Synthesis and biological activity of desmethoxy analogues of coruscanone A

Article abstract of DOI:10.1016/j.bmcl.2011.08.059

A series of simple desmethoxy analogues of coruscanone A was prepared via a novel version of Ti(iPrO)₄-mediated Knoevenagel condensation of cyclopentenedione with substituted benzaldehydes and cinnamic aldehydes, and the compounds were evaluated for antifungal activity and cytotoxicity. The most potent 2-benzylidenecyclopent-4-ene-1,3-dione possessed antifungal effect comparable to coruscanone A and a somewhat broader spectrum of activity against Candida species. The compound was also superior to fluconazole against several non-albicans Candida sp. Evaluation of the ability of the compound to influence cell proliferation using two different assays showed that 2- benzylidenecyclopent-4-ene-1,3-dione has lower cytotoxicity compared to the natural product.

Full text of DOI:10.1016/j.bmcl.2011.08.059

Bioorganic & Medicinal Chemistry Letters 21 (2011) 6062–6066
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Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Synthesis and biological activity of desmethoxy analogues of coruscanone A
a
a
a
a
b
a,c
ˇ
Lucie Tichotová , Eliška Matoušová , Marcel Špulák , Jirí Kuneš , Ivan Votruba , Vladimír Buchta
,
Milan Pour a,
⇑
a Centre for New Antivirals and Antineoplastics, Department of Inorganic and Organic Chemistry, Charles University, Faculty of Pharmacy, Heyrovského 1203, CZ-500 03 Hradec
Králové, Czech Republic
b Centre for New Antivirals and Antineoplastics, Institute of Organic Chemistry and Biochemistry, Czech Academy of Sciences, Flemingovo n. 2, CZ-166 10 Prague 6, Czech Republic
c Department of Clinical Microbiology, University Hospital and Charles University, Faculty of Medicine, Sokolská 581, CZ-500 12, Hradec Králové, Czech Republic
a r t i c l e i n f o
a b s t r a c t
Article history:
A series of simple desmethoxy analogues of coruscanone A was prepared via a novel version of
Ti(iPrO)4-mediated Knoevenagel condensation of cyclopentenedione with substituted benzaldehydes
and cinnamic aldehydes, and the compounds were evaluated for antifungal activity and cytotoxicity.
The most potent 2-benzylidenecyclopent-4-ene-1,3-dione possessed antifungal effect comparable to
coruscanone A and a somewhat broader spectrum of activity against Candida species. The compound
was also superior to fluconazole against several non-albicans Candida sp. Evaluation of the ability of
the compound to influence cell proliferation using two different assays showed that 2-benzylidenecyclo-
pent-4-ene-1,3-dione has lower cytotoxicity compared to the natural product.
Received 22 July 2011
Revised 10 August 2011
Accepted 11 August 2011
Available online 19 August 2011
Keywords:
Cyclopentenediones
Knoevenagel
Lewis acid
Ó 2011 Elsevier Ltd. All rights reserved.
Antifungal
Cytotoxicity
The development of novel antifungal agents is of undisputable
importance in view of a significant increase of incidence of invasive
fungal infections, especially among hospitalized patients.1 While
the structures of existing drugs, especially those of the azole series2
are continuously being modified, the realm of natural products has
been a permanent source of novel active structures.3 Undoubtedly,
the production and screening of small, natural product-based
libraries continues to be an important tool in the identification of
new lead structures.4
(Fig. 1). Based on the exploration of structure-antifungal activity
relationships of a number of synthetic analogues, they concluded
that (1) alterations of the methyl groups (both that on the cyclop-
entenedione ring and the enolic methoxy group) reduce in vitro
antifungal activity, (2) replacement of the styryl moiety by a phe-
nyl or methyl group also leads to a dramatic drop in the activity,
and (3) p-substitution of the benzene ring or its replacement with
five-membered heterocycles maintains the activity of the com-
Having described the activity of
a-haloaryl c-alkylidene
butenolides,5 our attention was captured by the report by Clark
et al.6 on the isolation, synthesis and antifungal activity evaluation
of a structurally similar natural cyclopentenedione, coruscanone A
and several of its derivatives (Fig. 1). The natural product was
found to possess in vitro antifungal activity comparable to ampho-
O
O
Ar
Me
O Me
O
O
R
coruscanone A
tericin B, albeit in terms of
Vero and LLC-PK1 cells (4.9 and 3.4
The relationship between -alkylidene butenolides and
lg/mL, and acceptable toxicity against
γ-alkylidene
lg/mL, respectively).
butenolides
c
Figure 1. Structures of coruscanone A and
c
-alkylidene butenolides.
coruscanone A is shown in Scheme 1, arising from a base-catalyzed
rearrangement of the former into the latter. Hence, the possibility
of the same or related mechanism of action was envisioned.
