaimstoencouragefutureresearch aboutthisgenusandtheirchemicalcompounds,indicatingtrends andtryingtoanswerhowdifficultitstillistodevelopascientifically
supportedproductbasedonPterodonvouacapanes.
Vouacapanebiosynthesis
Diterpenoids constitute a vast class of isoprenoid
com-pounds,biosynthesizedfrommevalonicacidthrough2E,6E,10E
-geranylgeranylpyrophosphate(GGPP)and deoxyxylulose
phos-phate(Dewick,2002).Diterpenes’ molecularstructure contains
skeletons with twenty carbon atoms and may reveal acyclic:
phytane(1),bicyclic:labdane(2)andclerodane(3),tricyclic: abi-etane(4),pimarane(5)andcassane(6),tetracyclic:gibberellane(7),
andtaxane(11)forms(Hanson,1995;Garcíaetal.,2007;Ramawat andMérillon,2013).
Thebasiccassaneskeleton(6)maybederivedfrompimarane (14) through methylmigration from C-13 toC-14 (14’)in the
biosyntheticpathway.Pimaranesareformedthroughthe
cycliza-tionofthelabdanepyrophosphate(12)(Xuetal.,2011;Maurya etal.,2012).Labdane-typediterpenebiosynthesisconsistsofan initialcyclization of GGPPpromoted by a class II diTPS
(diter-pene synthase) to produce a cyclic diphosphate intermediate,
followed by conversionof this intermediate (13)into the final diterpeneskeletonbyaclassIdiTPS(Peters,2010).Cassanes
con-taining a furan ring are called furanocassanes or vouacapanes
(Scheme1).
Vouacapanes represent an important group of tetracyclic
cassanesand theirstructure ischaracterizedbyaskeleton
con-structed from the fusion of three cyclohexane rings and one
furan ring (Jiang et al., 2001). Vouacapanes previously identi-fied in Pterodon species are summarized in Table 1, according
to structure 15, in addition to the lactones 37 (Mahajan and
Monteiro, 1973) and 38 (Demuner et al., 1996; Omena et al., 2006).
Extraction,quantificationandstructuralelucidationof vouacapanes
Extraction
Vouacapanes are low to medium polarity compounds, thus
beingmainlysolubleinhydrophobicsolvents.Vouacapane
diter-penesarecommonlyisolatedfromthefruitsofdifferentPterodon speciesthroughsimilarprocedures.Fruitsaregroundandextracted
bytheSoxhletmethodusingvarioussolvents,suchaspetroleum
Scheme1. Biosyntheticpathwayofthebasiccassaneskeleton(6).
2008).Otherextractionproceduresincludepercolationusing hex-ane(Fascioetal.,1976)andethanol90%(Omenaetal.,2006),heat extractionusingethanol(Camposetal.,1994),andcoldextraction usingdichloromethane(Spindolaetal.,2009,2010).
FollowingtheSoxhletextraction,thesolventmayberemoved
and the extract submitted to column chromatography to yield
vouacapanes(Mahajan andMonteiro, 1973; Fascioet al.,1976;
Demuneretal.,1996;Rubingeretal.,2004;Pimentaetal.,2006; Spindolaetal.,2009,2010;Servatetal.,2012).Moreover, fraction-ationbyliquid–liquidextraction(Omenaetal.,2006;Vieiraetal., 2008)oracid–baseextraction(MahajanandMonteiro,1973; Fas-cioetal.,1976;Camposetal.,1994;Arriagaetal.,2000)mayalso
beperformedbeforepurificationbycolumnchromatography.The
6␣,7-diacetoxyvouacapane(18)wasobtainedbydirect crystal-lizationfollowingextraction(MahajanandMonteiro,1973;Fascio etal.,1976).
Chromatographic purification of these compounds is
usu-ally performed using silica gel as a stationary phase (Fascio
etal.,1976;Rubingeretal.,2004;Vieiraetal.,2008).However, Mahajan and Monteiro (1973) used alumina to purify 6␣,7
-diacetoxyvouacap14(17)-ene (16) and 18, while Vieira et al.
(2008)usedflorisilcolumn inoneofthestages of vouacapane-6␣,7,14,19-tetraol(29)purification.
Open column chromatography is often a challenging and
time-consumingtechniquebecausefractionshavetobeanalyzed
following fractionation, not during it. Furthermore, thevarious
stages of this process may favor the occurrence of chemical
reactionsinvolvingsecondarymetabolites,henceleadingtothe for-mationofartifacts(Pizzolattietal.,2002).Toavoidthesesetbacks, Oliveiraetal.(2017)proposedasemipreparativehigh-performance liquidchromatography(HPLC)methodforisolatingP.emarginatus diterpenoids.
