Satd
(Htsfor Lqrinb b
[email protected];bne.net Mini-Reviews ln Medicinal Chemistry, 2014, 14, 322-331
322
Chemical Properties and Biological Activities of Cyclopentenediones: A Review
ZlnanaŠevčíkovál,Milan Pour2, David Novákl, Jitka Ulrichovál and Jan Vacekl'* ]Department
of Medical Chemistry and Bioch-emistry, Faculty of Medicine and DentisÍry, Palacky Llniversity, Hnevotinslq 3,77515 Olomouc, Czech Repubtic;2Department of Organic and Inorganic Chemistry, Charies ()niversity, Faculty of Pharmacy, Heyrovskeho 1203, CZ-500 05 Hradec Kralove, Czech Republic Abstract: Cyclopantenediones (CPDs) are secondary metabolites of higher plants, fungi, algae, cyanobacteria and bactcria. A common denominator of CPDs is the cyclopent4-ene-1,3
functional groups. The heterogeneity of these substitutions is reflectď in around one hundred CPDs reported to date, Most of the derivatives were isolated primarily from plant sources. Syntbetic analogues were then prepared with new biological activities and more interesting pharmacological potential. Antifungal substances called coruscanones (2, 3) are the most studied of the CPDs. Other intensely investigated CPDs include lucidone (4), linderone (5), asterredione ( ), involutone (7), nostotrebin 6 (8), TX- I 123 (9), GZZ}I-C (10), madindolines (l l, l2) and many others. In addition to anribacterial and antifungal effects, a broad spectrum of biological activities for CPDs has been reported in the past two decades, especially anti-inflammatory, cytostatic and specific enzyme inhibitory activities. The CPD skeleton has been identified in a number of substances isolated from the plant kingdom; hence, CPDs can be referred to as a new group of naťural bioactivc substances. The main goal of this review is to define CPDs with respect to basic chemistry, isotation, synthetic approachcs and description of their biological effects. Special attention is given to a detailcd vicw into biological acrivities of CPDs in vitro and their phamacological potential.
Keywords: Biological activity, cyclopentenediones, chemical properties, coruscanones, pharmacological potential, synthesis.
I.INTRODUCTION Cyclopentenediones (CPDs) are secondary metabolites of higher plants, fungi, algae, cyanobacteria and bacteria. A common denominator of CPDs is the cyclopent-4-ene-1,3dione skeleton (1, Scheme l), which is modified by several functional groups. The heterogeneity of these substinrtions is reflected in around one hundred known CpDs. Most of them were first isolated primarily from plant sources, but synthetic analogues with new biological activities and greater pharmacological potential were subsequently prepared. The most studied CPDs are coruscanone A (2) and B (3) isolated from Piper coruscans, which show significant antifungal activities Il]. other intensively investigatěd CPDs include lucidone (a) and linderone (5) isolatď from Lindera erythrocarpa |2f, asterredíone ( ) isolated from Aspergillus terreus [3], involutone (7) isolated from Paxillus inrěluu, [4], cyanobacterial
nostotrebin (B)
[5],
TX-l
123 (9) prepared
synthetically [6], GZ2al-c (10) isolated from fennentation
broths oÍ Streptomyces callleya [7], and madindoline A and B (l2) t8] bot}r isolated ťrom Strqtom}ves qp. (Scheme
(l1)
i).'
In addition to the well-known antibacterial and antifungal effects of the coruscanones, a broad spectrum of other CĚD
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biological activities has been reported in the past two decades including anti-inflammatory, hepato- and neuroprotective effects.
A
large number of
CPDs have been shown
to possess
relatively sfrong anti-inflammatory and cytostatic effects. Equally important are the inhíbitory effects of CPDs toward some enzymes.
This review is focused on chemical properties, isolation, synthcsis and biological effects of CpDs. To the best of our knowledge, no comprehensive overview of CpDs has been publíshed to date. This overview mainly provides information
g1_tlt. biological effects and pharmacological potential of cPDs as a group of less explored biologicallylctive substances; a complete overview of the topics considered is not a purpose of this paper.