Clark et al. have also investigated7 the importance of several
substructural fragments for antifungal activity, namely the cyclo-
pentenedione ring, enolic methoxy group and styryl moiety
O
O
base
O
O
⇑
Corresponding author. Tel.: +420 495 067 277; fax: +420 495 067 166.
E-mail address: milan.pour@faf.cuni.cz (M. Pour).
Scheme 1. Rearrangement of c-alkylidene butenolide into cyclopentenedione.
0960-894X/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2011.08.059

L. Tichotová et al. / Bioorg. Med. Chem. Lett. 21 (2011) 6062–6066
6063
Table 1
Lewis acid screening
O
O
R1
R2
R3
O
O
O
H
THF, rt, 12 hrs
O
R1 = Me, R2 = OH, OMe (ref. 7)
O
R1, R2 = H (this work)
1a
2a
Figure 2. General structure of the compounds studied.
Entry
LA
Amount of LA
Isolated yielda (%)
1
2
3
4
5
6
7
8
BF3ÁOEt2
Cu(OTf)2
Ti(OiPr)4
Ti(OiPr)4
Ti(OiPr)4
AuCl3
20.0
0.3
0.2
0.3
0.5
0.1
0.1
0.3
610
56
57
64
64
5
pounds at a level similar to the parent coruscanone A. However,
even though a number of analogues were prepared, the activities
of the most promising ones were only comparable to coruscanone
A, and antifungal activity was always accompanied by various de-
grees of cytotoxicity against the above-mentioned cell lines.
Interestingly, even though Clark and co-workers concluded7
that the cyclopentenedione moiety acts through its Michael
accepting ability, no attempt to prepare analogues with an unsub-
stituted cyclopentene double bond that would be even more easily
accessible by nucleophiles has been reported. Similarly, the SARs
clearly showed the importance of the methoxy group (as compared
to a free hydroxyl) for antifungal activity, but no deoxy derivatives
have been prepared.8 Since such compounds would be easy to
make via simple Knoevenagel condensations of cyclopent-4-ene-
1,3-dione with aldehydes, we set out to prepare a series of simple
Knoevenagel adducts with a variety of substituted cinnamaldehy-
des and benzaldehydes, and to evaluate the antifungal effect of
the derivatives (Fig. 2).
Knoevenagel condensation is a classical transformation that is
commonly carried out in basic media. However, basic conditions
are incompatible with the conjugated enone nature of the sub-
strate, which undergoes fast polymerization9 upon treatment with
a base. Prior to this work, only two papers describing a successful
Knoevenagel condensation of cyclopent-4-ene-1,3-dione with
benzaldehyde9 and cinnamaldehyde10 had been published, both
using a large excess (20 equiv) of BF3ÁOEt2. Even though the yields
reported were as high as 50%, in our hands the reaction repeatedly
afforded isolated yields 610%. In addition, the large excess of the
Lewis acid made the workup somewhat tedious. Since we intended
to prepare adducts with a number of aldehydes, we sought a more
user-friendly reagent that would deliver the Knoevenagel adduct
in a catalytic fashion in more acceptable yields.
Yb(OTf)3
Et2AlCl
30
0
a
3.0 equiv of cinnamaldehyde were used.
L
H
O
O
Ti
L
H
H
O
Ar
O
Figure 3. Tentative transition state for the condensation.
1. Pd(OAc)2
2. HCl
Z
OEt
OEt
Z
I
+
O
H
1a-d
Isolated
yield (%)
Product:
Z:
1a
1b
1c
1d
4-OCH3
4-CH3
4-Cl
70
58
61
47
4-NO2
Scheme 2. Preparation of substituted cinnamic aldehydes.
