Enhanced antimalarial activity of novel synthetic aculeatin derivatives

Article abstract of DOI:10.1021/jm8007322

We report the design, synthesis, and in vitro evaluation of novel polyspirocyclic structures, inspired by the antimalarial natural products, the aculeatins. A divergent synthetic strategy was conceived for the practical supply and has allowed the discover

Full text of DOI:10.1021/jm8007322

4870
J. Med. Chem. 2008, 51, 4870–4873
Enhanced Antimalarial Activity of Novel
Synthetic Aculeatin Derivatives
Marine Peuchmaur,† Nadia Saïdani,‡,§ Cyrille Botte´,‡
Eric Mare´chal,‡ Henri Vial,§ and Yung-Sing Wong*,†
De´partement de Pharmacochimie Mole´culaire, UniVersite´ de
Grenoble, CNRS UMR 5063, CNRS ICMG FR 2607, Baˆtiment E,
470 Rue de la Chimie, F-38 041 Grenoble Cedex 9, France,
Laboratoire de Physiologie Cellulaire Ve´ge´tale, UniVersite´ de
Grenoble, CNRS UMR 5168/CEA/INRA, IRTSV, CEA Grenoble,
17 Rue des Martyrs, F-38054, Grenoble Cedex 9, France, and
Dynamique des Interactions Membranaires Normales et
Figure 1. Antimalarial activity of aculeatins.
Scheme 1. Synthesis of 2 as Key Precursor for Accessing to
New Analogues 1a
Pathologiques, UniVersite´ de Montpellier 2, CNRS UMR 5235,
CP 107, Place E. Bataillon, F-34095 Montpellier Cedex 5, France
ReceiVed June 17, 2008
Abstract: We report the design, synthesis, and in vitro evaluation of
novel polyspirocyclic structures, inspired by the antimalarial natural
products, the aculeatins. A divergent synthetic strategy was conceived
for the practical supply and has allowed the discovery of two novel
and more potent analogues active on the Plasmodium falciparum 3D7
strain. Moreover, these compounds proved to be potent against
Toxoplasma gondii. A number of features that govern these inhibitions
were identified.
a Reagents and conditions: (a) BnBr, NaOH, Bu4NHSO4 cat., THF, 99%;
(b) (COCl)2, CH2Cl2, 4 h, then Meldrum’s acid, pyridine, CH2Cl2, 0°C; (c)
EtOH, reflux (72% from 4); (d) H2, Pd/C, AcOEt, 99%; (e) 1,3-
propanedithiol, BF3 ·Et2O, CH2Cl2, 79%; (f) DIBAL-H, toluene, -78°C,
73%.
Malaria is the most widespread parasitic disease in tropical
and subtropical regions, and its burden steadily increases,
infecting 300-500 million people and killing 1-3 million
people a year.1,2 This major disease is caused by blood protozoan
parasites of Plasmodium genus classified in the Apicomplexa
phylum, of which the most deadly species is Plasmodium
falciparum. The rise of malaria death toll is notably due to the
spread of resistance to all currently used antimalarial drugs,
artemisinin derivatives still remaining an exception, although
forerunners of resistant forms have recently given cause for
concern.3 There is thus a constant need for the search for novel
antimalarial molecules. Priority should be given to approaches
with novel mechanisms of action and whose compounds are
structurally unrelated to existing antimalarial agents. These new
compounds would keep a therapeutic rampart in controlling
malaria.4
Natural products extracted from traditional medicines (e.g.,
quinine and more recently artemisinin) have provided the
starting point for the discovery of the most efficient antimalarial
drugs.4-8 In 2000, a novel type of polyspirocyclic natural
products, the aculeatins (Figure 1), was isolated from the
rhizome of Amomun aculeatum by Heilmann and co-workers.9
This plant has been used in the folk medicine of Papua New
Guinea to treat fever and malaria.10 Very recently, Kinghorn
and co-workers have isolated from the leaves and rachis of
Amomun aculeatum new members of this family, the aculeatols,
the amomols, and novel analogues of aculeatin having a shorter
lipophilic side chain.11,12 Some of these compounds showed
interesting antimalarial activities with inhibitory effects in the
submicromolar range, and especially against P. falciparum strain
K1 (Figure 1), with a low cytotoxicity against human cell lines
in vitro.9,12 A selectivity for MCF-7 cells in an in vivo hollow
fiber assays has been reported for aculeatin A.12
A few years ago, we selected the aculeatins to start a program
aiming to develop new antiprotozoal agents inspired by natural
products. Interestingly, aculeatin A was described to be 5-fold
more efficient than aculeatin D (Figure 1) based on in vitro
proliferation assays of P. falciparum strain K1, suggesting that
a biological selectivity could arise from a proper spatial
arrangement of the polyspiro structure and their appendage
orientations. Moreover, this unexplored biologically active
scaffold represents a family of new probes, with the prospect
that new antimalarial biological targets, directly or indirectly
interacting with this scaffold, could be identified in the future.13
We report here the evaluation of new aculeatin analogues and
the discovery of improved antimalarial compounds, with the
identification of features contributing to their biological activity.
Recently, we were keen to develop novel diastereodivergent
and tandem one-pot synthetic approaches giving rise to desired
molecules within few steps.14,15 Although quite complex
polyspirocylic structures are targeted, the synthesis of new
aculeatin analogues 1 (Scheme 1) is designed in a practical
manner that allows a specific structural variability, mainly
located at the R tail position. All these new derivatives are
conveniently derived from a common precursor 2.
An approach allowing large amounts of products to be
handled was desired to synthesize the key precursor 2. Starting
from the acid 3 protected as a benzylated derivative 4, the
corresponding acyl chloride was condensed with Meldrum’s acid
to afford 5, which was then refluxed in ethanol to give the
* To whom correspondence should be addressed. Phone: +33-4-76-63-
53-10. Fax: +33-4-76-63-52-95. E-mail: yung-sing.wong@ujf-grenoble.fr.
†
De´partement de Pharmacochimie Mole´culaire, Universite´ de Grenoble.
‡
Laboratoire de Physiologie Cellulaire Ve´ge´tale, Universite´ de Grenoble.
§
Universite´ de Montpellier 2.
10.1021/jm8007322 CCC: $40.75
2008 American Chemical Society
Published on Web 08/05/2008

