Anticancer Activities of C18-, C19-, C20-, and Bis-Diterpenoid Alkaloids Derived from Genus ...

14 Pages·2017·0.9 MB·English

molecules
Review
Anticancer Activities of C -, C -, C -, and
18 19 20
Bis-Diterpenoid Alkaloids Derived from
Genus Aconitum
Meng-YueRen1,2,Qing-TianYu1,2,Chun-YuShi1,2andJia-BoLuo1,2,*
1 SchoolofTraditionalChineseMedicine,SouthernMedicalUniversity,Guangzhou510515,China;
[email protected](M.-Y.R.);[email protected](Q.-T.Y.);[email protected](C.-Y.S.)
2 GuangdongProvincialKeyLaboratoryofChineseMedicinePharmaceutics,SouthernMedicalUniversity,
Guangzhou510515,China
* Correspondence:[email protected];Tel./Fax:[phone]
AcademicEditors:Quan-BinHanandJian-XinPu
Received:27December2016;Accepted:6February2017;Published:13February2017
Abstract: Cancer is one of the most common lethal diseases, and natural products have been
extensivelystudiedasanticanceragentsconsideringtheiravailability,lowtoxicity,andeconomic
affordability. Plants belonging to the genus Aconitum have been widely used medically in many
Asian countries since ancient times. These plants have been proven effective for treating several
typesofcancer,suchaslung,stomach,andlivercancers. ThemaineffectivecomponentsofAconitum
plants are diterpenoid alkaloids—which are divided into C -, C -, C -, and bis-diterpenoid
18 19 20
alkaloids—arereportedlysomeofthemostpromising,naturallyabundantcompoundsfortreating
cancer. Thisreviewfocusesontheprogressofditerpenoidalkaloidswithdifferentstructuresderived
fromAconitumplantsandsomeoftheirderivativeswithpotentialanticanceractivities. Wehope
that this work can serve as a reference for further developing Aconitum diterpenoid alkaloids as
anticanceragents.
Keywords: anticancer;genusAconitum;diterpenoidalkaloids
1. Introduction
Cancerisoneofthemostcommonlethaldiseases,withapproximately14millionnewcasesof
cancer diagnosed and 8 million cancer-related deaths in 2012. This disease affects all populations
inallregionsaccordingtotheWorldHealthOrganization[1]. Thefivemostcommonincidentsites
ofcancersarethelung,breast,colorectum,prostate,andstomach,constitutinghalfofincidentsites
worldwide[1]. Inrecentyears,naturalproducts,includingmaterialsoriginatingfromplants,animals
andtheirderivatives,havebeenextensivelystudiedasanticanceragentsconsideringtheiravailability,
lowtoxicity,andeconomicaffordability. Over60%ofanticancerdrugsarenaturalproductsthathave
shownpotentialanticanceractivities[2],suchasanti-proliferation[3],anti-angiogenesis[4],reversal
ofmultidrugresistance(MDR)[5],andantimetastasis[6]effects.
The genus Aconitum belongs to the family Ranunculaceae, which comprises about 400 species
distributed in the temperate regions of the northern hemisphere, with half of them distributed in
China [7]. Since ancient times, about 40 of these species have been widely used to treat apoplexy
hemiplegia[8],asthma[9],andrheumatoidarthritis[10]inChina,Japan,andotherAsiancountries;
someexamplesareA.carmichaeliDebx.,A.kusnezoffiiRchb.,A.sinomontanumNakai,andA.leucostomum
Vorosch.[11]. ModernpharmacologicalstudieshavedemonstratedthatmedicinalAconitumplants
canexertanti-inflammatory,analgesic[12,13],anti-arrhythmia[14],antioxidant[15],antibacterial[16],
andanticancereffects[7,17]. Inanticancertherapy,Aconitumplantshavebeenproveneffectivefor
severaltypesofcancer,suchaslung,stomach,andlivercancers[18–20].