Table 2
Overview of the prepared compounds
A number of acids have been described as Knoevenagel reaction
promoters, including classical acidic reagents such as CeCl3Á7 H2O/
3.0 eq. RCHO
O
O
O
0.3 eq. Ti(OiPr)4
NaI,11 HClO4–SiO2,12 TiCl4,13 ZnCl2,14 NbCl5 as well as rare earth
15
THF, rt, 12 hrs
H
16
metal salts such as Yb(OTf)3. Some of the reagents were appar-
ently too harsh for sensitive compounds (TiCl4), while others
(NbCl5, Yb(OTf)3) seemed too costly given the simple nature of
the transformation. Even though some of the above reagents were
included in the screening for a suitable Lewis acid catalyst, our aim
was to identify an easily accessible, low cost reagent. As shown in
Table 1, 0.3 molar equivalents of Ti(iPrO)4 together with an excess
of the aldehyde enabled us to prepare compound 2a in an accept-
able, 64% isolated yield. Increasing the amount of the Lewis acid
had no appreciable effect, while decreasing led to a somewhat low-
er yield. Similar results were obtained using Cu(OTf)2. The use of
more expensive Yb(OTf)3 or AuCl3 in lower loadings (0.1) did not
lead to satisfactory yields. Solvent screening revealed that THF pro-
vided the best medium for the transformation.
As regards the mechanism of the reaction, it is interesting to note
that no changes in chemical shifts were observed upon monitoring
an equimolar mixture of cyclopent-4-ene-1,3-dione with Ti(iPrO)4
in THF-d8 by NMR. It would therefore seem that the Lewis acid
activates the aldehyde component and coordinates both partners
together. A tentative transition state derived from these consider-
R
O
Entry
R
Product
Isolated yield (%)
1
2
3
4
5
6
7
8
Ph-CH@CH–
4-MeOPh-CH@CH–
4-MePh-CH@CH–
4-ClPh-CH@CH–
4-NO2Ph-CH@CH–
Ph
2a
2b
2c
2d
2e
2f
2g
2h
2i
2j
2k
2l
2m
2n
2o
2p
2q
2r
64
21
36
30
0
43
31
49
49
25
57
31
10
0
4-MeOPh
4-MePh
4-ClPh
4-FPh
4-BrPh
3-BrPh
9
10
11
12
13
14
15
16
17
18
4-(Me)2NPh
4-NO2Ph
2-Furyl
3-Furyl
2-Thienyl
2-Naphthyl
70
0
45
22

6064
L. Tichotová et al. / Bioorg. Med. Chem. Lett. 21 (2011) 6062–6066
ations is shown in Figure 3. The cyclopentenone double bond as well
as the aldehyde aryl moiety must also play important roles, since
cyclopentane-1,3-dione did not react with benzaldehyde and cyclo-
pent-4-ene-1,3-dione did not afford any addition products with ali-
phatic aldehydes under the conditions described in Table 1, entry 4.
Having developed a suitable protocol, a number of 2-alkylidene-
cyclopent-4-ene-1,3-diones with substituted phenyl, substituted
styryl and heteroaryl moieties were prepared under the same con-
ditions. Substituted cinnamic aldehydes 1a–d, which were not
commercially available, were prepared17 via the Heck reaction of
substituted phenyl iodides with 3,3-diethoxypropene (Scheme 2).
The results summarized in Table 2 show that a substitution of
the phenyl ring generally decreases yields. This trend is more pro-
nounced for strong electron donors, even though the presence of
the strongly electron withdrawing NO2 group inhibited the reac-
tion completely. The yields of heteroaryl derivatives depend on
the nature of the heterocycles and position of the carbaldehyde
group. While furan-2-carbaldehyde furnished the highest yield of
alkylidene product 2o, its 3-isomer (2p) did not react at all.
Since the compounds were prepared for screening purposes, no
further optimization was attempted.
All compounds were subjected to screening for antifungal activ-
ity18 on a panel of both yeasts and filamentous fungi (Table 3). For
the purpose of a brief SAR evaluation, the antifungal activities ex-
pressed as IC80 were compared to coruscanone A as the parent
structure, and also to fluconazole as a drug standard. Surprisingly,
unsubstituted compound 2a with styryl side chain possessed sig-
nificant activity againstCandida albicans ATCC44859 strain, compa-
rable to coruscanone A, and was superior to the natural product
against Candida krusei and Candida glabrata. Thus, complete re-
moval of the methoxy group had very little effect on in vitro anti-
fungal activity, even though further substitution of the phenyl ring
meant a significant drop of biological effect. Appreciable activity
was detected only for the 4-methylstyryl derivative 2c, while the
4-OMe and 4-Cl styryl derivatives 2b and 2d were practically inac-
tive (IC50 P 62.5).