Classicchromatographicelutionsarecommonlymonitoredby
thin layerchromatography,which usesdefault wavelengthsfor
choosingthefractionscontainingpurecompounds.However,as
wehavenoticed(Oliveiraetal.,2017),somewavelengthsmaynot
allowtodiscriminatedifferentvouacapanesinasample.TheUV
diodearrayHPLCdetectorsenableassessingthechromatogramin
awidewavelengthrange,enhancingtheassurancesinthe
eval-uation of purity of the peaks. The assessment of the peaks in
theiroptimalabsorbancewavelength,instead ofdefault values,
alsodecreasesdetectionlimits,favoring theisolation of minor-itycompounds.Inaddition,theseparationpowerofhigh-pressure
columnsissuperiortotheonesachievedthroughopencolumns.
SincejustveryrecentlyHPLCisolationhasbeenappliedtoPterodon fruits(Oliveiraetal.,2017),itislikelythatmanyvouacapaneswere notyetdescribedforthisgenus.
Structuralelucidation
Followingextractionandisolation,thenextstepconsistsin elu-cidatingthestructureofvouacapanes.Thestructureofvouacapane diterpeneshasmainlybeendeterminedvianuclearmagnetic reso-nance(NMR)(Camposetal.,1994;Vieiraetal.,2008;Euzébioetal., 2009;Galceranetal.,2011).Vouacapanesmaybecharacterizedby theirfuranringsignals.The1HNMRspectraforvouacapanesshow hydrogenfuransatapproximately␦H6.4ppm(1H,d,J=1.9Hz,H15) and␦H7.2ppm(1H,d,J=1.9Hz,H16),whilethe13CNMRspectra showfuranringsignalsat␦C148.2ppm(C-12),141.9ppm(C-16), 123.9ppm(C-13),and107.2ppm(C-15)(Spindolaetal.,2009; Hur-tadoetal.,2013;Oliveiraetal.,2017).
Moreover,NMRanalysiscanbeusedtogetherwithother
spec-troscopictechniques,suchasinfrared(IR)(Spindolaetal.,2010) andmassspectrometry(MS)(Fascioetal.,1976;Arriagaetal.,2000; Servatetal.,2012;Oliveiraetal.,2017),ontheirownorcombined (Demuneretal.,1996;Omenaetal.,2006;Spindolaetal.,2009).
Ontheotherhand,infraredspectroscopyprovideslimited infor-mation for structural elucidation. However, it is very useful in
verifyingtheidentityofcompoundsbycomparingspectrafrom
newsampleswiththosefromreferencedsubstances.Omenaetal.
(2006)andSpindolaetal.(2009,2010)haveusedIRspectroscopy toobtainstructuralinformationaboutisolatedvouacapanes,e.g. evidencefor hydroxyl(absorption closeto3450cm−1)and car-bonyl functionalities (absorption closeto1710cm−1).Demuner
etal.(1996)haveobservedthatvouacapanes’IRspectrumshows
hydroxyl absorptionbands at3560(sharp,due tofreeOH)and
3425(broad,due tohydrogen-bondedOH)cm−1 and 1678and
1510cm−1(C C)forafuranring.
Massspectrometryhasalsobeenusedtoelucidatethe
struc-tureofvouacapanes.High-resolutionelectronimpactionization
(HREIMS) has proved to be a useful tool (Arriaga et al., 2000;
Spindolaetal.,2009;Servatetal.,2012),aswellas,morerecently, electronsprayionization(Cabraletal.,2013;Oliveiraetal.,2017).