2, CHEMICAL PROPERTIES, ISOLATION SYTHESIS
AND
Naturally occurring cpDs are mostly isolated in the form ^ of white, beige or even yellow-colored solid substances with melting points most frequently between 95 and 230 oc. Their
synthetically prepared analogs have similar properties. A wide spectrum of synthetic áerivatives t'as be"n prepared from coruscanone A (Z).Various other CpD derivatives, s.tructurally similar benzoquinones Il], and desmethoxy derivatives of coruscanone A [9] havl abo been prepared. Synthetically prepared derivativls of coruscanone A are yello_w_and light orange powders or yellow_colored oils Il]. The UV-vis absorption maxima of CpOs are usually found @
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-\-","ffi-,.re
Chemical Propertles and Biological Áctivities of Cyclopenuncdiones:
OH
Cyclopent4-ene-1,3-dione
Mini-Reviews in Medicinal Chemktry,2014, YoL 11,
o
No.4
323
Ho
OH
"ť/" (l)'
Review
ot'"-9
o$go
Scheme
Á
ío
(1) and its derivarives: coruscanone A (2), coruscanone B (3), lucidone (4), linderone (5), Tx-l 123 (9),G2201-c (10), madindoline A (l l) and madindoline B (12).
asterredione (6), involutone (7), nostotrebin 6 (t),
j,
between 200 and 350 nm f3,4,6, g-13]. However, for many substances, these data are not available.
Little is known about the solubiliťy and stability of CPDs
in an aqueous environment where sotuUifity is sigrrificantly influerrced by substitution of the hydroptrouic CPĎ skeleton (l). An overview of natural CpDs and their synthetically prepared derivatives together with the values of their melting
UV-vis absorption maxima, m/z values, given colors and molecular weights (Mry) is shown in Table l. points (m.p.), 2.1. Isolation
and Methods Used for Anatysis
CPDs were isolated from higher plants (piper
sp.,
I,tyderg sp.) [2, l4], fungi (Paxillus sp., Chamonrr;á sp.) i4, t5, l and cyanobacreria (Nostoc sp.) [5]. Their isolaiion'is
l
basď on classical liquid (liquiďliquid) extraction
from homogenizď biomass wit}r a suitable combination of nonpolar
and polar organic solvents and
chromatography [4,
below.
f'ral purification using preparative
5, l2]. Some examples
arě'described
The cPD antibioric G2201-c (r0) was isolated fronr
streptomyces cartlelta using a charcoar-based procedure and purification on sephadex LH-20 with a mixnrre of n-butanolmethanol-water followed by chromatographic repurification [7]. From the fruits of Lindera en,thiocarpa, lucidone (4)
linderone (5) and their methyl derivatives were isolated.
Ethanol was used as the extracfion solvent. The raw ex acr was resuspended in water and successively partitioned using
n-hexane and ethyl acetate. The selected fraction, *"rf separated by preparative chromarography [2]. Fungal CpDs, involutone (7) and its tetraacetyl derivátiué, *.'é isolated
from Paxillus involuÍils. Extraction was peďormed using ethanol and methanot. The alcohol was relnovď from the
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Mini-Revicws in Medicinal Chemistry,2014, VoL 14, No. 4
Teble
l.
Physico-chemical properties of selected cyclopent-4-enelJ-diones.
Substence
Asterredione 2,5 -di(
indol-3' -yl).3 -methoxy-5-methorycarbonylcyclopent-2
-ene-
G220t{ 2-hydroxy-2-hydroxymetrylcyclopent-4-ene-
1,3
dionei CuHoOr
Involutone 3,adihydroxyphenyl)-2-(4-hydroxyphenyl)-2-hydroxy-
cyclopent-4-ene-1,3-dionel CnH,:Or
Coruscanon A 2-(
I
-M ethoxy-3 -phenyl-2-propenylidene)-4-methylcyc
I
opent-4-
Coruscenone B I