Also surprisingly, when the styryl double bond was removed,
the compounds retained antifungal effect, and the activities of
the unsubstituted phenyl derivative 2f were slightly higher than
those of its styryl counterpart 2a, especially against Candida tropi-
calis, C. glabrata and Trichosporon asahii. Similar to the styryl ana-
logues, substitution of the aryl ring also had a negative effect on
Table 3
Antifungal activities of 2a–r, coruscanone A and fluconazole
Compound
Time (h)
CA1a
CA2b
CPc
CK1d
CK2e
CTf
CGg
CLh
TAi
AFj
ACk
TMl
2a
24
48
24
48
24
48
24
48
24
48
24
48
24
48
24
48
24
48
24
48
24
48
24
48
24
48
24
48
24
48
24
48
24
48
1.95
1.95
125
250
3.9
7.81
62.5
62.5
1.95
1.95
3.9
15.62
15.62
250
3.9
7.81
250
3.9
7.81
250
15.62
15.62
250
7.81
15.62
250
15.62
31.25
250
7.81
15.62
250
250
7.81
15.62
62.5
62.5
7.81
15.62
7.81
31.25
15.62
15.62
31.25
31.25
15.62
31.25
15.62
15.62
31.25
31.25
7.81
31.25
15.62
15.62
15.62
15.62
15.62
15.62
NT
7.81
15.62
250
31.25
31.25
250
250
62.5
>125
62.5
125
15.62
31.25
15.62
31.25
31.25
125
>125
>125
>500
>500
>125
>125
>250
>250
250
7.81
62.5
250
500
125
>125
62.5
250
1.95
3.9
3.9
7.81
125
2b
2c
250
250
250
250
250
250
500
7.81
7.81
62.5
62.5
3.9
7.81
7.81
7.81
3.9
15.62
31.25
31.25
15.62
31.25
15.62
15.62
15.62
31.2
31.25
62.5
15.62
15.62
15.62
15.62
15.62
15.62
NTn
7.81
31.25
62.5
62.5
3.9
7.81
15.62
62.5
62.5
3.9
3.9
3.9
3.9
7.81
15.62
31.25
31.25
15.62
31.25
15.62
15.62
15.62
31.25
7.81
7.81
7.81
15.62
7.81
15.62
15.62
31.25
NT
7.81
15.62
62.5
62.5
3.9
7.81
7.81
62.5
62.5
3.9
31.25
31.25
62.5
62.5
7.81
7.81
7.81
7.81
31.25
>125
62.5
125
1.95
3.9
2d
2f
3.9
7.81
3.9
3.9
250
2g
7.81
15.62
15.62
15.62
31.25
31.25
15.62
31.25
15.62
15.62
31.25
62.5
3.9
7.81
15.62
15.62
15.62
15.62
15.62
15.62
NT
7.81
7.81
7.81
15.62
31.25
31.25
15.62
31.25
15.62
15.62
31.25
62.5
62.5
>125
15.62
15.62
15.62
15.62
31.25
31.25
3.91
7.1
7.81
31.25
15.62
62.5
31.25
62.5
31.25
62.5
15.62
15.62
32.5
125
7.81
15.62
15.62
31.25
15.62
31.25
15.62
62.5
0.98
7.81
4
>250
>250
>250
>250
>125
>125
>125
>125
>125
>125
>125
>125
>125
>125
250
>500
500
>500
125
>125
31.25
250
7.81
3.9
7.81
15.62
15.62
31.25
62.5
15.62
31.25
15.62
15.62
31.25
31.25
7.81
7.81
15.62
15.62
7.81
7.81
31.25
31.25
125
2h
2i
15.62
15.62
62.5
7.81
7.81
31.25
7.81
15.62
7.81
15.62
15.62
31.25
31.25
31.25
7.81
15.62
7.81
7.81
15.62
15.62
0.98
3.91
1
>250
125
62.5
62.5
62.5
>125
15.62
15.62
15.62
15.62
15.62
15.62
0.98
0.98
7.81
7.81
15.62
15.62
7.81
15.62
3.91
7.81
17
2j
31.25
31.25
15.62
15.62
31.25
62.5
31.25
62.5
31.25
31.25
125
2k
2l
125
2m
2o
2q
2r
62.5
15.62
31.25
15.62
31.25
15.62
15.62
15.62
31.25
31.25
250
>125
15.62
15.62
7.81
15.62
31.25
31.25
125
CorAm
FLUo
NT
0.8
3.3
NT
6.5
13
NT
>50
>50
250
>50
>50
125
22
>50
NT
3.3
3.3
3
5
>50
>50
>50
>50
2
9
26
a
b
c
Candida albicans ATCC44859.