Letters
Journal of Medicinal Chemistry, 2008, Vol. 51, No. 16 4871
Scheme 2. Synthesis of the Precursor (()-10 from 2 and the
Successive Conversions To Give the Range of New Aculeatin
Analoguesa
Scheme 3. Synthesis of (()-20, (()-21, and 22 (with
Representative NOE Signals) and Further Derivations To form
(()-25a-c and 26a,ba
a Reagents and conditions: (a) (i) BF3.OEt2, -78°C, CH2Cl2; (ii) TBAF,
THF; (b) PIFA, acetone/H2O, 18 h; (c) DMAP, Et3N, CH2Cl2; (d) THF,
reflux, 6 h.
To explore the biological effect of cyclohexadienone ring,
we suspected that introducing twice this moiety on the same
molecule, while keeping a polyspirocyclic structure, would
amplify the putative pharmacophoric feature. Within the context
of our oxidative spiroannulation strategy, we envisioned that
the diphenolic product 20 should be the precursor of choice
(Scheme 3). Compound 20 in racemic form was easily obtained
in good yield (84%) by the reaction of the aldehyde 2 with the
enolsilane 1914b according to the Mukaiyama coupling reaction,
followed by a treatment with TBAF to remove all silyl groups.
When treating this linear precursor (()-20 with PIFA in acetone/
H2O, we were pleased to mainly obtain in one step two novel
and complex structures (()-21 (19%) and 22 (11%) having five
successive spirocyclic rings in junction. As evidenced by the
NMR spectroscopy, product 22 has a symmetric structure and
NOE measurements assigned the configuration, notably with
the NOE signals observed between the axial proton at geminal
position of the hydroxyl group and the protons of both
cyclohexadienone rings. For product (()-21, representative NOE
signals also confirm the configuration. No NOE signal between
the proton at geminal position of the hydroxyl and the proton
of cyclohexadienone ring has been observed, suggesting that
the hydroxyl group is at axial position.
a Reagents and conditions: (a) THF, -78°C, 80%; (b) toluene, 110°C;
(c) Et3B, NaBH4, THF/MeOH (4:1), -78°C; (d) (CH3)4NBH(OAc)3,
CH3CN/AcOH (4:1), 0°C; (e) NaBH4, MeOH/CH2Cl2, 0°C; (f) PIFA,
acetone/H2O, 15 min.
ꢀ-ketoester 6 (71% overall yield from 3). Hydrogenation of 6
gave the phenol ꢀ-ketoester 7, which was next transformed into
the dithiane ester 8. Finally, reduction with DIBAL-H gave the
corresponding aldehyde 2 in good yield.
To introduce different lipophilic side chains, the dioxinone
(()-10 was prepared by condensing the aldehyde 2 with the
lithiated dioxanone dienol ether 9 (Scheme 2). The dioxinone
functional group of (()-10 allows the facile addition of various
nucleophiles 11a-e by simply heating both reactants in toluene,
giving rise to a series of ꢀ-ketoesters (()-12a-e.16 Although
the yields range from 35% to 64%, it is noteworthy that neither
the secondary alcohol nor the phenol group of (()-10 needs to
be protected.17
Hydroxyl-directed selective reductions of (()-12a-d were
successfully applied to obtain syn diols (()-13a-d18 or anti
diols (()-14b,c.19 Same conditions were applied to the ꢀ-ke-
toamide (()-12e but failed to run the reactions until completion
resulting in poor yields. The ꢀ-ketoamide (()-12e was finally
reduced by NaBH4, yielding an inseparable mixture of diaster-
eomers (()-13e/14e (76%).
To restore the hydrophobic part of aculeatins, different
lipophilic chains were grafted on the remaining hydroxyl group,
either with the acyl chlorides 23a,b or by heating with 24 to
give either the polyspirocyclic esters (()-25a,b and 26a,b or
the polyspirocyclic ꢀ-ketoester (()-25c, respectively.
Finally, to verify the plausible role of the cyclohexadienone
ring on the biological activity, (()-aculeatin A14a was converted
into the cyclohexanone derivative (()-27 by catalytic hydro-
genation with palladium (Scheme 4). A dramatic decrease in
activity should confirm that the cyclohexadienone ring plays a
crucial role.
According to our previous work,14 the diols (()-13a-d and
(()-14b,c were treated by phenyliodine(III) bis(trifluoroacetate)
reagent (PIFA) in acetone/H2O to promote a tandem phenolic
oxidation/dithiane deprotection sequence leading to the forma-
tion of aculeatins polyspirocyclic structures. Hence, the trans-
formation of syn diols (()-13a-d gave two separable aculeatin
derivatives (()-15a-d (12-19%) and (()-16a-d (11-21%),
as analogue of aculeatins A and B, respectively, whereas the
anti diols (()-14b,c led to two separable products (()-17b,c
(16%) and (()-18b,c (16-17%), as analogues of aculeatins D
and 6-epi-D, respectively. The mixture of syn/anti diols (()-
13e/14e gave with PIFA a mixture of stereoisomers of which
only (()-15e (9%) could be isolated from the other products
by flash chromatography. Comparisons of the NMR data of (()-
15a-e, (()-16a-d, (()-17b,c, and (()-18b,c with those arising
frompreviousconfigurationalNMRstudiesofnaturalproducts12,14c,15b,c
allow the assignment of their structures.
Considering that another pathogenic member of the Apicom-
plexa phylum includes Toxoplasma species, the series of natural
and non-natural aculeatins A, B, D and 6-epi D14b and the new
synthesized analogues were evaluated for their potency against
both P. falciparum 3D7 and Toxoplasma gondii RH-ꢀ1 (Table
1). We also tested our compounds for their toxicity against
mammalian cells using the human erythroblasts K562 to