-Hydroxy-3 -phenyl-allylidene)-4-methyl-cyclopent-4-ene-
1,3 -
dione; CrsHr:Or
Crlythrone l,3-dione; C11H
16O3
Linderone
Yellow powder
1,3
dione; C,u l sOs
Lucidone 2-Cinnamoyl-4-methoxycyclopent4-ene-
l,3dione;
C rsH rrOr
Nostotrebln 6 2,2'-bis[a,5-bis(4-hydroxybenzyl)-2-(4-hydroxyphenyt)cyclopent4-ene- 1,3-dione]; CsoHrrO'o
Medindoline A [[(2R),3 aR,8aS]-8-[4-(n-Butyt)-2,5dimerhyl-
dioxo-2 -(4-cyclopentyl )methyll-3,3 a,8,8a-tebahydro-3 a-
hydroxy-2 //-fu ro[2,3-á] indole]; Cl'H
>l12"c
UV-vis (aq.220nm,225 nm),IR, MS
Yellow crystals
(m/z 142.0195)
53 "C
'H NMR, ''c NMR" IR, MS (nlz 312.06170\
Yellow solid
l8l-182 "c
'H NMR, 'rc NMR, IR, UV-vis (MeOH, 732 nm,348 nm), MS
Yellow powder
86.C
'H NMR, ''c NMR,lR, UV-vis (MeOH, 232 nm,348 nm), MS (nlz 241.0849\
2
:lNol
Yellow needles 124 "C
Yellow solid
NMR, MS (m/z 296.0796)
92-94 "C
'H NMR,lR, UV-vis (acidic EtoH, 244 and,355 nm), MS (nlz 256.0'152)
Yellow solid
TX-l123 2-hydroxyarylidene-cyc lopenr-4-ene- l,3dione; C:oH:nOr
l6 -1 8"c
'H NMR, 'tc NMR,lR, X-ray, MS
Yellow needles
(mlz 799.2537)
205-207 "C
'H NMR, ''c NMR, lR UV-vis (MeOH, 20'1,245 and 299 nm),
Yellow needles
80-94'c
MS (n/z 370.2020) 'H NMR, ''c NMR, IR, UV-vis (MeOH,208 and 246 and 304 nm), MS (m/z 370.203 )
Mrďndoline B diastercomer to madindoline A; C,,HzrNOa
Ycllow oil
5 nm),
MS (n/z 208.1098) rH
2-Cinnamoyl4,5dimethoxycyclopent4-ene-
1,3
'H NMR, 'tc NMR,IR, uV-vis (EtOH, 4l I nm, 269 nm,2l8 nm),
IR, UV-vis (MeOH, 240 nm,
2-lsobutyryl4,5dimethylcyclopent-4-ene-
(+fMadindoline A:
Color m.p.
(mlz 255.1016)
ene-1.3-dione, Crollr rOr
2-(
Methods
MS(m/2414.1216)
1,4-dione; C:+HrrN:Os
5-(
ševčíkovdet aL
'H Huq IR, uV-vis (173 and 473 nrn)
M1ry
Ref.
4t4
t3l
142
l7)
312
14l
754
[1, re,5e]
240
[5e]
208
ilol
286
í.l2)
256
u2,441
798
t5l
369
[s0, s r]
3Ó9
Is0]
312
[
, 1r]
544
I
r, 381
262
[43]
264
t43l
Yellow needles
105-t07.c Yellow solid
t55-157.C
TX-203 Yellow crystals
2-niboimi.lrzole-aminornethylene cyclopent4_ene_ 1,3-dionc;
'H NMR. tR
Chrysotrione A
'H NMR, 'tc NMR,IR Uv_vis (EIOH, 229 and 27t nm), MS
C:rH:rN.O'
J-hydroxy_2_undec_ | 0-enoyIryclopenta-2,4{ien_
l
-one;
ClJÍ]ror
Chrysotrbne B -j
-hydroxy-2-undecanoylcyclopenta-2,4_dien-
.
I
one; Croll:rOr
186-l8g.c Pale yellow
crystals
(m/z 261.1494)
38-40
'H NMR, ',c NMR, tR. uV_vis (EIOH, 22s,268),MS (n/z 263.1649)
resulting extracts' which were digested successively with and acetoni ile' n-hexane' benzene' ethyl acetate' aia benzene, ethyl acetate separated
Th_e
.c
Yellow crystals
3941 "C
fractions acquirď were chÍomatogpphicaily
and the fungal metaboÍites identified [4]. Asterredione
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A Revlcw
Mini-Rcvieps in Mcdicinal Chenbtry,2014, VoI
(
) was extracted from Aspergillus terreus by methanol and ethyl acetate. The exmct was evaporated and parritioned by hexane and aqueous methanol. The methanolic fracrion was then extracted by CHCI3 and the final extract was separated on Sephadex LH-20 [3]. Hydroxyfuroindoline ring modified CPDs, madindoline A and B (tl and l2), were isolated from sírePtomyces sp. using ethy] acetate. The extracts were separated by silica gel column chromatography, and selected fractions were used for the purification of madindolines by HPLC [8]. To isolate nostotrebin (8) from Nostoc sp., a
gíven amount
of
biomass was extracted
by
methanol,
acetone and hexane, and the final exrract was fractioned using chromatography on a polyamide column [5].
