New antitumour agents with α,β-unsaturated δ-lactone scaffold: Synthesis and antiproliferative activity of (?)-cleistenolide and analogues

Article abstract of DOI:10.1016/j.bmcl.2016.05.044

A stereoselective total synthesis of (?)-cleistenolide (1) from D-glucose has been achieved. This new approach for the synthesis of (?)-cleistenolide and analogues involves a one-C-atom degradation of the chiral precursor, (Z)-selective Wittig olefination, followed by the final δ-lactonisation. Synthesized compounds showed potent growth inhibitory effects against selected human tumour cell lines, especially 2,4,6-trichlorobenzoyl derivative 12, which in the culture of MDA-MB 231 cells displayed the highest activity (IC₅₀0.02?μM) of all compounds under evaluation. A preliminary SAR study reveals the structural features that are beneficial for antiproliferative activity of synthesized δ-lactones, such as presence of either electron-withdrawing or electron-donating substituents in the aromatic ring, as well as the presence of cinnamoyl functionality instead of benzoyl group at the O-7 position.

Full text of DOI:10.1016/j.bmcl.2016.05.044

Accepted Manuscript
New antitumour agents with α,β-unsaturated δ-lactone scaffold: Synthesis and
antiproliferative activity of (−)-cleistenolide and analogues
Goran Benedeković, Ivana Kovačević, Mirjana Popsavin, Jovana Francuz,
Vesna Kojić, Gordana Bogdanović, Velimir Popsavin
PII:
S0960-894X(16)30529-7
DOI:
http://dx.doi.org/10.1016/j.bmcl.2016.05.044
BMCL 23903
Reference:
Bioorganic & Medicinal Chemistry Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
11 April 2016
13 May 2016
14 May 2016
Please cite this article as: Benedeković, G., Kovačević, I., Popsavin, M., Francuz, J., Kojić, V., Bogdanović, G.,
Popsavin, V., New antitumour agents with α,β-unsaturated δ-lactone scaffold: Synthesis and antiproliferative
activity of (−)-cleistenolide and analogues, Bioorganic & Medicinal Chemistry Letters (2016), doi: http://dx.doi.org/
10.1016/j.bmcl.2016.05.044
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Bioorganic & Medicinal Chemistry Letters
New antitumour agents with α,β-unsaturated δ-lactone scaffold: synthesis and
antiproliferative activity of (−)-cleistenolide and analogues
Goran Benedekovića, Ivana Kovačevića, Mirjana Popsavina, Jovana Francuza, Vesna Kojićb, Gordana
Bogdanovićb and Velimir Popsavina,
a Department of Chemistry, Biochemistry and Environmental Protection, Faculty of Sciences, University of Novi Sad, Trg Dositeja Obradovića 3, 21000 Novi
Sad, Serbia
b Oncology Institute of Vojvodina, Put Dr Goldmana 4, 21204 Sremska Kamenica, Serbia
———
Corresponding author. Tel.: +381 21 485 27 68; fax: +381 21 454 065. E-mail address: velimir.popsavin@dh.uns.ac.rs (V. Popsavin)

ARTICLE INFO
ABSTRACT
Article history:
Received
Revised
Accepted
Available online
A stereoselective total synthesis of (−)-cleistenolide (1) from D-glucose has been achieved.
This new approach for the synthesis of (−)-cleistenolide and analogues involves a one-C-atom
degradation of the chiral precursor, (Z)-selective Wittig olefination, followed by the final δ-
lactonisation. Synthesized compounds showed potent growth inhibitory effects against selected
human tumour cell lines, especially 2,4,6-trichlorobenzoyl derivative 12, which in the culture of
MDA-MB 231 cells displayed the highest activity (IC50 0.02 µM) of all compounds under
evaluation. A preliminary SAR study reveals the structural features that are beneficial for
antiproliferative activity of synthesized δ-lactones, such as presence of either electron-
withdrawing or electron-donating substituents in the aromatic ring, as well as the presence of
cinnamoyl functionality instead of benzoyl group at the O-7 position.
