Synthesis and antiviral properties of some polyphenols related to Salvia genus

Article abstract of DOI:10.1016/j.bmcl.2008.06.063

An efficient synthesis of the acid part of salvianolic acid E 2 is described. Compound 2 was obtained from vanillin in 10 steps and 21% overall yield. During the synthesis of 2 an unexpected 5-oxo-4b,9b-dihydroindano[1,2-b]benzofuran rac-12 was isolated.

Full text of DOI:10.1016/j.bmcl.2008.06.063

Bioorganic & Medicinal Chemistry Letters 18 (2008) 4736–4740
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Synthesis and antiviral properties of some polyphenols related to Salvia genus
Clémence Queffélec a, Fabrice Bailly a, Gladys Mbemba b, Jean-François Mouscadet b, Sean Hayes c,
Zeger Debyser c, Myriam Witvrouw c, Philippe Cotelle a,
*
a Laboratoire de Chimie Organique et Macromoléculaire, UMR CNRS 8009, USTL, 59655 Villeneuve d’Ascq, France
b Laboratoire de Biotechnologies et Pharmacologie Génétique Appliquée, UMR CNRS 8113, Ecole Normale Supérieure de Cachan, 61 Avenue du Président Wilson, 94235 Cachan, France
c Molecular Medicine, K.U.Leuven and IRC KULAK, Kapucijnenvoer 33, B-3000 Leuven, Flanders, Belgium
a r t i c l e i n f o
a b s t r a c t
Article history:
An efficient synthesis of the acid part of salvianolic acid E 2 is described. Compound 2 was obtained from
vanillin in 10 steps and 21% overall yield. During the synthesis of 2 an unexpected 5-oxo-4b,9b-dihydro-
indano[1,2-b]benzofuran rac-12 was isolated. Both compounds together with the acid part of salvianolic
acid D were active as HIV-1 integrase inhibitors at the submicromolar level. But they did not inhibit the
replication of the virus on MT-4 cells.
Received 23 May 2008
Revised 17 June 2008
Accepted 18 June 2008
Available online 21 June 2008
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords:
Natural polyphenols
Salvianolic acids
Boron tribromide
Integrase inhibitors
Antivirals
Currently, there are three distinct mechanistic classes of
antiretrovirals: inhibitors of the HIV-1 reverse transcriptase and
protease enzymes and inhibitors of HIV entry, including receptor
and co-receptor binding and cell fusion. The integration of viral
cDNA into the host genome is an essential step in the HIV-1 life cy-
cle and is mediated by the virally encoded enzyme, integrase (IN).
IN is an attractive drug target because it is essential for a stable and
productive HIV-1 infection, and there is no mammalian homologue
of IN. Inhibitors of integrase enzyme (INI) block the integration of
viral double-stranded DNA into the host cell’s chromosomal DNA.
HIV-1 integration has several potential steps that can be inhibited,
and many new compounds that target specific integration steps
have been identified. A great number of HIV-1 integrase inhibitors
have been described in the last decade, and numerous reviews
have been published.1–7 Two INIs, GS-9137 (Elvitegravir)8 and
MK-0518 (Raltegravir),9,10 demonstrated promising early clinical
trial results and have been advanced into later stage trials, the lat-
ter being the first US FDA-approved drug targeting IN under the
brand name IsentressÒ. Despite the enormous progresses made
in this new class of antiretrovirals, we need to find new IN inhibi-
tors to overcome the resistance to INIs.11 Today, many research
groups are exploring the biodiversity of the plant kingdom to find
new and better anti-IN drugs with novel mechanisms of action.
Natural caffeic acid derivatives which present anti-HIV-1 activities
were recently reviewed.12 Rosmarinic and lithospermic acids for
example (Fig. 1) may serve as lead structures for the development
of new anti-HIV agents from natural source.13–15
For a long time, our laboratory has been implicated in the syn-
thesis of natural polyphenols and the design of new HIV-1 integr-
ase inhibitors.16–19 We focused our attention on the caffeic moiety
of salvianolic acids since the ester function is expected to be easily
cleaved by esterases. Herein we present the total synthesis of the
acid part of salvianolic acid E, the anti-integrase activities and
the antiviral properties of the acid part of salvianolic acid D, 120
and E, 2 (Fig. 1) and of a side-product rac-12 (Scheme 2) obtained
during the synthesis of compound 2.
The entry into the backbone of 7 was first found in the aldol
condensation of 3,4-dimethoxybenzaldehyde and benzopyranone
421 (Scheme 1). This aldol condensation performed in piperidine/
pyridine mixture gave 522 in 49% yield as a mixture of E and Z iso-
mers. Opening of the lactone ring gave 6 as the E isomer exclu-
sively. Unfortunately, oxidation using the Swern reaction did not
allow us to isolate 7 in a satisfactory yield (only 15%) in contradic-
tion with a previous report,22 and then we turned to a more conve-
nient route. The designed common precursor
7 was more
efficiently obtained starting from the intermediate 8, previously
described in the preparation of the acid part of salvianolic acid
D.20 Compound 8 was converted into the acetal 9 with trimethyl
orthoformate according to Detterbeck et al.23 procedure in 91%
yield (Scheme 1). For the aldol-type reaction of 9 with veratralde-
hyde, we found of the greatest importance to carry out the whole
reaction, including the quenching process at low temperature
(ꢀ78 °C). Deprotonation of 9 was best done by a freshly prepared
* Corresponding author. Tel.: +33 0 320 434 858; fax: +33 0 320 336 309.
E-mail address: philippe.cotelle@univ-lillel.fr (P. Cotelle).
0960-894X/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2008.06.063