Several procedures and methods were proposed for isolation, identification and routine analysis of CPDs. The most coÍnmonly used methods involve HPLC, usually in preparative scale [2, 8]. Of the tools of sffucrural chemisby, nuclear magnetic resonance (NMR) [3, l2], mass specrometry (MS) [, l2], and infrared (tR) spectroscopy [10, 16] were applied. A detailed list of methods used for the srudy of CPDs is shown in Table l. 2.2. Synthetic
Approaches to Cyclopentenediones
2.2.1. Approaches Involving Construction Cy clop
e
ntene-
1, 3
-dio
ne Sys te m
of
the
An established general approach to the title compounds tl0] is based on isomeric relationship betweén the
ryclopentene-1,3-dione system (15) and 4-ylidenebutarolides (la). As shown in Scheme 2, the lafter can be converted into the former via a base-catalyzed rearrangement. Since 4ylidenebutenolides can, in tUÍÍt, be prepared via Wirtig methylenation of readily accessiblc maleic anhydride
derivatives (13), the sequence has been the fastest and most frequ ently used entry into cyclopen tene- 1,3 -diones.
ol}"
.'ťo
nr^í .,:
o
*'Y4o
nrfi '.*
o \ Y\,lJ lt
)
13
Interestíngly, in 2005 Dias et o/' published [20] an aldol_ based strategy towards a new natural product isolated from Piper carniconnectivum, the strucrure of which was identical to that of coruscanone B. ln the key step, 4-triethylsilyloxy2-methylcyclopent-2-enone (18) was treared with LDA, and the enolate quenched by the addition of cinnamic anhydride Deprotection of the silyl group gave hydroxy ketonc (19) in 600Á overall yield' oxidation of the liberated hydroxyl in the next step then completed the synthesis (Scheme 4). .
A
conceptually different approach, based
on
the
reactivity of aryliodonium ylides was developed [21] by Varvoglis et al. They found that the reacrion of 2-hydroxy1,4-benzoquinones (20) with diacetoxy iodobenzene leads to
phenyliodonium ylides
decomposition
into
(2l), whích undergo
thermaI
cyclopent-4-ene- I ,3-diones (ZZ) (Scheme 5). A likely mechanism of the rransformation [22] involves the formation of carbene, Wolff rearrangement to keter:e, the reaction of the laner with H2o presěnt in the reaction mixture and, finally, decarboxylation of the acid
NaOH
reflux
Ph
62
oÁ
1. LDA, -78 oC 2. cinnannnhydride
60%
R2
1,3-diones with olfactory properties, and others [18]. Most recently, Clark el al. prepared [9] antifungal coruscanones A (2) and B (3) and their analogues Il] via NaOH-catalyzed rearrangement of 4-ylidenebutenolides (17), Scheme 3.
A and B.
Y OTES
Rr
This srategy was used by Pattenden et al. [10] in the of calythronc and related compounds, Hailes er ni. !71 for the preparation of 2-atkyl-4,5dimethylcyclopenrene-
o/o
3.TBAF
*'
3Zs
synthesis
t6
Scheme (3). Synthesis of coruscsnones
baso.
4
Scheme (2). General access to cyclopentene-l,3diones.
PhCH=CHCOCH2-PPh3 73
n3 n=PP!
11, No.
Swem, -78 oC 79
o/a
.tE
Scheme (4). Coruscanone B via aldol condensation approach.
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376 NtnLRclkrx
tn
Llcdbt'ul CluniÚy,2011, yď
11,
Na 1
Ševčíhova
thus formed to (22). The process gives various yields I2l-231 of diones (22) depending on the nature of Rl and R2.