Keywords:
Cleistenolide
Cleistenolide mimics
Antitumour δ-lactones
SAR
2016 Elsevier Ltd. All rights reserved.
Analogue synthesis
Natural products and their synthetic derivatives are important
as drug candidates or lead structures for the discovery of novel
drugs.1 Natural products possessing α,β-unsaturated δ-lactone
ring, have long been considered as attractive scaffolds in drug
discovery because of their diverse array of biological activities
such as antibacterial, antifungal, and antitumour properties.2
Recently Nkunya et al. isolated the α,β-unsaturated δ-lactone (−)-
cleistenolide (1, Scheme 1) from the Cleistochlamys kirkii Oliver,
and found that it displays significant antibacterial activity against
Staphylococcus aureus and Bacillus anthracis, as well as anti-
fungal activity toward Candida albicans.3 Due to its interesting
structural features and evident pharmacological potential, the
synthesis of cleistenolide has attracted much attention among
synthetic medicinal chemists. Eight total syntheses of (–)-
cleistenolide have been reported so far, all of them using a chiral
pool strategy and D-mannitol,4 D-arabinose,5 (−)-isoascorbic
acid,6 or D-tartaric acid7 as starting materials. Moreover, a
chemoenzymatic approach to (−)-6-epi-cleistenolide was also
recently reported.8 Despite the existence of these synthetic
pathways, there still exists a need to develop novel procedures
for this class of compounds. In continuation of our ongoing
studies on the synthesis of bioactive natural products from
abundant monosaccharides,9 we have focused on the synthesis of
(−)-cleistenolide because of its potential antitumour activity.
Namely, despite the existence of numerous compounds with α,β-
unsaturated δ-lactone scaffold that exhibited strong antitumour
activities in vitro,10 there is no record in the literature about
antiproliferative activities of 1 or its analogues. Herein, we
disclose a new total synthesis of (−)-cleistenolide starting from D-
glucose, along with the preparation of several new mimics of 1
bearing electron-withdrawing or electron-donating substituents in
the aromatic ring. A new analogue of 1 in which a cinnamoyl
moiety replaces benzoyl group at the C-7 position was also
designed, since the cinnamoates represent a well known class of
anticancer agents.11 A brief study of in vitro antitumour activity
of synthesized compounds against a panel of human cancer cell
lines is an additional objective of this work.
As depicted in the retrosynthetic analysis (Scheme 1), the
required dihydropyran-2-one 1 was envisioned to be formed from
the (Z)-enoate 2a through an intramolecular transesterification
process. Intermediate 2a would be prepared from fully protected
glucofuranose derivative 2b through initial acetal deprotection,
subsequent glycol cleavage and final (Z)-selective Wittig (or
Horner-Wadsworth-Emmons) olefination. Finally, precursor 2b
can be prepared from commercially available monoacetone D-
glucose (2) through regioselective 6-O-monobenzoylation and
subsequent 3,5-di-O-acetylation.12

products 3 and 4 were in full agreement with the reported values
{compound 3: mp 198–199 °C (EtOAc/hexane), lit.13a mp 195–
196 °C (EtOH/CHCl3), [α]D=+6.0 (EtOH, c 1.0), lit.13a [α]D=+4.7
(EtOH, c 0.5); compound 4: mp 108 °C (EtOH), lit.14 mp 108 °C
(EtOH), [α]D=+5.5 (CHCl3, c 1.0); lit.14 [α]D=+7.1 (CHCl3, c
3.0)}. IR, NMR and HRMS data for both 3 and 4 are consistent
with their structures. Hydrolytic removal of the isopropylidene
protecting group in 4 gave the expected lactol 5 in 84% yield.
Oxidative cleavage of lactol 5 with periodic acid, followed by Z-
selective Wittig olefination15 of the resulting aldehyde 5a with
stabilized C2-ylide (Ph3P=CHCO2Me) afforded a mixture of the
unsaturated ester 6 (4%) and target 1 (10%). Prolonging the
reaction time and elevating the reaction temperature did not
increase the yields of Wittig olefination. Slightly better yields of
both products 6 and 1 were obtained, when the olefination step
was carried out in the presence of Still’s reagent16 derived from
unstable ylide using the Z-selective Horner-Wadsworth-Emmons
reaction protocol.17 Under these conditions, Z-enoate is obtained
as the main reaction product (25%), accompanied with minor
amounts of target 1 (13%). Treatment of 6 with toluene-4-
sulphonic acid in wet pyridine gave 64% yield of natural product
1. This procedure provided the target 1 in 17.9% overall yield
from six synthetic steps. The physical and spectral data of thus
obtained synthetic sample 1 were in excellent agreement with the
literature reports.12
Scheme 1. Retrosynthetic analysis of (−)-cleistenolide (1).