Molecules2017,22,267;doi:10.3390/molecules22020267 www.mdpi.com/journal/molecules
Molecules2017,22,267 2of14
Aconitum plants chemically comprise alkaloids, flavonoids, steroids, and glycosides, and the
mainefficacycomponentsaswellasthetoxiccomponentsarediterpenoidalkaloids[21–23],which
arereportedlysomeofthemostpromising,naturallyabundantcompoundsfortreatingcancer[24].
Diterpenoidalkaloidshavebeenstudiedsincethe1940s, andbasedonstructuraldifferencessuch
asthenumberofcarbonatomsonthemothernucleus,diterpenoidalkaloidsaregenerallydivided
into four categories: C -, C -, C -, and bis-diterpenoid alkaloids [25–29]. This review focuses
18 19 20
on the progress of diterpenoid alkaloids with different structures derived from Aconitum plants
and some of their derivatives (e.g., lappaconitine, aconitine, songorine, pseudokobusine, and
11-veratroylpseudokobusine)withpotentialanticanceractivities. Wealsosummarizesomeoftheir
antitumormechanisms. WehopethisworkcanserveasareferenceforfurtherdevelopingAconitum
diterpenoidalkaloidsasanticanceragents.
2. ChemicalStructureofDiterpenoidAlkaloids
Nearlyathousandnaturalditerpenoidalkaloidshavebeenreportedtodate,andalargepart
of them originate from Aconitum plants [30], and C -diterpenoid alkaloids are the most reported
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amongthem[27]. C -diterpenoidalkaloidsevolvefromC -diterpenoidalkaloidsanddegenerate
19 20
intoC -diterpenoidalkaloidsbylosingthe18thcarbonatom[25,31].
18
Basedonthepresenceofoxygen-containingfunctionalgroupsattheC-7position,C -diterpenoid
18
alkaloids,whichconstituteasmallgroupwithinthediterpenoidalkaloids,areclassifiedaslappaconine
or ranaconine types [28]. Concerning the carbon skeleton and substituents at specific positions,
theC -diterpenoidalkaloidsmaybeinitiallydividedintoaconitine,lycoctonine,pyro,lactonepe,
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7,17-seco,andrearrangedtypes[27]. ComparedwithC -andC -diterpenoidalkaloids,theskeletal
18 19
types of the C -diterpenoid alkaloids are extremely complex, which may be divided into four
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classes,including19types[29]. ThemajorityofC -diterpenoidalkaloidshaveanexocyclicdouble
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bond structure and are generally divided into atisine, denudatine, hetidine, hetisine, napelline,
andanopterinetypesnowadays[32].
Figures 1 and 2 show the chemical structures of C -, C -, bis-diterpenoid alkaloids and
18 19
C -diterpenoidalkaloidswithanticanceractivitiesderivedfromgenusAconitum,respectively.
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3. AnticancerActivitiesofDiterpenoidAlkaloids
3.1. C -DiterpenoidAlkaloids
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Lappaconitine(1),atypicalC -diterpenoidalkaloidextractedforthefirsttimeinChinafrom
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A.sinomontanumNakai,iscommonlyusedaspostoperativeanalgesiaandreliefforclinicalcancer
painasanon-addictiveanalgesic[33,34]. Lappaconitineexertsananalgesiceffectbyinhibitingthe
voltage-dependent sodium channels, increasing norepinephrine release in the synaptic cleft, and
inhibitingthereleaseofsubstanceP[35]. Lappaconitinereportedlyinhibitstheproliferationofthe
humannon-smallcelllungcancercellsA549dosedependently[36]. Withincreasedlappaconitine
concentration,theproportionofA549cellsincreasedgraduallyinG1+G0phaseanddecreasedinS
andG +Mphases,andtheapoptosisrateincreasedwiththedown-regulatedexpressionofCyclinE1.