Analyticalstudiesandquantification
Accurateandreproducibleanalyticalmethodsarerequiredto
etal.(2008),Santosetal.(2008), Euzébioetal.(2009,2010), Galceranetal.(2011) Methyl
6␣,7-dihydroxyvouacapan-17-oate (22)
(␣)OH ()OH ()COOMe (␣)H (␣)Me ()Me MahajanandMonteiro(1973), Fascioetal.(1976),Arriagaetal. (2000),Rubingeretal.(2004), Omenaetal.,2006,Santosetal. (2008),Spindolaetal.(2009,2010, 2011),Díazetal.(2010) Methyl7-acetoxy-6␣
-hydroxyvouacapan-17-oate (23)
(␣)OH ()OAc ()COOMe (␣)H (␣)Me ()Me MahajanandMonteiro(1973), Servatetal.(2012)
6␣,7-diacetoxyvouacapan-14-al(24) (␣)OAc ()OAc (␣)H ()CHO (␣)Me ()Me Fascioetal.(1976) 6␣,7-Diacetoxyvouacapan-14-oate(25) (␣)OAc ()OAc (␣)H ()COOMe (␣)Me ()Me Fascioetal.(1976) Methyl6␣-acetoxy-7
-hydroxyvouacapan-17-oate (26)
(␣)OAc ()OH ()COOMe (␣)H (␣)Me ()Me Fascioetal.(1976),Camposetal. (1994),Hoscheidetal.(2012), Servatetal.(2012),Oliveiraetal. (2017)
Methyl6␣-hydroxy-7 -acetoxyvouacapan-17-oate (27)
(␣)OH ()OAc ()COOMe (␣)H (␣)Me ()Me Fascioetal.(1976),Hoscheidetal. (2012),Servatetal.(2012)
6␣-Hydroxy-7 -acetoxyvouacap-14(17)-ene
(28)
(␣)OH ()OAc C=CH2 (␣)Me ()Me Camposetal.(1994)
Vouacapane-6␣,7,14,19-tetraol(29) (␣)OH ()OH (␣)Me ()OH ()CH2OH (␣)Me Demuneretal.(1996),Arriaga etal.(2000),Vieiraetal.(2008) 6␣-Acetoxyvouacapane(30) (␣)OAc ()H (␣)Me ()H (␣)Me ()Me Pimentaetal.(2006)
6␣-Hydroxyvouacapane(31) (␣)OH ()H (␣)Me ()H (␣)Me ()Me Arriagaetal.(2000),Pimentaetal. (2006)
Vouacapane(32) (␣)H ()H (␣)Me ()H (␣)Me ()Me Pimentaetal.(2006) 6␣,7-Dihydroxyvouacapan-17
-methylene-ol (33)
(␣)OH ()OH ()CH2OH (␣)H (␣)Me ()Me Spindolaetal.(2009)
6␣-Acetoxy-7-hydroxyvouacapan(34) (␣)OAc ()OH (␣)Me ()H (␣)Me ()Me Spindolaetal.(2009) 6␣,19-Diacetoxy-7,14
-dihydroxyvouacapan (35)
(␣)OAc ()OH ()OH (␣)Me (␣)Me (␣)OAc Oliveiraetal.(2017)
6␣-Acetoxy-7,14-dihydroxyvouacapan (36)
(␣)OAc ()OH ()OH (␣)Me (␣)Me ()Me Oliveiraetal.(2017)
orbiologicalsamples.Fingerprintingisindicatedforthe
qualita-tivedistinction ofsampleswithcomplex chemical composition
(Sawayaetal.,2010).Itcoversthescanningofavastnumberof intracellularmetabolitesdetectedbya selectedanalytical tech-niqueorbyacombinationofdifferenttechniques(Villas-Boasetal., 2005).
Cabraletal.(2013)usedmassspectrometryforfingerprintingP. emarginatusfruitoil.Thefruitsurfaceorpaperimprintedwiththe oilwasdirectlyanalyzedbyinfusionelectrosprayionizationmass spectrometry(DIESI-MS),aswellasbydesorption/ionizationvia easyambientsonic-sprayionizationmassspectrometry(EASI-MS). TypicalprofileswereobtainedfromthecrudeoilviathesedirectMS techniques.ThemainadvantagesofMSoverothertechniquesused
forfingerprintingareitshighsensitivityandselectivity(Villas-Boas etal.,2005;Dettmeretal.,2007).
Few studies have focused on quantifying Pterodon
vouaca-panes. Hoscheid et al. (2012) developed and validated a gas
chromatography method to quantify methyl 6␣-acetoxy-7
-hydroxyvouacapan-17-oate (26) and methyl 6␣-hydroxy-7
-acetoxyvouacapan-17-oate(27)in a semipurifiedextract of P. emarginatus fruits.Samples were quantified following
purifica-tion,whichincludedliquid–liquidpartitioningandopen-column
chromatography.Oliveira (2014)proposedanalternative
HPLC-PDA method to quantify 26 in P.emarginatus fruits. The main
Pharmacologicalactivities
Authorshavesuggestedthatthevouacapaneskeletonoffuran
diterpenesis linked withcertain pharmacologicalproperties of
extractsfromPterodonfruits(Carvalhoetal.,1999;Euzébioetal., 2009;Spindolaetal.,2010;Galceranetal.,2011;Nuccietal.,2012). Thissectiondescribesthepossiblepharmacologicalactivitiesand
actionmechanismsofvouacapanesisolatedfromPterodonfruits,
basedoninvitroandinvivostudies.
