Synthesis and antiplasmodial activity of bicyclic dioxanes as simplified dihydroplakortin analogues

Article abstract of DOI:10.1021/jm200686d

Here we report the synthesis and evaluation of antiplasmodial activity of a novel series of bicyclic peroxides inspired by the marine natural compound dihydroplakortin. We developed a synthetic strategy leading to the dihydroplakortin-related peroxides in only a few steps. The in vitro antiplasmodial potency of the peroxides was similar to, or greater than, that of the reference natural compound, and structure-activity relationship studies revealed several key structural requirements for activity and potency.

Full text of DOI:10.1021/jm200686d

BRIEF ARTICLE
pubs.acs.org/jmc
Synthesis and Antiplasmodial Activity of Bicyclic Dioxanes as
Simplified Dihydroplakortin Analogues
Sandra Gemma,†,‡,§ Sanil Kunjir,†,‡,§ Salvatore Sanna Coccone,†,‡,§ Margherita Brindisi,†,‡,§
||
Vittoria Moretti,†,‡,§ Simone Brogi,†,‡,§ Ettore Novellino,†, Nicoletta Basilico,†,^,§ Silvia Parapini,†,^,§
Donatella Taramelli,†,^,§ Giuseppe Campiani,*,†,‡,§ and Stefania Butini†,‡,§
†European Research Centre for Drug Discovery and Development (NatSynDrugs), 53100 Siena, Italy
‡Dipartimento di Farmaco Chimico Tecnologico, Universitꢀa di Siena, Via Aldo Moro 2, 53100 Siena, Italy
§CIRM Centro Interuniversitario di Ricerche sulla Malaria, Universitꢀa di Torino, Torino, Italy
Dipartimento di Chimica Farmaceutica e Tossicologica, Universitꢀa di Napoli Federico II, Via D. Montesano 49, 80131, Napoli, Italy
^Dipartimento di Sanitꢀa Pubblica-Microbiologia-Virologia, Universitꢀa di Milano, Via Pascal 36, 20133 Milano, Italy
S Supporting Information
b
ABSTRACT: Here we report the synthesis and evaluation of antiplasmodial activity of a novel series of bicyclic peroxides inspired
by the marine natural compound dihydroplakortin. We developed a synthetic strategy leading to the dihydroplakortin-related
peroxides in only a few steps. The in vitro antiplasmodial potency of the peroxides was similar to, or greater than, that of the reference
natural compound, and structureÀactivity relationship studies revealed several key structural requirements for activity and potency.
Chart 1. Reference and Title Compounds, Retrosynthetic
Analysisa
’ INTRODUCTION
Organic compounds from terrestrial and marine organisms are
important sources of new drugs and are good templates for syn-
thetic elaboration during drug development. Natural products
have profoundly influenced the history of malaria chemotherapy,1
a plague that kills millions of people worldwide, especially in the
poorest countries where it is endemic. Quinine was the first drug
to be used against malaria and has been exploited as a template
for the development of chloroquine (CQ),2 one of the most po-
tent and effective chemotherapeutics currently known. Despite
the initial efficacy of CQ and structurally related quinoline
derivatives, the emergence of Plasmodium falciparum (Pf) strains
resistant to CQ, the failure of vector control programs, and the
lack of progress in the development of vaccines have caused re-
crudescence of the disease and is leading to a worldwide catas-
trophe in terms of number of victims and socioeconomic costs.
The discovery of the endoperoxide-containing sesquiterpene
lactone artemisinin has been a major breakthrough in the fight
against multidrug resistant parasites. Artemisinin and its semi-
synthetic derivatives possess exceedingly potent and broad-
spectrum antimalarial activity. However, the complex molecular
architecture of artemisinin makes extraction from the medicinal
plant Artemisia annua the only available source of the drug and
poses a formidable economic barrier to its widespread distribu-
tion to the poorest malaria-endemic countries.3À5 Moreover, be-
cause of reports of delayed parasite clearance in patients receiving
artemisinin combination therapy (ACT), the identification of
structurally distinct classes of peroxides that are easy to synthe-
size by low-cost synthetic strategies and are structurally unrelated
to the parent natural compound is an urgent task.6,7 As a part of
our ongoing work in the field of antimalarial drug discovery, we
were interested in identifying simpler endoperoxide-containing
aR1, R2, and Ar are as defined in Schemes 1 and 2. Unwedged bold and
dashed lines indicate relative configuration.