oll
R.l
OO
nnlronc;
^'Y\* ť#t'.n*'Y1 n2f rntr oo
R2
mztu
presence of KolBu to furnísh the corresponding adduct (24) in high yield (Scheme ). Notably, thiophene 2-carboxaldehyde
[31] and ferrocenecarboxaldehyde
o
'n'''lí \ enrefi
Scbcmc (5I Preparation of cyclopcnrene-l J{iones from 2}ydroxy-
23
to
2-chloro-í,4-teir-
butylcyclopcnt-l,3-dione. The former reaÍTangement is by photochemically induced azide o ni ene decomposition, while the latter is likely to proceed via triggered
deprotonization of the starting 2_hydroxy-3,6-ái-terl-butyl_ 1'4_benzoquinonc, and oxidation of the eirsuing C3 enoláte by the Cu(lI) salt. Cyclopentsne-1,3{iones
were also identified [26,27j as . Tingf products of decomposition of Cr 126l .ii i" flzf
:T{T.]P" complex-es. Rlcently, -(r_pháyi.y.r"n--yril,4_bis(fenocenyl)-2^
1-cyclopent[e]pyridazine'*á' o*lo-ilJo
6-( l 1heny-l -. dihydro_5}/-cyclopeirt[ [
2.8
J
.
to
c-yc
lohex vt j- í,a-ui'1 renoceny
e]pyridazine-5,7_dione cyclopartene- 1,3-dione substnrcture.
2.2.2. Approacha Inwbing Cyclopc ntca cd ionc Syícrr -
A
ii,i
.o"'.iíiog í"
-
d.pm;J" of the protected hvdroxyklt"". rrďts"heme 4). However eaÚnent of',t-methvi.i"rJpít5_*._l,3-ďone witli LDA followed the
by rtre aaoiíioí
on
the other
orlni"mi.'"liydJ;;'*;
huť, Knoevenaget
condensafion of
1i-lirt.aiphenytphosphino)cyclop"o",_t,3-dione witb ttincthylaminobenzaldehyde
t:o]'was
D_
.'"'i;_;', #,í;
R
=
o
pt'rpŤ it ozl
ferrocenyl
9T
Yo
% %
Scheme (6). Base-promoted Knoevenagel condensations of
A
possible solution to the incompatibility of
cyclopentene-
1,3
rn
was
-{\ Ii l, ,r4t
disubstitutď cyclopentar- l,3 -dione (23).
4,5-
many
-diones, especially the unsubstituted parent
compound and monosubstituted derivatives, and basic conditions was recently published by Miftakhov and
corvglkers [33]. One oxo group in 4,5-dichlorocyclopenteno1,3-dione was protected as a ketal with ethylenb gVcol; tbe monoprotected compound was then readily enolized with LDA and subsequent treatrnent with electrophiles gave the 1 corresponding producrc in high yields. l,
An attractive possibility to avoid a basic medium in the Knoevenagel reaction is the use of Lewis acids. To this eu4 Pour and coworkers [9] have recently described Ti(Ol?r)rmediated condensations of the parent cyclopent-1,3-dione with unsaturated, aromatic and heteroaiomátic aldehvdes (Scheme 7).
,'t y ir
./
OO
i,iJgf,Tl*,
,l -{
)-a 21_to% y-*
25 *=i3'!'Hplwíi"
both
B (3) Ú'm trar'invotving
RCHO
R = paminophenyl 95 g0 = 2-thienyt
Functionaliution of the
ca onyts. Depuy and Wells..p.".O fZSl as;;!; * 19 0 that rmsubstituiď underqoes 'y"top'ntá.-l,3{ione fast polymerization, prou"rty .*rrtn ;; ffi,r";l-; addition, in basic .media. T *, áo'rr"ooo under basic c.ondirions- is practical T ly fo. *rn. 4,S_disubstituted diones, since the. conjugatJ .aair"" process may be decererated or hindered-! ,rr" *uoi,o,ioo of e yn.bulp Srouns. E;p"riil;f resurts obraineddouble !-na later are pcďectly in line with this ."*,,,|tioo F;;;ffil;:'i" the above_mentionď.paper r20j, Di;'eÍ o/. also anempted enolisation of l'3{io""l*orái. Jy,",,oo as a shorter ryprorh to cÚlJscmon
required no base
R
The structure of cyclopentene_|,3_dione seems to offer a facile further functionalization or éz via basic enolizatioď alkylarion or acylation: nls possibility, trowener, is fi* ; by the substitution of the c+'cs aouuíe bond, dj;gilJ;"
mere 22 % yteld.
í. KoťBu en'R.-
2.
o
1,4$cnaquinoncs.