Anti-inflammatory,antinociceptiveandanalgesicactivities
Duetopotentialsideeffectsandlowefficacyofsyntheticand
chemicaldrugs,consumptionofothercomplementarydrugs,
espe-ciallyherbalremedies,tocontrolpainisincreasing(Bahmanietal.,
2014).Painisdefined as“anunpleasantsensoryand emotional
experienceassociatedwithactualorpotentialtissuedamage,or describedintermsofsuchdamage”(MerskeyandBogduk,1994). Thus,painhassensory,affectiveandacognitivecomponent asso-ciatedwiththeanticipationoffutureharm(Garland,2012).The nociceptionisthesensorycomponent(LoeserandTreede,2008). Inflammatoryresponsesintheperipheralandcentralnervous
sys-temsplaykeyrolesinthedevelopmentandpersistenceofmany
pathologicalpainstates(ZhangandAn,2007).
Variousneurotransmittersand receptorsystems takepartin
themodulationofpainprocessesinthecentralnervoussystem
and peripheral nervous system, such as the vanilloid, opioid,
non-opioids(i.e.-adrenergic,dopaminergic),glutamate,protein kinase C, potassium ion (K+) channels, and nitric oxide/cyclic
guanosinemonophosphatepathways(JuliusandBasbaum,2001;
Zakariaetal.,2016).Theantinociceptiveactionofthevouacapans isolatedfromPterodonwasassessedinchemicalandthermal mod-elsofnociceptioninmice,suchasaceticacid-inducedabdominal constriction,pawcompression,formalinandhotplatetest.
The first evidence that vouacapan has an analgesia effect
wasdemonstratedbyinhibitionofaceticacidwrithingresponse
in mice (Duarte et al., 1992).The authors assessed the role of endogenousopioidpeptidesintheantinociceptiveeffectinduced by6␣,7-dihydroxyvouacapan-17-oatesodium(20),usingacetic
acid-inducedabdominalcontortionandpawcompressiontestson
mice.Inbothmodels,compound20causedadose-dependent
anal-gesiawhenadministeredthroughoral(p.o.),intraperitoneal(i.p.), andsubcutaneous(s.c.)routes(rangingfrom62.5to500mol/kg).
Results showed that opioid antagonists only partially blocked
theantinociceptiveeffect.Theauthorssuggestedthatendorphin releasemaybeinvolved inthevouacapane’sanalgesiceffect.In anotherstudy,Duarteetal.(1996)assessedthepossible involve-mentofbiogenicaminesintheantinociceptiveeffectof20,using
aceticacid-inducedabdominalcontortiononmice.Thiscompound
exhibitedanantinociceptiveeffect(500mol/kg,i.p.)when com-paredwiththecontrolgroup.Resultssuggestedthatvouacapane’s
antinociceptiveresponsemaybeassociatedwithdopamine.
Spindola et al. (2010) examined the contribution of
geranylgeraniol (acyclic diterpene) and methyl 6␣,7
-dihydroxyvouacapan-17-oate(22)isolatedfromP.emarginatus fruits in the extract’s antinociceptive activity. The open field testwasperformedtoruleoutthepossibilitythatthe antinoci-ceptiveeffects of geranylgeranioland 22 are linked tospecific
disturbancesin animals’locomotion(30mg/kg or82.8mol/kg,
i.p.). Compounds reduced acetic acid-induced abdominal
con-tortionsonmicetreatedviai.p.andp.o.routes,withdifferences
in potency being linked to administration routes (10, 30, 100,
and 300mg/kg). Results suggested that the diterpenes essayed
mayproducesynergisticactivity.Followingtheuseofnaxolone
hydrochloride (1mg/kg or 2.75mol/kg, p.o.), a non-specific
opioidantagonist,inthehot-platetest,itwasconcludedthatthe
antinociceptive activity is unrelated to opioidergic routes and
canbelinkedtotheinvolvementofVR1vanilloidreceptorsand
peripheralglutamatereceptors.