C. albicans ATCC90028.
C. parapsilosis ATCC22019.
C. krusei ATCC 6258.
C. krusei E28.
C. tropicalis 156.
C. glabrata 20/I.
C. lusitaniae 2446/I.
d
e
f
g
h
i
Trichosporon asahii 1188.
Aspergillus fumigatus 231.
Absidia corymbifera 272.
j
k
l
Trichophyton mentagrophytes 445 (MIC values were determined after 72 and 120 h).
m
n
o
Coruscanone A.
NT = not tested.
Fluconazole.

L. Tichotová et al. / Bioorg. Med. Chem. Lett. 21 (2011) 6062–6066
6065
Table 4
Cytostatic activities
antifungal action of the compounds, albeit not so dramatic. Only
the 4-methoxyphenyl compound 2g was comparable to 2f for most
species, with the exception of C. albicans ATCC44859, Candida
parapsilosis and T. asahii, for which somewhat higher MICs were
recorded. 4-methylphenyl substance 2h displayed the same
inhibitory effect as the 4-methoxyphenyl derivative 2g against
C. albicans ATCC44859, and there are no significant differences for
most other strains, with the exception of C. krusei ATCC 6258, Asper-
gillus fumigatus and Trichophyton mentagrophytes. On the whole,
however, the profile of activity of 2h is worse than those of 2f
and 2g, and the same applies to haloaryl compounds 2i–l, the
effects of which are even lower. A partial exception was the
4-dimethylaminophenyl substance 2m with better MIC values
against both C. krusei strains, C. parapsilosis and T. mentagrophytes.
As regards the derivatives with a different aryl than phenyl
(2o–r), their MICs were also higher than those of unsubstituted
styryl and phenyl derivatives 2a and 2f.
The in vitro activities of the most effective derivative 2f were
comparable to coruscanone A against C. albicans, C. tropicalis and
T. asahii, and better than those of the natural product against C.
krusei, C. glabrata and A. fumigatus. Hence, the deoxygenation of
the methoxy function combined with the removal of the styryl
double bond in the natural product has very little influence on
the biological activity, and the simple benzylidene analogue has
a broader spectrum of activity against Candida strains. Compound
2f (and, in some cases, coruscanone A as well) is in vitro clearly
superior to fluconazole against non-albicans Candida sp., namely
C. parapsilosis, C. krusei, and C. glabrata, and comparable to the drug
against C. albicans, C. tropicalis and C. lusitaniae. In line with the
conclusions by Clark et al, further substitution of the phenyl ring
generally led to a decrease in the activity. However, unlike the pre-
viously described7 methoxy derivatives, the drop in the activity for
the substituted styryl analogues described herein was much more
pronounced, as demonstrated by the loss of activity of 2b and 2d.
On the other hand, the activities of the substituted benzylidene
derivatives 2g–m were not far from that of unsubstituted 2f. The
high in vitro antifungal effect of 2f is a possible indication that
the compounds of the simple benzylidene series described in this
paper may bind in a different way to the target protein, since
methoxy compound 37 (Fig. 4) lacking the styryl double bond
was inactive. However, Michael addition of a nucleophile also
seems to be the major driving force behind the interaction with a
cellular target.