molecular scaffolds as lead compounds for drug development
and found inspiration from nature in the form of the endoper-
oxide 9,10-dihydroplakortin (DHP, 1, Chart 1), isolated from the
Caribbean sponge Plakortis simplex,8 which shows interesting
antimalarial properties and has a remarkably simpler skeleton
Received: June 6, 2011
Published: July 17, 2011
r
2011 American Chemical Society
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Journal of Medicinal Chemistry
BRIEF ARTICLE
than artemisinin.9 Consequently, we chose DHP as a lead com-
pound for developing synthetically affordable antiplasmodials. In
our previous work, we had already synthesized some semisyn-
thetic analogues of DHP and related peroxides and identified
some of the structural requirements necessary for achieving
antiplasmodial activity.10 On the basis of the original structureÀ
activity relationships (SARs) for semisynthetic DHP and plakortin
analogues, the endoperoxide moiety was deemed to be crucial for
antiplasmodial activity, as well as the “western” chain at C6 of the
1,2-dioxane scaffold (depicted in violet in Chart 1). Regarding the
“eastern” groups (depicted in magenta in Chart 1), the ester moiety
was not viewed to be essential for potency. Although it has been
intensely debated in the literature,11À13 the mechanism of action of
peroxide-containing compounds seems to be related to their ability
to react with iron(II) to form radical species that are harmful for the
parasite, and formation of radical species is similarly involved in the
mechanism of action of plakortin and DHP.14 Indeed, upon in vitro
reaction with iron(II) chloride, the peroxide system of DHP forms
an O-centered radical that undergoes an intramolecular 1,5-H shift
to form a C-centered radical in the western lateral chain, in
agreement with the previously observed SARs. We recently
described the first synthetic strategy leading to DHP and used it
to prepare the first DHP synthetic analogues 2a,b, 3a,b, and 4a,b
(Chart 1) with simplified western side chains.15,16 As an extension
of this work, we directed our efforts to modifications of the 1,2-
dioxane skeleton of DHP in order to further simplify the synthesis
while maintaining or improving the antiplasmodial potency of the
natural compound. For this purpose, we merged the eastern groups
of DHP (C3 and C4, Chart 1) by creating a condensed tetrahy-
drofuran ring (rac-5aÀm). The resulting tetrahydrofuro[2,3-c]-
[1,2]dioxane system was chosen since (i) it gave access to a
synthetic strategy based on the well-known acid-catalyzed dehy-
drative cyclization of lactols (Chart 1) and (ii) it partially recapi-
tulated the peroxyacetal system of artemisinin. Here we report the
synthesis and the investigation of the SARs of the novel DHP
bicyclic analogues rac-5aÀm and rac-6aÀh and the antiplasmodial
activity of DHP synthetic analogues 2a,b, 3a,b, and 4a,b.
Scheme 2. Synthesis of Endoperoxides rac-6aÀha
a Reagents and conditions: (a) (i) 7a, LiHMDS, THF, À78 ꢀC, 30 min;
(ii) 11, À78 ꢀC, 10 min, then 25 ꢀC, 16 h; (b) for 13a, (i) NBS, AIBN,
CCl4, reflux, 4 h; (ii) DBU, sealed tube, 70 ꢀC, 20 min; (c) (i)
+
(MeOCH2)PPh3 ClÀ, NaHMDS, THF, 0 ꢀC, 30 min; (ii) 14bÀe,
À78 ꢀC, 30 min, then 25 ꢀC, 1.5 h; (d) 6 N HCl, acetone, 25 ꢀC, 16 h;
(e) 7a, LiHMDS, THF, À78 ꢀC, 30 min, then 15bÀe, À78 ꢀC f 25 ꢀC,
2 h; (f) (i) Tf2O, pyridine, DCM, from À78 ꢀC to 0 ꢀC, 1 h; (ii) DBU,
25 ꢀC, 1 h; (g) Co(acac)2, Et3SiH, O2, t-BuOOH (5 M in nonane), 1,2-
DCE, 25 ꢀC, 3 h; (h) DIBAL, DCM, À78 ꢀC, 1.5 h; (i) TMSOTf, DCM,
À78 ꢀC, 5 min. Bold and dashed lines indicate relative configuration.