2
LappaconitinecanalsoinhibittheexpressionofVEGF-A,andthecombinationoflappaconitineand
oxaliplatincanarrestthecellsinG1/G0phaseandinhibittheexpressionofCyclinE1[37].
Asthederivativeoflappaconitine(1),lappaconitehydrobromidecanreportedlyexertanefficient
antitumoreffectinmicebytheNationalInstitutesofHealth(NIH)mice. Inparticular,theinhibition
ratesrangedwithin11.20%–53.08%forlivertumorgrowthandwithin29.81%–53.96%forS180tumor
growth[38].
Molecules2017,22,267 3of14
Molecules 2017, 22, 267 3 of 14

FigFiugruer1e. 1C. Chehmemiciaclasl tsrtuructcuturerseso offt htheeC C18--,, CC19--,, aanndd bbisis-d-ditieterprpeennooidid alaklkalaoliodids swwithit hanatnictiacnacnecre arcaticvtiitviietsie s
18 19
derived from the genus Aconitum.
derivedfromthegenusAconitum.
Molecules2017,22,267 4of14
Molecules 2017, 22, 267 4 of 14

FFiigguurree 22.. CChheemmiiccaall ssttrruuccttuurreess ooff tthhee CC20--ddiitteerrppeennooiidd aallkkaallooiiddss wwiitthh aannttiiccaanncceerr aaccttiivviittiieess ddeerriivveedd ffrroomm
20
the genus Aconitum.
thegenusAconitum.
3.2. C19-Diterpenoid Alkaloids
Lycaconitine (2) is a C19-diterpenoid alkaloid isolated from the roots of Aconitum pseudo-laeve
var. erectum through bioassay-guided fractionation and repeated column chromatography. Although
lycaconitine (2) does not present cytotoxicity to KB cells, it has potent inhibitory effects on pgp-MDR
Molecules2017,22,267 5of14
3.2. C -DiterpenoidAlkaloids
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Lycaconitine(2)is aC -diterpenoidalkaloidisolated fromthe rootsof Aconitumpseudo-laeve
19
var. erectumthroughbioassay-guidedfractionationandrepeatedcolumnchromatography. Although
lycaconitine(2)doesnotpresentcytotoxicitytoKBcells,ithaspotentinhibitoryeffectsonpgp-MDR
upon testing on the multidrug resistant human fibrocarcinoma KB V20C (resistant to 20 nM
vincristine)[39].
In the 1980s, preliminary experimental studies on the antitumor effect of aconitine (3) were
performedbymultiplemedicalinstitutions.Theydemonstratedthat200µg/mLaconitineinhibitedthe
proliferationofgastriccancercellsbyinhibitingitsmitosis,andthattheinhibitoryrateofhepatocellular
carcinomainmicewas47.77%–57.38%[18]. Aconitinealsoreportedlyhasanticanceractivitytothe
miceinoculatedwithgastriccancercellsandS180cells,aswellastheabilitytoinhibitthespontaneous
metastasis of Lewis lung cancer cells [40]. Moreover, aconitine (150–400 µg/mL) can significantly
inhibittheproliferationofHepal-6hepatomacellsinvitro,withtheinhibitoryrateofHepal-6cells
inC75BL/6malemicerangingwithin26.12%–65.43%atconcentrationsof0.15and0.375mg/kg[41].
MDRisakeyfactorthathinderscancertreatment. Theanticancereffectofaconitine(3)hasbeen
evaluatedindrug-resistanthumanoralsquamouscellcarcinoma(KBv200),whichshowsthataconitine
has a small inhibitory effect on the growth of KBv200 (IC = 224.91 µg/mL). However, aconitine
50
can increase the sensitivity of vincristine to kill cells, and the IC values of vincristine in KBv200
50
are0.2715and0.9185µg/mLwhencombinedwith12.5and6.25µg/mLaconitine,respectively[42].