4872 Journal of Medicinal Chemistry, 2008, Vol. 51, No. 16
Letters
Table 1. In Vitro Activity of the Compounds against the Parasites Plasmodium falciparum (P.f.) and Toxoplasma gondii (T.g.) and against the Human
Erythroblasts (h.e.) K-562a
IC50 (µM)
compd
chloroquine
substituent
CC50 (µM), h.e. K-562
P.f. 3D7
T.g. RH-ꢀ1
9.7
0.008
0.288
0.454
0.478
0.451
0.335
0.329
0.220
0.366
1.840
0.654
0.770
1.151
0.899
1.364
1.031
1.133
0.414
0.343
0.081
0.120
0.584
0.331
0.092
>5
(-)-aculeatin Ab
(+)-aculeatin Bb
(+)-aculeatin Db
(+)-aculeatin 6-epi-Dc
(+)-aculeatin Ac
(-)-aculeatin Bc
(-)-aculeatin Dc
(-)-aculeatin 6-epi-Dc
(()-15a
25.5
27.5
28.0
30.2
25.8
22.1
26.7
30.8
109.3
28.2
13.9
22.1
0.39
41.2
17.5
15.6
0.39
<0.38
8.75
<0.38
cytot.
<0.38
11.3
25.6
17.6
34.5
0.309
0.365
0.640
0.377
0.436
0.627
0.436
0.400
0.500
0.341
2.40
4.45
ND
1.63
3.54
3.52
0.173
ND
0.346
ND
1.50
ND
X ) O; R3 ) (CH2)2CH3
(()-15b
X ) O; R3 ) (CH2)9CH3
(()-15c
X ) O; R3 ) (CH2)17CH3
(()-15d
X ) O; R3 ) CH[(CH2)9]CH3]2
X ) N(CH2)5CH3; R3 ) (CH2)5CH3
(()-15e
(()-16b
(()-17c
(()-18c
(()-21
Z ) H
(()-25a
Z ) CO(CH2)5CH3
Z ) CO(CH2)12CH3
Z ) COCH2CO(CH2)12CH3
Z ) H
Z ) CO(CH2)5CH3
Z ) CO(CH2)12CH3
(()-25b
(()-25c
22
26a
26b
0.636
11
ND
(()-27
(+)-28
4.80
>10
(-)-29
ND
a All IC50 values were calculated from experiment carried out in triplicate on T.g. and from two independent experiments carried out in duplicate on P.f.
b Natural product. c Non-natural product.
Scheme 4. Reduction of (()-Aculeatin A to the Cyclohexanone
(()-27a
gave a SI of 219. Furthermore, a comparison of the ester
analogues (()-15 revealed that the length of the lipophilic chain
can impact the selectivity between P. falciparum 3D7 and T.
gondii RH-ꢀ1. When this alkyl chain is short ((()-15a, R3 )
(CH2)2CH3), a better inhibitory effect was observed for T. gondii
(IC50 ) 0.50 µM) compared with P. falciparum (IC50 ) 1.84
µM). A much longer chain ((()-15c, R3 ) (CH2)17CH3) resulted
in a reversal of affinity in favor of P. falciparum (0.77 µM versus
2.40 µM with T. gondii). An intermediate chain length ((()-
15b, R3 ) (CH2)9CH3) in turn proved adequate to have a similar
effect on both parasites at submicromolar concentrations (IC50
) 0.65 and 0.34 µM). To extend the study of the lipophilic
a Reagents and conditions: (a) H2/Pd, EtOH, 16 h, 71%.
establish an in vitro selectivity index (SI, the ratio of the IC50
for in vitro cytotoxicity on K-562 to the IC50 of inhibition on
parasite).
First, we confirmed the submicromolar antimalarial activity
of natural aculeatins, with their corresponding non-natural