In a follow-up tothe previousstudy, Spindola et al.(2011)
investigated the possible action mechanisms involved in the
antinociceptiveactivityofgeranylgeranioland22.Theallodynia
test,which assessedthetouchresponse ofmicesubmittedtoa
subplantarinjectionofcompleteFreund’sadjuvant(CFA; Mycobac-terium tuberculosis, 1mg/ml), showed that compounds tested (30mg/kg,or103.3mol/kgofgeranylgeranioland82.8mol/kg ofcompound 22;i.p.)reduced painsensitivityduringtheacute
phase. In the hyperalgesia test, which verified response to a
painful stimulus, mice treated with geranylgeraniol showed a
significant reduction in carrageenan-induced hypernociception.
Regarding the action mechanism, the antinociceptive
activ-ity of geranylgeraniol and 22 during the acetic acid-induced
contortion test may be related to serotonergic and imidazole
systems.
Servat et al. (2012) assessed the antinociceptive activity of themixtureofisomersmethyl7-acetoxy-6␣ -hydroxyvouacapan-17-oate(23)and26.Thetreatmentdidnotsignificantlychange animals’locomotionandreducedaceticacidabdominalcontortions
inmiceinadose-dependentmanner,whencomparedwiththe
con-trolgroup,presentinganeffectivedose50(ED50)of35.6mg/kg(or 88mol/kg).Moreover,theformalintestshowedthatthe antinoci-ceptiveactivityoftheisomermixtureis moreclosely linkedto neuropathicpainthantoinflammatorypain.Intheallodyniatest, thedosestested(30mg/kgor74.2mol/kg;i.p.)provedeffective
inthefirsttwo phases:acute andsubacute(4and 24h
follow-ingCFAadministration).Inthehyperalgesiatest,themixtureof
vouacapane isomers was not effective in reducing pain, which
suggeststhatthesampleshowsahigheraffinityforneuropathic components.
Galceranetal.(2011)assessedtheanti-inflammatoryand anal-gesicpotentialof6␣,7-dihydroxyvouacapan-17-oicacid(21).
Oral administration of 50mg/kg (equivalent to 143.5mol/kg)
of21 inhibitedtheinflammatory mechanismstriggeredby
car-rageenanandprostaglandinE2,whilenotsignificantlyinhibiting
theedemaproducedbydextran.Theaceticacid-induced
contor-tiontestshoweddose-dependentinhibitioninmicetreatedorally withthediterpene(50,200or400mg/kgp.o.).Intheformalintest,
21showedantinociceptiveactivityonneurogenicand
inflamma-torypainmodelsinmicegivenoraltreatment(50and100mg/kg
p.o.).However,inthe100mg/kg(or287mol/kg)dose(p.o.),the compoundwasnotabletoincreasethelatencytimeduringthe hot-platetest.Together,theseresultssuggestthat21hasperipheral anti-inflammatoryandanalgesiceffects.
Todate,fewvouacapanediterpenesfromPterodonhavebeen
evaluated for anti-inflammatory and antinociceptive activities.
Sincethetestsevaluatedonlyonevouacapaneatatime,thereis notacomparisonregardingthepotentialofdifferentvouacapanes.
The antinociceptive effect of vouacapans may involve multiple
mechanismsofactionasopioid,catecholaminergic,vanilloid, glu-tamate,serotonergicandimidazolesystems.Thesedatashowthat vouacapanshaveapromisingeffectasantinociceptivesubstances. Itisexpectedthatfurtherstudiesinvolvingtoxicitytrialswillbe carriedoutinordertoensureasafeuseofthesesubstances.Thus, despitesignificantresults,theevaluationsmadesofarhavebeen limitedtopreliminarytests,involvingonlyfivecompounds.
Larvicidalactivity
Aedesaegyptimosquitoesarevectorsfortransmittingseveral arbovirusessuchaszika(ZIKV),chikungunya(CHIKV),anddengue
(DENV).AccordingtotheWorldHealthOrganization(WHO),DENV,
acetoxyvouacapane (30) against stage 3 Aedes aegypti larvae,
in concentrations ranging from 12.5 to 500g/ml. Compound
30 showedmedian lethal concentration(LC50)of 186.21g/ml
(540.5nmol/ml).FeaturinganLC50of24g/mlinthisstudy,the
hexanicextractshowedtobemorepromisingthantheisolated
vouacapane.Thisstudydidnotinvestigatewhethersucha remark-ablevaluewasduetosynergicactionoftheconstituentsfromthe hexanicfractionortothepresenceintheoilofsomemorepotent vouacapanes.Itseemsclearthatthechoiceofanaturalproduct foreffectivelycontrollingAedesmosquitoshouldtakeintoaccount
many other factors besideslethal concentration,like resources
availabilityandthecostsforobtainingthisproduct.Inthestudy ofPimentaetal.(2006),1.5kgoffruitsyielded364gofhexanic
extractandonly181mgofcompound17afterachromatographic
elution.Therefore,thishexanicextractseemstobemore promis-ingthanthePterodonvouacapanesassesseduntilnow.Inthisstudy, plainoilwasnotevaluatedagainstthelarvae.