Thus,aconitineisconsideredtohavenosignificantcytotoxiceffectandcanevenreversetheMDRof
cancercells. Throughimmunohistochemistryandgenechiptechnology,follow-upstudieshasshown
thataconitinecandownregulatetheexpressionofProteinPgpandchangetheexpressionofMdr1
genebyaffectingapoptosis-relatedgenesandthemitogen-activatedproteinkinase(MAPK)signal
transductionsystem,therebyultimatelyreversingthedrugresistance[43,44].
(1α,6α,8α,14α,16α)-20-Ethyl-8,14-dihydroxy-1,6,16-trimethoxy-4-(methoxymethyl)-aconitane(4)
wasisolatedfromtherootsofAconitumtaipaicumHand.–Mazz,andcytotoxicityassaysindicatethat
compound4exhibitsstrongergrowthinhibitorythanadriamycinagainstleukaemiacellsHL-60and
K-562[45]. Inthesameyear,compound4hasbeenfoundtoinhibittheproliferationandinvasionof
HepG2(liverhepatocellularcarcinoma)cellsandarrestcellsinG0/G1phasetopromotecellapoptosis,
themechanisminvolvestheupregulationofBaxandCaspase-3expressionandthedownregulationof
Bcl-2(B-celllymphoma-2)andCCND1expression[46].
Found in A. carmichaeli Debx., five compounds including oxonitine (5), deoxyaconitine (6),
hypaconitine(7),mesaconitine(8),andcrassicaulineA(9)showobviouscytotoxicactivitiesagainst
various cancers, such as leucocythemia, breast cancer, and liver cancer. Compared with two
other diterpenoid alkaloids without cytotoxic activities, compounds 5–7 and 9 have two ester
groups in the structure, which may have an effect on the cytotoxicity of the compounds [47].
8-O-Azeloyl-14-benzoylaconine(10)isalsoanewC -diterpenoidalkaloidwithtwoestergroupsin
19
thestructurefoundintherootsofA.karacolicumRapcs. Itshowsgoodantiproliferativeactivitieswith
anIC ofabout10–20µMagainstHCT-15(coloncancercell),A549(lungcancercellline),andMCF-7
50
(breastcancercellline)cells[48].
Cammaconine(11)wasisolatedfromtheethanolextractofAconitumvaginatumPritz.andidentified
byspectroscopicanalysis. IthasgreaterinhibitoryeffectonAGS(gastriccancercell),HepG2,and
A549 cells compared with 5-Fluorouracil [49]. Two C -diterpenoid alkaloids, neoline (12) and
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14-O-acetylneoline (13) were further isolated and identified from an enriched alkaloid fraction of
AconitumflavumHand.–Mazz;theyhavebeenproventopossessgrowth-inhibitioneffectsonhuman
gastriccarcinomaSGC-7901,hepaticcarcinomaHepG2,andlungcancerA549cells[50].
3.3. C -DiterpenoidAlkaloids
20
Together with cammaconine (11), anatisine-type C -diterpenoid alkaloid named atisinium
20
chloride (14) was isolated from A. vaginatum Pritz. and found to inhibit the growth of various
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cancers [49]. In addition, songorine (15), 12-epi-napelline (16), and 12-epi-dehydronapelline (17)
derivedfromAconitumflavumHand.–Mazz. inhibitedthegrowthofSGC-7901(gastriccarcinoma),
HepG2,andA549cellssuchasneoline(12)[50].