Scheme 1 for rac-5aÀm. The key intermediates for the synthesis of
the bicyclic scaffold are 9aÀm, embodying an olefin moiety,
necessary to introduce the peroxide functionality through the
Mukaiyama protocol, and a lactone functionality that can serve as
the precursor to the lactol intermediate (Chart 1 and Scheme 1).
The olefin was introduced by R-alkylation of butyrolactones 7a,b
with the appropriate allyl iodides 8aÀg. Intermediates 9l,m were
prepared from 9h by alkylation with ethyl iodide and isobutyl iodide,
respectively. Starting from 9aÀm, the hydroperoxysilylation reac-
tion was accomplished by using cobalt(II) bis[2,2,6,6-tetramehtyl-
heptane-3,5-dienoate] as the catalyst, in the presence of oxygen and
triethylsilane.17 The resulting intermediates 10aÀm were regiose-
lectively obtained as a mixture of diasteroisomers. In the next steps,
diisobutylaluminum hydride (DIBAL) promoted reduction of
lactones 10aÀm furnished the corresponding lactols in quantitative
yields. These latter intermediates were finally treated with an excess
of trimethylsilyl triflate in DCM at À78 ꢀC, resulting in simulta-
neous deprotection of the silyl peroxide moiety and cyclization to
afford the desired products rac-5aÀm. Compounds rac-5a,h,l,m,
containing only two chiral centers, were obtained as mixtures of
enantiomers with cis-fused 1,2-dioxane and furan rings, while rac-
5bÀg,iÀk, with an additional chiral center at C3, were obtained as
inseparable mixtures of diasteroisomers. rac-5g was resolved in the
corresponding enantiomers via semipreparative chiral HPLC (see
Figures 1 and 2 of Supporting Information for further details).
The synthesis of noncommercially available allyl iodides 8bÀg
is reported in Scheme 1 of the Supporting Information. The
synthesis of C3-aryl-substituted analogues rac-6aÀh was realized
as described in Scheme 2, and the relative configuration at C3 of
rac-6a and rac-6f was assigned by NOESY experiments (see
Supporting Information for further details).
’ RESULTS AND DISCUSSION
Chemistry. The synthetic strategy for the construction of the
tetrahydrofuro[2,3-c][1,2]dioxane bicyclic system is described in
Scheme 1. Synthesis of C3-Aliphatic Derivatives rac-5aÀma
a Reagents and conditions: (a) (i) 7a,b, LiHMDS, THF,À78 ꢀC, 30 min; (ii)
8aÀg, À78 ꢀC, 10 min, then 25 ꢀC, 2h;(b) (i) 9h, LiHMDS,THF,À78 ꢀC,
30 min; (ii) EtI for 9l, i-BuI for 9m, THF, À78 ꢀC, 10 min, then 25 ꢀC, 2 h;
(c) Co(thd)2, Et3SiH, O2, t-BuOOH (5 M in nonane), 1,2-DCE, 25 ꢀC, 4 h;
(d) DIBAL, DCM, À78 ꢀC, 1.5 h; (e) TMSOTf, DCM, À78 ꢀC, 5 min.
Antiplasmodial Activity and StructureÀActivity Relation-
ships. All synthesized compounds were tested in vitro against two
Pf strains, namely, the CQ-sensitive (CQ-S) D10 and the CQ-resistant
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BRIEF ARTICLE
(CQ-R) W2. The antiplasmodial activity (IC50, μM) was quan-
tified as inhibition of parasite growth measured with a stan-
dardized parasite lactate dehydrogenase assay (Tables 1À3).