3,6-di-tert-buryl-l,4_benzoquinone
l3}l
the same process; the presence of molecular sieves suffrcient to shíft the equilibrium toward the products.
nrt-(
Notably, more than 20 yean before Varvoglis, in 1971, Moore and coworkers reported I24,2Sl a couple of related reactions whictr" however, have not found goreral application. Onc of these [24] includes photochemical ring contraction of 2,s-diazido l,+b nzoquinones to,l-azidoryclopent- I J {iones substituted with a nitrile goup and alkyl at Cž, the other is a CuCl2-mediated oxidarive rearrangernent [25] of 2-hydroxy_
ď
26
Scbeme (7). Lewis acid medialed Knoevenagel condensations of -
the parent systern.
though the reaction was not applicable to aliphatic ^,,-TuT and most yields alclehydes, were modeiuj" to low, no better Írccess to diones (2 has been reported so far. ) 3.
TOXICITY AND BIOLOGICAL ACTIVITY
3.1.
Cytotoxicity end jn uruo Toxicity
.. The cytotoxic effects
diones and treir derivatives egg cells of the sea urchin
l*.:TloT{.T
of 2-acetylcyclopent4-ene-1,3;;;;Jdgatď using fertilizod
(sffongb;entotus
intermedius')
employed **,h" ."io"n". a*g. rrr. results ndicated that all CpDs tested are less toxi than carminorycin (MICroo: I pglml) .ft";; h incubation period [34].
C}totoxicity of coruscanone A (2) was testď on monkey kidney fibrobíasts rvooi*J *u' ..
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o'I,o*"ilil,h.lil-
chenical Propertbs and Biological Activitics of cyclopcntenediones:
A
(LLC-PKI) for 48 hours. Neutral red retention (NR) was monitorď and doxorubicin (DoX) was used as the comparative substance. Coruscanone A was more toxic than doxorubicin
in the case of Vero cells (lcso (DOX) IC5p(coruscanone
A)
:
:
7.5 pglml
vs.
4.9 pglml). ln contrast to Vero cells, lower cytotoxicity was found for
for LLC-PKI cells, coruscanone A (lCso :3.4 pglml) in comparison to DOX (lCso : 0. 5 pglml) [l1. Anorher srudy showed that the cytotoxicity of coruscanone
amphotericin B
!91.
A
was comparable to that of
Cytotoxicity and effects on apoptosis and necrosis were described for nostonebin (8) in detail [35]. The cyrotoxiciry was studied on mouse fibroblasts (BALB/c cells) in a concentation range l-25 pM. ln order to evaluate cytotoxicity, methods based on the NR and intracellular dehydrogenase activity measurements (MTT method) were used. The lC56 values after 24 h were 8.48 pM and 12.15 pM by NR and MTT methods, respectively. As the reference compound, doxorubicin was used (1C50(DOX): 1.26 pM (for NR assay) and2.04 pM (for MTT assay) t351.
The cytotoxicity of asterredione (6) and other compounds isolated ftom Aspergillus terreu.' was reported ín various cell lines, NCI-H460 (human non-small cell lung cancer), MCF-7 (human breast cancer) and SF-268 (human CNS cancer) and compared to taxol. IC56 values for asterredione varied from 17.4 pM to 25.2 pM using above cell lines as derermined by
MTT assay after 48 h. ICso values of taxol were generally 1000 times lower [3].
DCPC substance (2-[ I -hydroxy-3-phe nyl-(Z,28)-2propenylidene]-4-methyl-cyclopent-4-ene- 1,3-dionc) was isolated from the roots of Piper carniconnectivum and its
cytotoxicify tested on peritoneal macrophages obtained from BALBic mice. The cell viabiliry was evaluated using the filpan blue exclusion test for g hours. The IC5p in the macrophages treated with DCPC was 129 pg/ml [3 ].
Cytotoxicity was also evďuated for madindolines (ll, 12) by MTT assay for 72 h using various cell lines; IL- _N4H 0 (nterleukin 6 dependent cells), Bl (melanoma cell line), P388/ADM (adriamycin-resisranr p3gg leukernia cells), HUVEC (human umbilical vein endothelial cells), CPAE
(calf pulmonary artery endothelial cells), HL
0
(human
antiangiogenic hypoxic
I. Cytosutic Effecr
one of the first observations of the antitumor potential of CPDs was shown in 2-arylidene-cyclopent-4-ene-1,3-diones Í37l. Cytostatic effects
of synthetically
2-hydroxyaryl iden e-4-cyc lopan t-4-enc-
ÍÚr
1,3
prepared series of -diones were tesred
cell
radiosensitizer
with EGFR
(epidermal growth factor receptor) kinase inhibition acriviry (lc5o