In 2007, 13 natural diterpenoid alkaloids were isolated and purified from Aconitum yesoense
var. macroyesoenseandAconitumjaponicumand22derivativesweresubsequentlypreparedfromthe
parentalkaloids. Theveatchine-typeC -diterpenoidalkaloidnamed12-acetylluciculine(18)andthe
20
sixderivativesdesignedfrompseudokobusine(19),including6,11-dibenzoylpseudokobusine(20),
11-veratroylpseudokobusine(21),11-cinnamoylpseudokobusine(22),11-(m-trifluoromethylbenzoyl)
pseudokobusine(23),11-anisoylpseudokobusine(24),and11-p-nitrobenzoylpseudokobusine(25)are
proventoinhibitthegrowthofhumanmalignantA172cells[51]. ThehydroxylgroupsatC-6and
C-15ofpseudokobusineareconsideredtobeessentialtotheinhibitoryeffect,andtheesterification
ofthehydroxylgroupatC-11mayenhancesuchactivity. In2009,KojiWadadetectedtheanticancer
activitiesofthesameabovementionedditerpenoidalkaloidswithfourdifferentcancercells. They
demonstratedthatallsixderivatives(20–25)havestronginhibitoryactivityagainstA172,A549,HeLa
(cervicalcancercellline),andRaji(lymphomacellline)cells(exceptcompound21toHeLacells)[52].
Compounds23and24,whichshowsignificantsuppressiveeffectsagainstRajicells,havethesame
structureexceptforthegroupintheC-11position. Compound23inhibitsthephosphorylationof
extracellular signal-regulated kinasein Raji cells but does not affect the growth of human CD34+
hematopoieticstem/progenitorcells,whichcanbesignificantlyinhibitedbycompound24[53].
Ten new acylated alkaloid derivatives were prepared from the natural diterpenoid alkaloids
of A. yesoense var. macroyesoense and A. japonicum; they are 11,15-dianisoylpseudokobusine
(26), 11,15-di-p-nitrobenzoylpseudokobusin (27), 11-(p-trifluoromethylbenzoyl)kobusine
(28), 11-(m-trifluoromethylbenzoyl)kobusine (29), 11,15-di-p-nitrobenzoylkobusine (30), 11-p-
nitrobenzoylpseudokobusine(31),11-cinnamoylpseudokobusine(32),6,11-dianisoylpseudokobusine
(33),11-veratroylpseudokobusine(34),and11-anisoylpseudokobusine(35). Theyinhibitedthegrowth
ofA549cellsthroughG1arrest,andtheirIC valuesrangedwithin1.72–5.44µM.Theircytotoxic
50
effectscanbeenhancedbyreplacinganacylgroupatbothC-11andC-15positions[54].
In2015,theantiproliferativeeffectsof108diterpenoidalkaloidsweretestedbythesameresearch
teamaboveagainstfourcancercells,namely,lung,prostate,nasopharyngeal,andvincristine-resistant
nasopharyngeal(KB-VIN)cancercelllines. Thealkaloidsthatshowsubstantialsuppressiveeffectsin
11newlysynthesizedC -diterpenoidalkaloidderivatives[55]: 11,15-dibenzoylkobusine(36),11,15-
20
dianisoylkobusine(37),11,15-di-(4-nitrobenzoyl)kobusine(38),11,15-di-(4-fluorobenzoyl)kobusine
(39), 11,15-di-(3-trifluoromethylcinnamoyl)kobusine (40), 11,15-dibenzoylpseudokobusine (41),
11-(4-nitrobenzoyl)pseudokobusine (42), 11,15-di-(3-nitrobenzoyl)pseudokobusine (43), 11-(3-
trifluoromethylbenzoyl)pseudokobusine (44), 11-cinnamoylpseudokobusine (45), and 11-
tritylpseudokobusine (46). All of them were hetisine-type C -diterpenoid alkaloids with two
20
differentsubstitutionpatternsofC-11andC-11,15,andtheGI softhemweresummarizedinTable1.