In partnership with our group, Oliveira et al. (2016) found
thatLC50 fora nanoemulsionofPterodon oilis about35g/ml, whichreinforcesthepotentialofnon-purifiedPterodonproducts. Thus, furtherlarvicidal studiesshould involve chemically
well-characterizedoilsinsteadof isolated vouacapanes,which could
alsobeassessedagainstotherspeciesofmosquito.Surveysonthe availabilityoftheplantsthatproduceasuitableoilaswellason theeconomicfeasibilityoftheapproachbasedonlarvaecontrol arerequired.DuetothelowmiscibilityofPterodonoilinwater,
nanoemulsionspreparedbyalowenergyandsolvent-freemethod,
asoptimizedbyOliveiraetal.(2016),shouldbeconsideredin fur-therstudies.
Leishmanicidalactivity
Leishmaniasisiswidelydistributedacross88tropical,
subtrop-icaland temperate countries,affecting about12 millionpeople
worldwide(Georgiadouetal.,2015).Leishmaniasisiscausedby aprotozoaparasitefromover20Leishmaniaspeciesandis
trans-mitted tohumansby thebiteof infected femalephlebotomine
sandflies (WHO, 2017a).In 2014,more than90% of new cases
reportedtoWHOoccurredinsixcountries:Brazil,Ethiopia,India,
Somalia, South Sudan and Sudan (WHO, 2017b).Current
clini-callyuseddrugs against leishmaniasisare relatedto numerous
shortfallsincludingtoxicity,mustbeadministeredoverprolonged periodsandareoftenassociatedwithserioussideeffects(Croftand Coombs,2003).Thus, itisnecessarytodevelopmentnew leish-manicidalagents.
Oliveiraetal.(2017)testedtheleishmanicidalactivityof
com-pound26againstpromastigotesofLeishmaniaamazonensisandL.
braziliensis,inconcentrationsrangingfrom8.0to128.0g/ml,and
Cardiovascular-relatedactivity
Cardiovasculardiseasescoverarangeofheartandbloodvessel disorderse.g.coronaryheart,cerebrovascular,peripheralarterial, andrheumaticheartdiseases,andWHOestimatesthat17.5million peopleworldwidediefromheart-relateddiseaseseachyear(WHO, 2016d).Someofthesedisordersinvolveoneormoreriskfactors suchashypertension,diabetes,hyperlipidemiaorotherestablished diseases.Severalnaturalproductshavebeenusedtoalleviateor preventsomeofthesedisordersorrelatedevents,suchascardiac glycosidesandreserpine.
Reis et al. (2015) assessed blood vessel relaxation and the
possibleactionmechanisms ofcompound 26in isolatedmouse
aortapreparations.Resultssuggestedthat26induces
endothelium-independent vascular relaxation by blocking the L-type Ca2+
channel(Cav1.2).Theseresultssupportapossiblecardiovascular
effectofcompound26 andPterodonoilthroughvascular
dilata-tion;however,noneofthemanyotherPterodonvouacapaneswas
assessed.Sincethisclassrevealedapotentialforuseasa cardio-vascularrelaxationagent,othervouacapanesshouldalsobetested inpreliminarystudies.Furtherinvestigationsofthemost
promis-ingsubstancesshouldincludeassessmentsinhumantissuesand
invivosystems.
Cytotoxicityandantitumoractivity
Certain substances, such as verapamil or cyclosporine, have
beenusedtoovercomemultidrugresistance(MDR),animportant
obstacletothesuccessofcancerchemotherapy.However,these
P-gpmodulatingagents havenotshown significantpotentialin
clinicalpractice(Meschinietal.,2003),andtheidentificationof newcompoundswithfewsideeffectsishighlydesirable.The induc-tionofapoptosisrepresentsacriticalfactorincancertherapyand contributedtosignificantanti-tumoractivityforthecompounds associatedwithcytotoxicityproperties withpotentialtoinhibit cellulareventsrelatedtotheprogressionoftumors.
