Synthesis and cytotoxic activity of acetogenin analogues

Article abstract of DOI:10.1016/S0960-894X(00)00236-5

A set of 16 new simplified analogues of acetogenins has been designed based on: (i) the replacement of the bis THF moiety of these natural products by an ethylene glycol bis ether unit; (ii) the introduction of different lipophilic side chains (alkyl, ary

Full text of DOI:10.1016/S0960-894X(00)00236-5

Bioorganic & Medicinal Chemistry Letters 10 (2000) 1373±1375
Synthesis and Cytotoxic Activity of Acetogenin Analogues
Stephane Rodier,a Yvan Le Huerou,b Brigitte Renoux,a Julien Doyon,b
Pierre Renard,c Alain Pierre,d Jean-Pierre Gessona,*
and Rene Greeb,*
a
Á Â Â Â
Laboratoire de Synthese et Reactivite des Substances Naturelles, Universite de Poitiers et CNRS, 40, Av. du Recteur Pineau,
86022 Poitiers, France
Laboratoire de Synthese et d'Activation de Biomolecules, ENSCR et CNRS, Avenue du General Leclerc, 35700 Rennes, France
b
Á
  Â
ADIR, 1 rue Carle Hebert, 92415 Courbevoie Cedex, France
c
Â
dInstitut de Recherche Servier, 11 rue des Moulineaux, 92450 Suresnes, France
Received 11 February 2000; accepted 20 April 2000
AbstractÐA set of 16 new simpli®ed analogues of acetogenins has been designed based on: (i) the replacement of the bis THF
moiety of these natural products by an ethylene glycol bis ether unit; (ii) the introduction of di€erent lipophilic side chains (alkyl,
aryl, dialkylamino, O-cholesteryl); (iii) the presence of the same terminal isolactone. In vitro cytotoxic activity against L1210 leu-
kemia is reported. # 2000 Elsevier Science Ltd. All rights reserved.
Annonaceous acetogenins display various potent biolo-
gical activities (cytotoxic, pesticidal, immunosuppres-
Taking into account the limited availability (either by
plant extraction or by total synthesis) of bis-THF aceto-
and genins, it seemed worthwhile to prepare simpli®ed
analogues bearing the same key features. First, the
replacement of the bis-THF moiety by an ethylene gly-
col bis-ether unit has been considered. This strategy
retained only two stereogenic centers (instead of 6) in the
central part of the target compound and both enantio-
meric synthons could be prepared. These analogues have
been designed to incorporate di€erent lipophilic terminal
side chains (n-alkyl, aryl, dialkylamino, O-cholesteryl)
and the same ketolactone moiety. Their synthesis and
preliminary results of their cytotoxic activity are now
reported.
sive, antimicrobial,. . .).1 Impressive cytotoxicities as low
13
as 10
mg/mL have been reported against various
tumor cell lines,1 including multidrug resistant ones.2
The potent cytotoxic properties of acetogenin derivatives
is mainly due to inhibition of mitochondrial NADH:
ubiquinone oxido-reductase3 and/or of an NADH
oxidase4 of the cytoplasmic membrane. The structures
of the most active members of this large family of nat-
ural products are characterized by the presence of a
terminal linear side chain and one to three THF rings
connected via an intermediate linear chain (eventually
functionnalized by hydroxyl or keto groups) to a term-
inal lactone moiety. Several types of lactones are
known, the most active being the b-hydroxyalkyl bute-
nolide found, for example, in bullatacin 1.5 However, an
easy rearrangement to ketolactones (usually obtained as
an unseparable thermodynamic 2:1 mixture of 2,5-cis
and 2,5-trans isomers) has been observed under mild
hydrolytic conditions.6 The latter, such as bullatacinone
2,5 are less potently cytotoxic, and toxicity,7 a main
limitation to the therapeutic use of acetogenins, is
markedly reduced compared to the former acetogenins.
The seven-step preparation of enantiomerically pure
alkynes (+)-3a±i and ( )-3a±i from solketal has been
recently described.8 After ¯uoride induced desilylation,9
Sonogashira coupling with 1 equiv of lactone synthon
510 a€orded in 18±81% yield the desired enynes 6a±g
and 7a±g. Hydrogenation (H2, Pd/C or PtO2) gave the
target acetogenin analogues 8a±g and 9a±g in 59±92%
yield. Indeed, carbonyl reduction was observed in three
cases leading to mixtures of lactone alcohols 10 and 11
(in equilibrium with the other possible butanolide
through translactonization).
The panel of 16 acetogenin analogues thus obtained has
been tested against L1210 leukemia cells in vitro (Table
*Corresponding author. Fax: +33-549±4535-01; e-mail: jean-pierre.
gesson@cri.univ.poitier.fr
0960-894X/00/$ - see front matter # 2000 Elsevier Science Ltd. All rights reserved.
PII: S0960-894X(00)00236-5