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3.4. Bis-DiterpenoidAlkaloids
Threebis-[O-(14-benzoylaconine-8-yl)]esters[56],includingnewsemisyntheticalkaloidswith
diversealkylchainsontheheterocyclicmoiety,includingbis-[O-(14-benzoylaconine-8-yl)]-pimelate
(47),bis-[O-(14-benzoylaconine-8-yl)]-suberate(48),andbis-[O-(14-benzoylaconine-8-yl)]-azelate(49),
built from the 8-O-azeloyl-14-benzoylaconine (11) skeleton, present remarkable cytotoxic activity
invitroagainstlungcancerA-549,coloncancerHCT-15,andbreastcancerMCF-7cells;theirIC s
50
were<28µM.Theanticanceractivitiesinvivoofbis-[O-(14-benzoylaconine-8-yl)]-suberate(48)was
subsequentlytestedinimmunodeficientmicetransplantedwithhumantumorsMCF-7andHCT-15
cells because of its significant cytotoxicity invitro. Its antitumor activity is obviously shown at a
dose below the maximum tolerated dose. The impact of the alkyl-linker length of the designed
bis-diterpenoidalkaloidsoncytotoxicityisclearlyelucidatedinthestudyandcanserveasareference
fordesigningnovelantiproliferativeagents[57].
Molecules2017,22,267 7of14
Table1.Theanti-proliferativeactivitiesofthediterpenoidalkaloidsderivedfromthegenusAconitum.
No. Compounds CancerTypes CellLines IC50 Reference
C18-diterpenoidalkaloids
1 Lappaconitine Lungcancer A549 6.71×103µM/48h [39]
C19-diterpenoidalkaloids
2 Lycaconitine Fibroblastcarcinoma KBV20C 110.65µM/72h [39]
3 Aconitine Oralsquamouscellcarcinoma KBv200 348.29µM/72h [42]
Hepatomacarcinoma Hepal-6 590.03µM/48h [41]
Hepatomacarcinoma HePG2 0.85×10−2µM/72h [47]
Coloncancer HCT8 8.12×10−2µM/72h
Breastcancer MCF7 2.45×10−2µM/72h
(1α,6α,8α,14α,16α)-20-ethyl-8,14-dihydroxy-1,6,
4 Leukemia HL-60 0.44µM/24h [46]
16-trimethoxy-4-(methoxymethyl)-aconitane
Leukemia K-562 1.55µM/24h
5 Oxonitine Coloncancer HCT8 29.48×10−2µM/72h [47]
Breastcancer MCF7 3.13×10−2µM/72h
Hepatomacarcinoma HePG2 8.61×10−2µM/72h
6 Deoxyaconitine Coloncancer HCT8 5.14×10−2µM/72h [47]
Breastcancer MCF7 10.35×10−2µM/72h
Hepatomacarcinoma HePG2 9.21×10−2µM/72h
7 Hypaconitine Coloncancer HCT8 12.05×10−2µM/72h [47]
Breastcancer MCF7 6.46×10−2µM/72h
Hepatomacarcinoma HePG2 0.92×10−2µM/72h
8 Mesaconitine Coloncancer HCT8 13.16×10−2µM/72h [47]
Breastcancer MCF7 4.57×10−2µM/72h
Hepatomacarcinoma HePG2 1.45×10−2µM/72h
9 CrassicaulineA Coloncancer HCT8 16.45×10−2µM/72h [47]
Breastcancer MCF7 12.86×10−2µM/72h
Hepatomacarcinoma HePG2 2.36×10−2µM/72h
10 8-O-Azeloyl-14-benzoylaconine Coloncancer HCT-15 16.8µM/24h [48]
Lungcancer A549 19.4µM/24h
Breastcancer MCF-7 10.3µM/24h
11 Cammaconine Gastriccarcinoma AGS 0.32µM/48h [49]
Hepatomacarcinoma HepG2 34.55µM/48h
Lungcancer A549 0.32µM/48h
12 Neoline Gastriccarcinoma SGC-7901 37.55µM/48h [50]
Hepatomacarcinoma HepG2 28.36µM/48h
Lungcancer A549 34.74µM/48h
13 14-O-acetylneoline Gastriccarcinoma SGC-7901 16.97µM/48h [50]
Hepatomacarcinoma HepG2 33.76µM/48h
Lungcancer A549 18.75µM/48h
Molecules2017,22,267 8of14
Table1.Cont.