Compd L1210a
HL 60b
HeLa S3c
CCRF-CEMd HT-29e Colo 201f
2a
2b
2c
2d
2f
2g
2h
2i
NAg
NA
NA
NA
NA
NA
NA
NA
NA
NA
NA
NA
NAg
NA
NA
NA
NA
NA
NA
NA
NA
NA
NA
NA
NA
NA
NA
NA
NA
NA
NA
NA
7.3 0.2
NA
NA
NA
NA
NA
NA
4.9 0.8
NA
NA
5.4 0.7
NA
13.5 1.1 3.7 0.1
3.6 0.2
4.4 0.2
NA
NA
NA
NA
NA
NA
NA
NA
NA
NA
NA
NA
NA
NA
NA
NA
NT
NA
NA
NA
NA
NA
NA
NA
NA
NA
NA
NA
NA
NA
2.6 0.2
3.8 0.2
2.7 0.2
6.1 0.4
1.6 0.1
1.8 0.3
7.5 0.5
4.3 0.1
2.5 0.3
4.2 0.2
2j
2k
2l
2m
2o
2q
2r
1.3 0.1
NA
NA
2.4 0.2
NT
CorAh
3.8 0.2 4.5 0.3 NTi
a
b
c
d
e
f
L1210 (ATCC CCL 219)—mouse lymphocytic leukemia cells.
HL-60 (ATCC CCL 240)—human promyelocytic leukemia cells.
HeLa S3 (ATCC CCL 2.2)—human epithelial carcinoma cells.
CCRF-CEM (ATCC CCL 219)—human leukemic T-cell lymphoblasts.
HT-29 (ATCC HTB 38)—human colon adenocarcinoma cells.
Colo 201 (ECACC 87091201)—human colon adenocarcinoma cells.
NA = not active at 10
Coruscanone A.
NT = not tested.
g
h
i
lmol/L.
compounds on the proliferation of HEK293 cells (human embryo-
nal kidney cells). With the exception of coruscanone A and com-
pounds 2a, 2c and 2k, for which a cytostatic-like action was
recorded (a mild decrease in proliferation, followed by a slow rise
and plateauing), no effect was observed. This, taken together with
the results of screening for cytostatic activity shown in Table 4
could be an indication that, compared to the previously prepared
derivatives,7 the cytotoxicity of the desmethoxy compounds de-
scribed herein may be reduced.
In summary, we have described reproducible conditions for the
Knoevenagel condensation of cyclopent-4-ene-1,3-dione with a
variety of aromatic and unsaturated aldehydes, and prepared a ser-
ies of desmethoxy analogues of the antifungal natural product, cor-
uscanone A. Evaluation of antifungal activity showed that some of
the compounds retained antifungal effect on the level of the natu-
ral product. Similar to previously described derivatives of corusca-
none A, further substitution of the phenyl or styryl moiety as well
as switch from phenyl to a naphthyl or heterocyclic ring led to a
decrease or complete loss of the biological effect. The most active
compound 2f was comparable to fluconazole as the drug standard
against C. albicans, C. tropicalis and C. lusitaniae, and was superior to
the drug against C. parapsilosis, C. krusei, and C. glabrata. Even
though Michael addition could be the reason for the binding of
the compound to its cellular target, it is notable that further
screening experiments indicated reduced cytotoxicity of the com-
pound in comparison to coruscanone A.
All compounds were also subjected to screening on a panel of
cancer cell lines, including three types of leukemic cells and three
solid tumors19; cell viability was quantified using XTT standard
spectrophotometric assay20 (Table 4). A majority of the new com-
pounds possessed moderate IC50 values (micromolar range)
against the CCRF-CEM line, and four of them also against HeLa
cells. The most active derivative 2f inhibited the growth of just
the CCRF-CEM cells, while moderate IC50 values against all leuke-
mic lines used in this study were recorded for coruscanone A.
In addition, all compounds were subjected to a preliminary
kinetic cell-based morphological screening.21 In this experiment,
impedance readout was used for monitoring the effect of the
Acknowledgments
This work was supported by the Ministry of Education, Youth
and Sports of the Czech Republic (Project No. 1M0508) and by
the Czech Science Foundation (Project No. P207/10/2048). L.T.
and E.M. also acknowledge partial financial support from Charles
University Grant Agency (Projects Nos. 98908 and SVV-263-001).
O
O
O
O
Me
O Me
3
2f
Supplementary data
not active
active
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.bmcl.2011.08.059.
Figure 4. Comparison of 3 and 2f.

6066
L. Tichotová et al. / Bioorg. Med. Chem. Lett. 21 (2011) 6062–6066
10. Aoyama, Y.; Konoike, T.; Kanda, A.; Naya, N.; Nakajima, M. Bioorg. Med. Chem.
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