Vieira et al. (2008) assessed the antiproliferative activity of
29viaMTT(3-(4,5-dimethylthiazol-2-yl)2,5-diphenyltetrazolium
bromide)colorimetricassaybyusingSK-MEL-37humanmelanoma
cells,inconcentrationsrangingfrom1.4to92mol/l,andshowed inhibitory concentration 50% (IC50) of 32mol/l. Doxorubicin (positivecontrol)showedanIC50valueof35mol/L,similartothat ofthevouacapanetested.Thisresultshowedthatthevouacapanes testeddisplayedcytotoxicityactivityagainstthetestedcellline.
Spindola et al. (2009) tested the activity of
(34)againsthumantumorcelllinesUACC-62(melanoma),MCF-7
(breast), NCI-H460 (lung), OVCAR-03 (ovary), PC-3 (prostate),
HT-29(colon),786-0(kidney),K562(leukemia),andNCI-ADR/RES
(ovary withmultidrug resistancephenotype). Cell proliferation
wasdeterminedbyspectrophotometricquantificationofcell
pro-teincontentviasulphorhodamineB.Compound34was26times
morepotentininhibiting50%growth(GI50)ofPC-3(prostate),15 timesmorecytostatic(totalgrowthinhibition–TGI),andsixtimes lesstoxicthantheconcentrationleadingto50%celldeath(LC50)
whencomparedwiththecontrol(doxorubicin).
Thisstudyalsoassessedthecytotoxicityofcompounds22,33, and34againstnormalmurinecellline(3T3)usingtheMTTmethod, inconcentrationsrangingfrom0.25to250g/ml.Regarding cyto-toxicity against 3T3, 34 had less toxicity (IC50 of 34.33g/ml, equivalentto95.2nmol/ml),followedby33(IC50of23.55g/ml, equivalentto70.4nmol/ml)and22(IC50of22.83g/ml,equivalent to63.0nmol/ml).Compounds22,33,and34presentedhigh selec-tivityfor prostatecancer. Theselectiveactivityagainstprostate
cancercells and thelower cytotoxicityover normal cells show
Pterodonvouacapanesmeritfurtherinvestigationsinaneffortto developselectivemedicinesthattreatcancerwithgreaterpatient safetyinthefuture.
Formoreinformationontheantiproliferativeactivityof fura-noditerpenesagainstdifferentcelllines,newactiveconstituents weresynthesizedfrom21isolatedfromP.emarginatusfruits.
Euzébio et al. (2009) synthesized three lactones deriva-tives from 21: 6␣-hydroxyvouacapan-7,17-lactone (38), 6␣
-acetoxyvouacapan-7,17-lactone (37), and
6-oxovouacapan-7,17-lactone(39).The antiproliferative activityof21 and its
derived lactones was assessed against thesame human cancer
celllinesusedbySpindolaetal.(2009).Compound38 wasthe
mostactiveofthefourfuranoditerpenes,aswellasmorepotent ininhibiting50%growth(GI50)ofadriamycin-resistantovary can-cercells(NCI-ADR/RES)anderythromyeloblastoidleukemia(K562)
whencomparedwithdoxorubicin.Compound37onlyshoweda
growthinhibition effectagainst erythromyeloblastoid leukemia
cells (GI50 of27.4g/ml, or73.6nmol/ml). Resultsindicated 38 asthemostpromisingderivativeforfuturestudies,inadditionto theimportanceof7,of17-lactonering,andoftheC-6hydroxyl groupfortheantiproliferativeactivityof38.
In a follow-up to the previous study, Euzébio et al. (2010)
synthesized six new derived amines from lactone derivative
38: 16-(N,N-diethylaminomethyl)-6␣
-hydroxyvouacapan-7,17-lactone (40); 16-(N,N
-dipropylaminomethyl)-6␣-hydroxyvouacapan-7,17-lactone (41); 16-(N,N
-diisobutylaminomethyl)-6␣-hydroxyvouacapan-7,17-lactone (42); 16-(1-pyrrolidinylmethyl)-6␣-hydroxyvouacapan-7,17
-lactone (43); 16-(1-piperidinylmethyl)-6␣
-hydroxyvouacapan-7,17-lactone (44); 16-(4-morpholinylmethyl)-6␣
-hydroxyvouacapan-7,17-lactone (45). These compounds
weretestedonthesamecancercelllinesfromthepreviousstudy
andweremorepotentagainstmostofthem,showinglowerGI50
valuesthanthoseobtainedfor38(Euzébioetal.,2009).Compounds
40–45were,likedoxorubicin(control),potentgrowthinhibitors
of adriamycin-resistant ovary cancer cells (NCI-ADR/RES), lung
cancer cells (NCI-H460), and erythromyeloblastoid leukemia
(K562).TheoreticalcalculationsshowedthatC-16aminogroups
may be crucial to the antiproliferative activity of vouacapane
derivatives.