No. Compounds CancerTypes CellLines IC50 Reference
C20-diterpenoidalkaloids
14 Atisiniumchloride Gastriccarcinoma AGS 0.44µM/48h [49]
Hepatomacarcinoma HepG2 66.69µM/48h
Lungcancer A549 2.29µM/48h
15 Songorine Gastriccarcinoma SGC-7901 46.55µM/48h [50]
Hepatomacarcinoma HepG2 87.72µM/48h
Lungcancer A549 61.90µM/48h
16 12-epi-napelline Gastriccarcinoma SGC-7901 64.79µM/48h [50]
Hepatomacarcinoma HepG2 96.99µM/48h
Lungcancer A549 65.91µM/48h
17 12-epi-dehydronapelline Gastriccarcinoma SGC-7901 65.00µM/48h [50]
Hepatomacarcinoma HepG2 46.63µM/48h
Lungcancer A549 76.50µM/48h
18 12-acetylluciculine Malignantglioma A172 13.95µM/24h [51]
19 Pseudokobusine Malignantglioma A172 >15.18µM/24h [51]
20 6,11-dibenzoylpseudokobusine Malignantglioma A172 2.42µM/24h [51]
21 11-veratroylpseudokobusine Malignantglioma A172 2.52µM/24h [51]
Lungcancer A549 3.5µM/24h [52]
22 11-cinnamoylpseudokobusine Malignantglioma A172 1.94µM/24h [51]
Lungcancer A549 5.1µM/24h [52]
23 11-(m-trifluoromethylbenzoyl)pseudokobusine Malignantglioma A172 Notshown [51]
Lungcancer A549 4.4µM/24h [52]
Lungcancer A549 4.67µM/24h [54]
Lymphoma Raji 4.39µM/96h [53]
24 11-anisoylpseudokobusine Malignantglioma A172 2.80µM/24h [51]
Lungcancer A549 1.7µM/24h [52]
Lymphoma Raji 5.18µM/96h [53]
25 11-p-nitrobenzoylpseudokobusine Malignantglioma A172 3.13µM/24h [51]
Lungcancer A549 3.5µM/24h [52]
26 11,15-dianisoylpseudokobusine Lungcancer A549 1.72µM/24h [54]
27 11,15-di-p-nitrobenzoylpseudokobusin Lungcancer A549 2.66µM/24h [54]
28 11-(p-trifluoromethylbenzoyl)kobusine Lungcancer A549 5.44µM/24h [54]
29 11-(m-trifluoromethylbenzoyl)kobusine Lungcancer A549 3.75µM/24h [54]
30 11,15-di-p-nitrobenzoylkobusine Lungcancer A549 5.08µM/24h [54]
31 11-p-nitrobenzoylpseudokobusine Lungcancer A549 4.24µM/24h [54]
32 11-cinnamoylpseudokobusine Lungcancer A549 3.02µM/24h [54]
33 6,11-dianisoylpseudokobusine Lungcancer A549 3.68µM/24h [54]
34 11-veratroylpseudokobusine Lungcancer A549 4.07µM/24h [54]
35 11-anisoylpseudokobusine Lungcancer A549 2.20µM/24h [54]
36 11,15-dibenzoylkobusine Lungcancer A549 GI50=8.4µM/72h [55]
Prostatecancer DU145 GI50=9.3µM/72h
Epidermoidcarcinoma KB GI50=6.0µM/72h
Epidermoidcarcinoma KB-VIN GI50=7.5µM/72h
Molecules2017,22,267 9of14
Table1.Cont.