DHP Synthetic Analogues 2a,b, 3a,b, and 4a,b. We pre-
viously synthesized the C10-desethyl analogue of DHP (2a), its
epimer at C6 (2b), and the corresponding diols 3a,b. Compounds
4a,b, lacking the western lateral chain, were also previously
prepared. Here we report for the first time their in vitro
antimalarial activities (Table 1). Compound 2a displayed an
antiplasmodial potency against D10 and W2 strains similar to
that of the natural compound DHP, while the epimeric derivative
2b displayed a decreased potency against the CQ-R Pf strain (2b
vs 2a) and slightly greater potency against the CQ-S Pf strain.
Diols 3a and 3b proved to be less potent than the corresponding
ester analogues 2a and 2b when tested against CQ-S and CQ-R
Pf strains. Finally, 4a,b, lacking the western lateral chain, were not
active against either of the Pf strains at concentrations up to 10 μM.
The antipalsmodial data reported here confirm the previous
SARs for western side chain analogues and provide further
information regarding the role of stereochemistry at the C6
stereogenic center of the dioxane ring, i.e., that this seems to have
only a minor influence, especially against CQ-R strain.
C3-Alkyl Substituted DHP Bicyclic Analogues rac-5aÀm.
Because of the importance of the western side chain in modulating
antiplasmodial activity and potency in DHP synthetic analogues,
we examined this as well in the novel series of DHP bicyclic
analogues (rac-5aÀg) that were tested as a diasteroisomer mix-
tures. As expected, rac-5a, with a methyl group on the western side
chain, displayed no activity up to 10 μM. On the other hand,
introduction of linear alkyl chains as in rac-5b (n-butyl) and rac-5c
(n-pentyl) resulted in compounds endowed with single digit
micromolar potencies and higher potency against CQ-R Pf strain
than the CQ-S strain. Branching of the alkyl chain at C3 resulted in
compounds withbetter activities (rac-5dÀg). Thus, rac-5d, bearing
the same western side chains as DHP synthetic analogue 2a, was 4
times more potent than the unbranched analogue rac-5b. Intro-
duction of cyclohexylmethyl or cyclopentylmethyl side chains as in
rac-5e or rac-5f, respectively, had only a marginal effect on the
antiplasmodial potency relative to rac-5d. Introduction of an
adamantyl-2-methylene moiety (rac-5g) resulted in the most
potent analogue of the series, being twice as potent as the natural
compoundDHP. Compounds rac-5iÀm, lacking the methyl group
Table 1. Antiplasmodial Activity of 2a,b, 3a,b, 4a,b, and
Reference Compounds DHP (1) and CQ
a IC50 values are the mean of at least three determinations. Standard
errors were all within 10% of the mean. b Synthesis reported in ref 15.
c Synthesis reported in ref 16. d IC50 value from ref 10.
Table 2. Antiplasmodial Activity of rac-5aÀm and Reference Compounds DHP (1) and CQ
a Unwedged bold and dashed lines indicate relative configuration. b IC50 values are the mean of at least three determinations. Standard errors were all
within 10% of the mean. c IC50 value from ref 10.
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BRIEF ARTICLE
Table 3. Antiplasmodial Activity of rac-6aÀh and Reference
Table 4. Percentage of Conformers Displaying a Distance
Compounds DHP (1) and CQ
O1 H5 e 3 Å
3 3 3
% of conformers
compd
with O1 H5 e 3 Å
3 3 3
rac-5d
rac-5k
rac-6c
rac-6h
55.3
39.9
50.0
36.8
<3 Å between O1 and H5 (Table 4, cf. ref 14). Compound rac-
5k, differing from rac-5d by the lack of a methyl group at C4a,
showed a lower percentage (39.9%) of conformers with a cal-
culated O1 H5 distance of <3 Å (putative bioactive con-
3 3 3
formers), which presumably explains its lower potency. More-
over, the two diasteroisomers of rac-5d showed a similar
percentage of putatively bioactive conformers. In contrast, the
same conformational analysis performed on the two C3-aryl sub-
stituted diasteroisomers rac-6c and rac-6h revealed a higher
percentage of putatively bioactive conformers predicted for rac-
6c than for rac-6h (50.0% and 36.8%, respectively). Moreover,
C3-aryl derivatives were less effective than the corresponding
C3-alkyl analogues rac-5aÀg, presumably because of the differ-
ent spatial requirements of the resulting C-centered radicals.