1374
S. Rodier et al. / Bioorg. Med. Chem. Lett. 10 (2000) 1373±1375
2), and the activity was compared to doxorubicin and
known acetogenins (Table 1).11
formation of the polyoxygenated moiety of acetogenins
either for interaction with cell membranes12 and/or
with metal ions13 since replacement of the THF rings by
the ethylene glycol bis-ether leads to more conform-
ationnally mobile compounds. Taking into account
this hypothesis the synthesis and biological evaluation
of conformationnally restricted, but yet simpli®ed,
analogues is underway.
Cytotoxicity of these simpli®ed acetogenin analogues
turns out to be lower than for bullatacinone. Indeed,
several trends should be pointed out: no signi®cant
di€erences are observed between both series (6 and 7)
for similar side chains; phenyl or (para substituted
phenyl) and piperidinyl side chains lead to lower activity
than more lipophilic ones such as n-decyl, naphthyl,
N-dialkylamino or O-cholesteryl; ketone reduction
seems to have little e€ect (see 11e versus 7e).
Table 1. IC50 (mM) of doxorubicin and acetogenins (L1210)
Compound
IC50
Doxorubicin
Annonacin
Bullatacin
0.025
0.042
0.0004
0.016
Overall, these results indicate that the terminal lactone
moiety confers limited potency to annonaceous acet-
ogenins in contrast to the THF nucleus. This may
strengthen the hypothesis of required U-shaped con-
Bullatacinone
Scheme 1. (i) 1.3 equiv TBAF, THF, rt, 3 h, 15±84%; (ii) : 1 equiv 5, 0.1 equiv Pd(PPh3)2Cl2, 0.38 equiv CuI, 10 eq. i-Pr2NH, PhH, 2 h, rt, 16±81%;
(iii) 1 atm H2, cat. 10% Pd/C (or cat PtO2 for amine derivatives), AcOEt, 4±6 h, rt, 58±92%.

S. Rodier et al. / Bioorg. Med. Chem. Lett. 10 (2000) 1373±1375
1375
Table 2. IC50 (mM) of acetogenin analogues (L1210)
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Smith, D. L.; Chang, C.-J.; McLaughlin, J. L. J. Nat. Prod.
1989, 52, 463.
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A. Heterocycles 1994, 39, 741. Duret, P.; Figadere, B.; Hoc-
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R
Compound
IC50
Compound
IC50
n-C10H21
Ph
p-MeOC6H4
p-CF3C6H4
2-Nph
Bu2N
Oct2N
N-piperidinyl
3-O-cholesteryl
6a
6b
6c
6d
11e
6f
6g
6h
6i
3.5
19.8
>1 0
3.3
2.1
3.9
3.7
28.7
2.8
7a
7b
7c
Ð
7e
1
21.6
32
Ð
3
2.5
Ð
7f
Ð
11h
11i
23.3
12.2
Acknowledgements
Financial support from MENRT, CNRS, ADIR
(Courbevoie) and the Ligue Nationale contre le Cancer,
Comite de Charente-Maritime is gratefully acknowl-
edged. We thank Dr. Thomas Leese and Dr. Erwin
Warmerdam for preliminary experiments.
8. Le Huerou, Y.; Doyon, J.; Gree, R. L. J. Org. Chem. 1999,
64, 6782.
9. Unoptimized isolated yields are given. All new compounds
1
have been characterized by H, 13C NMR and FAB HMRS.
Optical rotations have been measured for ®nal compounds.
All lactones exist as a 2:1 thermodynamic mixture of cis and
trans isomers.
10. Synthon 5 (c.a. 2:1 E:Z ratio, ee 86%) has been prepared in
9 steps from 1,7-octadiene (Warmerdam, E.; Rodier, S.;
Renoux, B.; Gesson, J.-P. unpublished results).
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