The resultspresented in this topiccontributed toshow the
potentialofthecitedmoleculestoobtainprototypesfor
antitu-mordrugs.Theusualsubstancesemployednowadaysinantitumor
therapypresentseveralsideeffects,andinthiscontextthesearch fornewstructureswithmorespecificitycouldbeagoodstrategy infutureinvestigationsregardingcytotoxicityeffects.
H
H
OH
H
O
OH
CO
2H
12
3 4
18 19 5
6 7 8 9
10 2011
12
13
14
17 15 16
41
R
1=R
2= -CH
2-CH
342
R
1=R
2= -CH
2-CH
2-CH
343
R
1=R
2= -CH
2-CH
2-(CH
3)
244
R
1and
R
2= -CH
2-CH
2-CH
2-CH
245
R
1and
R
2= -CH
2-CH
2-CH
2-CH
2-CH
246
R
1and
R
2= -CH
2-CH
2-O-CH
2-CH
2N
1'1" 2" 3"
1" 2" 2" 1"
2" 1" 1" 2"
R
2R
21" 2" 3" 2" 1"
Technologicalapplications
Vouacapanescanbeusedasphytochemicalmarkerforquality
controlandstandardizationoftheproductsderivedfromPterodon duetotheirpharmacologicalactivities.Aimingtomaskthetaste
of theextractsstandardized in vouacapans, sometechnological
alternativeshavebeendevelopedfortheoilsofPterodonspecies,
suchas microcapsulesin polymeric systems
(alginate/medium-molecular-weightchitosan(F1-MC),alginate/chitosanwithgreater
than 75% deacetylation (F2-MC), and
alginate/low-molecular-weightchitosan(F3-MC))(Reinasetal.,2014).
Nanoemulsionsareanalternativetodrugdeliveryforlipophilic
compounds, which can be administrated via oral, ocular, and
intravenousinordertoreducesideeffectsandtoimprove pharma-cologicalproperties(Solansetal.,2005;HormanandZimmer,2016; Singhetal.,2017).Hoscheidetal.(2017)optimizedananoemulsion withP.pubescensoil,whichprovidedfasterinjectionsduring
intra-muscularadministration,comparingtoconventionalformulation.
In thisstudy,thenanoemulsionsystemwasevaluated for
only recently has beenused in their obtainment. New studies
areencouragedtocarry outa phytochemicalassessmentofthe
rawmaterialandtoconsiderthepossibilityofpurifying
minor-ityvouacapanestobetested,sincethestudiesaccomplishedso
far only encompass a small portion of Pterodon vouacapanes.
Anti-inflammatory,antinociceptiveandanalgesicactivitieswere confirmedbyscientificstudiesinanimals.However,thereisstill alackofscientificsupportjustifyingtheproductionofamedicine withthesecompounds.Toxicityandsafetyevaluationstudiesare stillneededtoassuresafetyforclinicalapplication.The pharma-ceuticaltechnologyaimingatsuitabledeliveryofthevouacapanes, inthedifferentapplications,isalsoveryscarce.Newpreliminary studiesregardingthecardiovascularandleishmanicidalactivities
shouldbecarriedoutwithothervouacapanes,beforemore
spe-cificassessmentswiththeoneswhichprovetobemostpotent.In ouropinion,Pterodonoiloroil’sfractionsaremoreconvenientthan vouacapanesforlarvicidalactivity,andseemstobemore promis-ingforfutureresearch.Asthelatesttrendsandperspectivesfor
futureresearchofPterodonvouacapaneswesuggesttheneedfor
studiesregardingthesustainabilityoftheplantspeciesaimingat theproductionofmedicines.
Authorscontributions
LARO, GARO and LLB contributed to the concept, literature
searchandwritingofthisreviewarticle.DSandMTFBcontributed totheconceptandcriticalreadingofthisreview.
Conflictsofinterest
Theauthorsdeclarenoconflictsofinterest.
Acknowledgments
WewouldliketothankUniversidadedeBrasília,Universidade
FederaldeGoiás,UniversidadeEstadualdeGoiás,FAP-DF,Capes
andCNPqforthefinancialsupport.
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