No. Compounds CancerTypes CellLines IC50 Reference
C20-diterpenoidalkaloids
37 11,15-dianisoylkobusine Lungcancer A549 GI50=6.7µM/72h [55]
Prostatecancer DU145 GI50=7.1µM/72h
Epidermoidcarcinoma KB GI50=5.3µM/72h
Epidermoidcarcinoma KB-VIN GI50=5.2µM/72h
38 11,15-di-(4-nitrobenzoyl)kobusine Lungcancer A549 GI50=6.9µM/72h [55]
Prostatecancer DU145 GI50=7.0µM/72h
Epidermoidcarcinoma KB GI50=5.3µM/72h
Epidermoidcarcinoma KB-VIN GI50=5.5µM/72h
39 11,15-di-(4-fluorobenzoyl)kobusine Lungcancer A549 GI50=8.1µM/72h [55]
Prostatecancer DU145 GI50=6.8µM/72h
Epidermoidcarcinoma KB GI50=5.2µM/72h
Epidermoidcarcinoma KB-VIN GI50=7.1µM/72h
40 11,15-di-(3-trifluoromethylcinnamoyl)kobusine Lungcancer A549 GI50=5.5µM/72h [55]
Prostatecancer DU145 GI50=6.2µM/72h
Epidermoidcarcinoma KB GI50=4.1µM/72h
Epidermoidcarcinoma KB-VIN GI50=3.1µM/72h
41 11,15-dibenzoylpseudokobusine Lungcancer A549 GI50=8.8µM/72h [55]
Prostatecancer DU145 GI50=7.6µM/72h
Epidermoidcarcinoma KB GI50=5.2µM/72h
Epidermoidcarcinoma KB-VIN GI50=6.3µM/72h
42 11-(4-nitrobenzoyl)pseudokobusine Lungcancer A549 GI50=5.8µM/72h [55]
Prostatecancer DU145 GI50=7.2µM/72h
Epidermoidcarcinoma KB GI50=6.4µM/72h
Epidermoidcarcinoma KB-VIN GI50=6.4µM/72h
43 11,15-di-(3-nitrobenzoyl)pseudokobusine Lungcancer A549 GI50=5.0µM/72h [55]
Prostatecancer DU145 GI50=5.2µM/72h
Epidermoidcarcinoma KB GI50=5.6µM/72h
Epidermoidcarcinoma KB-VIN GI50=5.6µM/72h
44 11-(3-trifluoromethylbenzoyl)pseudokobusine Lungcancer A549 GI50=6.8µM/72h [55]
Prostatecancer DU145 GI50=7.7µM/72h
Epidermoidcarcinoma KB GI50=8.9µM/72h
Epidermoidcarcinoma KB-VIN GI50=6.2µM/72h
45 11-cinnamoylpseudokobusine Lungcancer A549 GI50=8.4µM/72h [55]
Prostatecancer DU145 GI50=6.5µM/72h
Epidermoidcarcinoma KB GI50=7.0µM/72h
Epidermoidcarcinoma KB-VIN GI50=6.4µM/72h
46 11-tritylpseudokobusine Lungcancer A549 GI50=6.4µM/72h [55]
Prostatecancer DU145 GI50=6.0µM/72h
Epidermoidcarcinoma KB GI50=6.6µM/72h
Epidermoidcarcinoma KB-VIN GI50=5.3µM/72h
Molecules2017,22,267 10of14
Table1.Cont.
No. Compounds CancerTypes CellLines IC50 Reference
Bis-diterpenoidalkaloids
47 Bis-[O-(14-benzoylaconine-8-yl)]-pimelate Lungcancer A549 9.50µM/72h [56]
Breastcancer MCF-7 7.56µM/72h
Coloncancer HCT-15 4.64µM/72h
48 Bis-[O-(14-benzoylaconine-8-yl)]-suberate Lungcancer A549 7.53µM/72h [56]
Breastcancer MCF-7 6.90µM/72h
Coloncancer HCT-15 4.01µM/72h
49 Bis-[O-(14-benzoylaconine-8-yl)]-azelate Lungcancer A549 19.5µM/72h [56]
Breastcancer MCF-7 16.9µM/72h
Coloncancer HCT-15 28.0µM/72h