In order to develop a more efficient procedure for the
preparation of (−)-cleistenolide (1) we envisioned an alternative
seven-step route which is shown in Scheme 3. The sequence also
started from monoacetone D-glucose 2, which was converted to
the known18 tri-O-benzyl ether 7 under the standard conditions,12
and in an almost quantitative yield. Rather different optical
Scheme 2. Reagents and conditions: (a) BzCl, 1:1 CH2Cl2/Py, rt, 4 h, 75%;
(b) Ac2O, 1:1 CH2Cl2/Py, rt, 20 h, 98%; (c) 90% aq TFA, CH2Cl2, 0 °C, 0.5
h, then rt for 2 h, 84%; (d) H5IO6, EtOAc, 4.5 h; (e) Ph3P:CHCO2Me, Et3N,
MeOH, N2, 0 °C, 2.5 h, 4% of 6 (from 5), 10% of 1 (from 5); (f)
(CF3CH2O)2P(O)CH2CO2Me, NaH, THF, Ar, −10 °C, 3 h, 25% of 6 (from
5), 13% of 1 (from 5); (g) TsOH, aq Py, rt, 5 days, 64 % of 1.
The first synthetic route to (−)-cleistenolide (1) started from
commercially available monoacetone D-glucose 2 (Scheme 2),
which was treated with benzoyl chloride in the presence of
pyridine in dichloromethane using a slightly modified literature
procedure.12 The known13 7-O-benzoyl derivative 3 was obtained
in 75% yield. Treatment of 3 with acetic anhydride in a mixture
of dry pyridine and dichloromethane, gave fully protected
intermediate 4 in 98% yield. Physical constants of thus prepared
Scheme 3. Reagents and conditions: (a) BnBr, NaH, DMF, 0 °C, 0.5 h, then
rt for 2 h, 97%; (b) 50% aq TFA, rt for 18 h, 83%; (c) H5IO6, EtOAc, H2O,
rt, 3 h; (d) Ph3P:CHCO2Me, MeOH, 0 °C, 1 h, rt, 22 h, 84% (from 8); (e)
TsOH, CH2Cl2, rt, 96 h, 94%; (f) FeCl3, CH2Cl2, rt, 24 h, 64%; (g) (i) BzCl,
Py, CH2Cl2, rt, 4 h; (ii) Ac2O, rt, 20 h, 81%.

target molecule (−)-cleistenolide (1). This procedure provided the
target 1 in 33% overall yield from seven synthetic steps. It further
means that this new approach to 1 provided the highest overall
yield and the least number of synthetic steps than the majority of
previously published syntheses (seven of eight). The single
exception is the synthesis from D-arabinose,5 which provided a
total yield of 49% from eight synthetic steps. The spectroscopic
1
and physical data (IR, H and 13C NMR spectra, optical rotation
and melting point) of synthesized natural product 1 were
identical in all respects to the data reported in the literature.12 An
additional advantage of this new approach is that it provides
access not only to the natural product 1, but also to a variety
analogues of 1 for biological testing. Therefore, our next studies
are directed to prepare analogues with additional electron-
withdrawing and electron-donating substituents in the aromatic
ring (12 and 13, Scheme 4), as well as a new analogue of 1 in
which cinnamoyl moiety replaces benzoyl group at the C-7
position (14).
One-pot procedure involving trichlorobenzoylation of primary
hydroxyl group in 11, followed by the acetylation of secondary
hydroxyl groups (Py, CH2Cl2), provides the required analogue 12
in 85% yield. Similarly, reaction of 11 with 3-methoxybenzoyl
chloride, followed by acetylation under the similar conditions
afforded a 67% yield of analogue 13. Finally, the cinnamoyl
protection of primary alcohol 11 followed by the acetylation of
secondary hydroxyl groups (Py, DMAP, CH2Cl2) provided a
moderate yield of target 14 (35%).