effect, we tested the ester analogue (()-15d (R3
)
CH[(CH2)9CH3]2) and the amide analogue (()-15e (X )
N(CH2)5CH3, R3 ) (CH2)5CH3), which have an extra side chain.
We observed no improvement on the inhibition of P. falciparum,
while the amide analogue (()-15e was shown to be too toxic.
We next focused on the impact of aculeatin configurations
on the biological activities. Considering the most potent ester
analogue (()-15b for P. falciparum and T. gondii, we tested
the corresponding stereoisomer (()-16b of aculeatin B type.
This aculeatin B configurration proved to be less efficient over
(()-15b for both parasites (IC50 ) 1.36 and 1.63 µM). We also
evaluated the stereoisomers of aculeatins D and 6-epi D types,
i.e., (()-17c and (()-18c, respectively, which hold the proper
enantiomers displaying the same level of inhibition (IC50
)
0.22-0.48 µM). Interestingly, these compounds similarly
inhibited the growth of T. gondii RH-ꢀ1 at submicromolar
concentration (IC50 ) 0.31-0.64 µM). Moreover, these mol-
ecules showed a good to excellent SI, which ranges from 35 to
121 for both parasites. For the new aculeatin A ester analogues
(()-15a-d, the SI was in general lower, mainly because of a
less pronounced antiparasitic potency. A remarkable exception
was the low cytotoxicity (IC50 ) 109 µM) together with a good
antitoxoplasmal activity (IC50 ) 0.50 µM) of (()-15a which
alkyl length to be selective for P. falciparum (R3
)

Letters
Journal of Medicinal Chemistry, 2008, Vol. 51, No. 16 4873
(CH2)17CH3). Although these tests again confirmed the selectiv-
ity observed for P. falciparum over T. gondii, the inhibition on
P. falciparum was lower than with the stereoisomer (()-15c.
As a result, it seems from this series that the aculeatin A
configuration (()-15 exhibits a higher antiparasitic potency over
the other stereoisomers.
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Acknowledgment. We thank the University of Grenoble,
the Institut de Chimie Mole´culaire de Grenoble (ICMG), and
the CNRS for financial support and the MENRT for doctoral
fellowship (M.P.). Part of this study was funded by Conseil
Re´gional Rhoˆnes-Alpes (N.S.) and supported by ANR and the
SAFETI MalariaChemogenoSpace programme (N.S., C.B., and
E.M.).
Supporting Information Available: Details of biological assays
and synthetic procedures of new compounds tested and precursors,
product characterization, 1H and 13C NMR spectra, and HPLC
purity results for (()-25b and 26b. This material is available free
of charge via the Internet at http://pubs.acs.org.
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JM8007322