a Bold and dashed lines indicate relative configuration. b IC50 values are
the mean of at least three determinations. Standard errors were all within
10% of the mean. c IC50 value from ref 10.
at C4a, did not show activity at the concentration tested, suggesting
that this group is important for activity (rac-5i,j,k vs rac-5b,c,d). On
the other hand, elongation of the alkyl chain at C4a as in rac-5l,m
gave inactive compounds, presumably because of the lack of an
appropriate alkyl substituent at C3. To determine whether diaster-
oisomers at C3 had different antiplasmodial activities, the most
potent compound of the series, rac-5g, was resolved into single
enantiomers by semipreparative chiral HPLC (see Supporting
Information for details). Two well-resolved peaks, eluting at 10.6
and 11.4 min, respectively, and identified by NMR as C-3
diasteroisomers, were tested for antiplasmodial activity (data not
shown) and were found to have potencies similar to that of rac-5g,
suggesting that in this series of compounds stereochemistry of the
substituents on the dioxane ring is not critical for activity.
C3-Aryl Substituted DHP Bicyclic Analogues rac-6aÀh. We
also tested rac-6aÀh bearing an aromatic substituent at C3
(Table 3). The C3 diasteroisomers in this series were easily
separated by column chromatography and were tested indepen-
dently. Compounds rac-6a and rac-6f, bearing an unsubstituted
phenyl ring, displayed no activity up to 20 μM. Because of the
importance of the C3 side chain that was noted in the previous
series, a set of o-alkylaryl derivatives was prepared, and a slight
improvement of activity over rac-6a was observed for rac-6cÀe.
Although potency improved slightly upon modifcation of the
alkyl chain at the ortho position, this set of compounds con-
sidered as a group showed an antiplasmodial potency 30À50
times lower than was observed in the alkyl series.
’ CONCLUSIONS
In summary, we present herein the synthesis and antiplasmo-
dial evaluation of a novel series of structurally simplified en-
doperoxide-containing compounds related to the natural product
DHP. Several of the newly synthesized bicyclic endoperoxides
(rac-5dÀg) exhibit in vitro potencies similar to that of DHP
based on standard in vitro assays of lactate dehydrogenase
activity. More importantly, the bicyclic scaffold of these com-
pounds is accessible via a high-yielding, four-step procedure
starting from readily available starting materials. By contrast,
the preparation of DHP synthetic analogues such as 2a requires a
longer and more expensive 11-step procedure. SAR analysis of
these simplified compounds allowed definition of some of the
structural requirements necessary for potency.
’ EXPERIMENTAL SECTION
General Methods. Starting materials and solvents were pur-
chased from commercial suppliers and used without further purification.
Reaction progress was monitored by TLC using silica gel 60 F254
(0.040À0.063 mm) with detection by UV. Silica gel 60 (0.040À0.063
mm) was used for column chromatography. Yields refer to purified materials
and are not optimized. 1H NMR and 13C NMR spectra were recorded on a
Varian 300 MHz or a Bruker 400 MHz spectrometer using the residual signal
of the deuterated solvent as internal standard. Splitting patterns are described
as singlet (s), doublet (d), triplet (t), quartet (q), and broad (br); chemical
shifts (δ) are given in ppm and coupling constants (J) in hertz (Hz). Mass
spectra were recorded utilizing electrospray ionization (ESI). All moisture-
sensitive reactions were performed under argon atmosphere using oven-
dried glassware and anhydrous solvents. All compounds that were tested in
Conformational Analysis. The key role played by the side
chain at C3 for antiplasmodial potency observed for rac-5aÀg led
us to hypothesize that this series of compounds could react with
iron(II) heme following a mechanism similar to the one de-
scribed for DHP,14 probably by forming an initial O1-centered
radical (Table 4) that can subsequently undergo an intramole-
cular 1,5-H shift to form a C-centered radical. Analysis of
predicted conformational energies (see Supporting Information
for further details) of the four enantiomers of rac-5d revealed that
55.3% of conformers within 20 kJ/mol should have a distance of
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BRIEF ARTICLE
the biological assays were analyzed by combustion analysis (CHN) to
confirm the purity, g95%. R* and S* indicate relative configurations.