Scheme 4. Reagents and conditions: (a) (i) 2,4,6-trichlorobenzoyl chloride,
Py, CH2Cl2, rt, 4 h; (ii) Ac2O, rt, 20 h, 85%; (b) (i) 3-methoxybenzoyl
chloride, Py, CH2Cl2, rt, 6 h; (ii) Ac2O, rt, 20 h, 67%; (c) (i) cinnamoyl
chloride, Py, DMAP, CH2Cl2, rt, 4 h; (ii) Ac2O, rt, 20 h, 35%.
rotations are reported in the literature for 7 {lit.18 [α]D=−61.8 (c
0.3, CHCl3); lit.19 [α]D=−33.0 (c 9.3, CHCl3)} and both of these
values are different from our value {[α]D=−45.2 (c 1.0, CHCl3)}.
Such different optical rotation values can be caused by
differences in the concentration and by the measurement
The biological activities of the synthesized natural product 1,
and the corresponding analogues 12–14 were evaluated by an in
vitro cytotoxicity test carried out with a panel of eight human
tumour cell lines including myelogenous leukaemia (K562),
promyelocytic leukaemia (HL-60), T cell leukaemia (Jurkat),
Burkitt's lymphoma (Raji), ER+ breast adenocarcinoma (MCF-7),
ER− breast adenocarcinoma (MDA-MB-231), cervix carcinoma
(HeLa), lung adenocarcinoma epithelial cells (A549) and one
normal cell line (foetal lung fibroblasts MRC-5). Cell growth
inhibition was evaluated after 72-h cells treatment by MTT
asay.22 The commercial antitumour agent doxorubicin (DOX)
was used as the positive control in this assay.
1
temperature. By contrast, H NMR data of 7 were in reasonable
agreement with the reported values.18,19 Additionally, IR, 13C
NMR and HRMS data are in full agreement with structure 7.
Hydrolytic removal of the isopropylidene protective group in 7
(50% aq TFA), gave the corresponding lactol 8 (83%). This is
followed by oxidative cleavage of 8 with periodic acid, and by
subsequent Z-selective Wittig olefination of the resulting
aldehyde 8a. We assume that the low yield observed during the
conversion of lactol 5 into enoate 6 (Scheme 2) is a consequence
of the enhanced stability of intermediate 5a, which contains two
electron-withdrawing groups at both adjacent positions to the
formyl group. In order to avoid the formation of formyl ester, the
oxidative step was carried out in aqueous ethyl acetate,20 to
afford the corresponding aldehyde 8a. Wittig reaction of crude 8a
with a stabilized C2-ylide (Ph3P=CHCO2Me) gave (Z)-enoate 9 in
84% yield. Treatment of 9 with toluene-4-sulphonic acid in
dichloromethane (rt, 96 h) gave an excellent yield of pyranone 10
(94%). Compound 10 was subsequently treated with FeCl3 in
anhydrous dichloromethane to afford the expected triol 11 in
64% yield.21 Finally, the O-benzoyl protection of primary alcohol
11 followed by the acetylation of secondary hydroxyls gave the
As shown in Table 1, natural product 1, and the corresponding
mimics 12–14 exhibit moderate to potent in vitro anticancer
activities, with maximal activities in the submicromolar range.
The natural product 1 and analogues 13 and 14 were completely
inactive toward normal MRC-5 cells, in contrast to the
commercial drug DOX that showed a potent cytotoxic activity
toward these cells (IC50 0.10 µM). Only analogue 12 exhibited a
weak cytotoxicity against this cell line (IC50 45.68 µM). All three
analogues 12–14 demonstrated potent antiproliferative effects
Table 1. In vitro cytotoxicities of (−)-cleistenolide (1), the corresponding analogues 12–14 and DOX
IC50 (µM) a
Compounds
K562
7.65
1.02
2.69
0.28
0.25
HL-60
1.21
Jurkat
14.22
6.25
Raji
MCF-7
26.07
0.62
MDA-MB 231
2.25
HeLa
7.32
14.02
1.95
0.21
0.07
A549
16.34
4.23
MRC-5
>100
45.68
91.34
>100
0.10
36.94
11.24
25.64
11.21
2.98
1
36.21
0.89
0.02
12
8.31
4.71
7.46
11.02
2.02
13
24.59
0.92
0.25
15.98
0.20
1.46
14
0.03
0.09
4.91
DOX
a IC50 is the concentration of compound required to inhibit the cell growth by 50% compared to an untreated control. The values are means of three
independent experiments done in quadruplicates. Coefficients of variation were <10%.

toward K562 cells in the low micromolar range. The most active
compound is 7-O-cinnamoyl derivative 14 that displayed 27-fold
higher potency when compared to lead 1 and showed similar
activity as DOX in the culture of these cells. The highest potency
in the culture of HL-60 cells was recorded after treatment with 13
(IC50 0.89 µM), which is similar to that observed for the
commercial drug doxorubicin (IC50 0.92 µM) as well as for the
parent compound 1 (IC50 1.21 µM) in the same cell line.
Cinnamoate 14 is the most active analogue against Jurkat cells. It
is 57-fold more potent than natural product 1 in the same cell
culture, but was over 8-fold less active then DOX against this cell
line. Raji cells are the least sensitive to lead 1. Analogues 12 and
14 are the most potent compounds against this malignant cell
line, being approximately 3-fold more active than 1 and almost 4-
times less active than DOX. Trichlorobenzoyl derivative 12
showed the highest potency toward MCF-7 cells (IC50 0.62 µM).
It exhibited 42-fold stronger activity with respect to lead 1 and
approximately 3-times lower potency when compared to DOX.
The parent compound 1 and all synthesized analogues (12–14)
exhibited notable antiproliferative effects on MDA-MB 231 cells,
with IC50 values in the low-micromolar range. The most active
molecule against this cell line is 7-O-trichlorobenzoyl derivative
12 (IC50 0.02 µM) being over 100-fold more potent than 1. In the
same time, molecule 12 exhibited 4.5-fold higher potency than
DOX in this cell line. Additionally, this molecule represents the
most active compound synthesised in this work. (−)-Cleistenolide
(1) and analogues 12–14 demonstrated diverse antiproliferative
effects toward HeLa cells in the range of IC50 0.21–14.02 µM.
The highest potency in the culture of these cells was recorded
after treatment with 14 (IC50 0.21 µM), which was approximately
35-fold more active than lead 1. However, comparing to DOX,
this analogue exhibited 3-fold lower activity against HeLa cells.
The most potent (−)-cleistenolide mimic toward the A549 cell
line is compound 14, that exhibited over 8 and 2.5-fold higher
potency when compared to lead 1 and DOX, respectively.
231 and HeLa cells, all of the remaining cell lines were more
sensitive to analogues 12–14 than to lead 1. Certain compounds
showed very potent antitumour activity, especially analogues 12
(IC50 0.02 µM against MDA-MB 231 cells) and 14 (IC50 0.21 µM
against HeLa cells), which displayed the highest activity of all
compounds under evaluation. A brief SAR study points to the
structural features that are beneficial for antiproliferative activity
of synthesized lactones, such as presence of either electron-
withdrawing or electron-donating substituents in the aromatic
ring, as well as the presence of cinnamoyl functionality instead of
benzoyl group at the O-7 position. This represents a possible clue
for the development of a variety of new anticancer agents bearing
an α,β-unsaturated δ-lactone scaffold and modified aromatic
moieties. This will be the subject of our future studies.
Acknowledgments
Financial support of the Ministry of Education, Science and
Technological Development of the Republic of Serbia is
acknowledged (Grant No. OI1612036).
Supplementary data
Supplementary data (experimental procedures, full
characterization data, and copies of NMR spectra of final
products) associated with this article can be found, in the online
version. These data include MOL files and InChiKeys of the
most important compounds described in this article.
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New antitumour agents with α,β-unsaturated δ-
lactone scaffold: synthesis and antiproliferative
activity of (−)-cleistenolide and analogues
Leave this area blank for abstract info.
Goran Benedeković, Ivana Kovačević, Mirjana Popsavin, Jovana Francuz, Vesna Kojić, Gordana Bogdanović
and Velimir Popsavin