(3R*,4aS*,7aR*)-3-(Adamantan-2-ylmethyl)-3,4a-dimethyl-
tetrahydrofuro[2,3-c][1,2]dioxane and (3S*,4aS*,7aR*)-3-
(Adamantan-2-ylmethyl)-3,4a-dimethyltetrahydrofuro[2,3-
c][1,2]dioxane (5g). The title compound was prepared as described
for the synthesis of 5a. The mixture of four enantiomers was separated by
semipreparative chiral HPLC (10% isopropanol in n-hexane) and two
out of four enantiomers were obtained in pure form. tR = 10.6 min; 1H
NMR (300 MHz, CDCl3) δ 5.03 (s, 1H, H-7a), 4.26À4.16 (m, 1H, H-6),
3.98 (dd, J = 15.4, 7.6 Hz, 1H, H-6), 2.40À2.24 (m, 1H, H-5), 1.93 (d, J
= 14.1 Hz, 1H, H-4), 1.88À1.68 (m, 11H, Ada), 1.65À1.46 (m, 8H,
Ada/H-5/H-4), 1.30 (s, 3H, 3-Me), 1.14 (s, 3H, 4a-Me); tR = 11.4 min;
1H NMR (300 MHz, CDCl3) δ 5.01 (s, 1H), 4.30À4.19 (m, 1H),
4.04À3.91 (m, 1H), 2.42À2.28 (m, 1H), 1.94 (d, J = 14.1 Hz, 1H),
1.88À1.69 (m, 11H), 1.65À1.51 (m, 10H), 1.42 (dd, J = 14.3, 4.0 Hz,
1H), 1.25 (s, 3H); MS (ESI) m/z 324 (M + Na)+, 345 (M + K)+, 635
(2M + Na)+. Anal. (C19H30O3) C, H, N.
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’ ASSOCIATED CONTENT
S
Supporting Information. Experimental procedures and
b
elemental analysis results. This material is available free of charge
via the Internet at http://pubs.acs.org.
’ AUTHOR INFORMATION
Corresponding Author
*Phone: +39-0577-234172. Fax: +39-0577-234333. E-mail:
campiani@unisi.it.
’ ACKNOWLEDGMENT
(16) Gemma, S.; Marti, F.; Gabellieri, E.; Campiani, G.; Novellino,
E.; Butini, S. Synthetic studies toward 1,2-dioxanes as precursors of
potential endoperoxide-containing antimalarials. Tetrahedron Lett. 2009,
50, 5719–5722.
(17) O’Neill, P. M.; Hindley, S.; Pugh, M. D.; Davies, J.; Bray, P. G.;
Park, B. K.; Kapu, D. S.; Ward, S. A.; Stocks, P. A. Co(thd)(2): a superior
catalyst for aerobic epoxidation and hydroperoxysilylation of unacti-
vated alkenes: application to the synthesis of spiro-1,2,4-trioxanes.
Tetrahedron Lett. 2003, 44, 8135–8138.
The authors thank EU Commission (Grant Antimal-LSHP-
CT-2005-18834) for financial support. Thanks are also given to
the Associazione Volontari Italiani Sangue (AVIS Comunale
Milano) for providing fresh blood for parasite cultures.
’ ABBREVIATIONS USED
CQ, chloroquine; Pf, Plasmodium falciparum; ACT, artemisinin
combination therapy; DHP, dihydroplakortin; DIBAL, diisobu-
tylaluminum hydride; DBU, 1,8-diazabicyclo[5.4.0]undec-7-ene;
CQ-S, chloroquine-sensitive; CQ-R, chloroquine-resistant
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