C. Queffélec et al. / Bioorg. Med. Chem. Lett. 18 (2008) 4736–4740
4737
OH
CO2R1
CO2R2
HO
OH
OH
O
CO2X
OH
R1 = X, R2 = H Lithospermic acid
R1 = R2 = X Lithospermic acid B
R1 = R2 = H Przewalskinic acid
Rosmarinic acid
CO2R
CO2H
CO2R
CO2R
HO
OH
HO
OH
R= X, Salvianolic acid D
R= H, 1
HO
OH
OH
CO2H
R= X, Salvianolic acid E
R= H, 2
X =
OH
Figure 1. Structures of some caffeic acid natural derivatives. Rosmarinic acid, lithospermic acids, przewalskinic acid and salvianolic acids.
HO
O
O
O
O
COOMe
i
ii
OH
OH
OH
OMe
OMe
iii, iv
OMe
OMe
OMe
OMe
OMe
MeO
6
5
4
CHO COOMe
CHO
31%, 6 steps
OMe
CHO
OMe
OMe
OMe
vi, vii
OH
v
CO2Me
CO2Me
OMe
OMe
OMe
OMe
7
OMe
3
51%, 6 steps
OMe
9
8
Scheme 1. Reagents and conditions: (i) 3,4-dimethoxybenzaldehyde, pyridine, piperidine, 49%; (ii) MeONa, MeOH, reflux, 91%; (iii) (COCl)2, DMSO, 15%; (iv) K2CO3, MeI, 95%;
(v) HC(OMe)3, MeOH, NH4Cl, reflux, 2 h, 91%; (vi) 3,4-dimethoxybenzaldehyde, LDA, THF, ꢀ78 °C, 1 h; (vii) 3 N HCl, reflux, 12 h, 63%.
solution of lithium diisopropylamide (LDA) in dry THF followed by
the addition of 3,4-dimethoxybenzaldehyde. Classical work up un-
der acidic conditions afforded the product 7 in very low yield after
purification. Conversely, when the reaction mixture was refluxed
for 12 h under acidic conditions (3 N HCl), 7 was easily obtained
in good yield after column chromatography purification (63%). This
procedure afforded a substantial improvement in terms of yield
and simplification of the process versus the reaction described by
Detterbeck et al.23
first applied. Under these conditions, the crude ester 11 polluted
by the target molecule was obtained in 60% yield. Attempts to iso-
late compound 2 by saponification of this crude product failed. At
this stage, no intramolecular cyclization leading to przewalskinic
acid was observed. In order to improve the yield in 2 or to obtain
przewalskinic acid, reaction time in presence of boron tribromide
was prolonged to 12 h at room temperature. A new major product
rac-12 (75%) was isolated with 2 (24%). From the 1H and 13C NMR
data, the structure of rac-12 was proposed and its formula was
confirmed by mass spectrometry. In the 1H NMR spectrum, the
classical 1,2,4-trisubstituted set of splitting due to the aromatic
ring was replaced by two singlets characteristic of a 1,2,4,5-tetra-
substituted aromatic ring whilst two doublets appeared at
4.72 ppm and 6.21 ppm indicating the formation of a dihydroben-
The construction of the
a,b-unsaturated carboxylic acid chain,
via a Knoevenagel condensation, was easily performed to give 10
in 90% yield (Scheme 2). Our standard conditions of deprotection
(1 h reaction time, room temperature, 7 equivalents of BBr3,
quenching by water at room temperature and 1 h stirring) were

4738
C. Queffélec et al. / Bioorg. Med. Chem. Lett. 18 (2008) 4736–4740
COOH
COOH
CO2Me
CO2Me
CO2Me
CHO
MeO
MeO
MeO
MeO
HO
HO
i
ii
MeO
MeO
HO
7
MeO
MeO
HO
10
11
iii
CO2H
OH
CO2H
H
O
HO
HO
OH
OH
+
HO
H
O
HO
2
COOH
rac-12
CO2H
CO2Me
CO2H
CO2H
CHO
CHO
MeO
HO
HO
HO
iii
i
MeO
HO
MeO
HO
HO
7
MeO
HO
13
HO
2
Scheme 2. Reagents and conditions: (i) CH2(COOH)2, pyridine, piperidine, reflux, 7 ? 10, 90%, 13 ? 2, 95%; (ii) BBr3, 7 equiv, CH2Cl2, rt, 1 h then water, rt, 1 h, 60%; (iii) BBr3, 7
equiv, CH2Cl2, rt, 12 h then water, rt, 1 h, 10 ? rac-12 (75%) + 2 (24%), 7 ? 13, 75%.
zofuran ring. The presence of a carbonyl function was confirmed by
its 13C chemical shift at 199.3 ppm. These data are in accordance
with a 5-oxo-4b,9b-dihydroindano[1,2-b]benzofuran, a new tetra-
cyclic system.24 According to the literature, the 3J value suggests
that the stereochemistry of the junction bond is expected to be
cis.25,26
1, 2 and rac-12 were found to be very active against wild-type
IN in the presence of Mg2+. Caffeic acid had been previously evalu-
ated as IN inhibitor in the presence of Mn2+, and presented IC50 of
2.8 and 24 lM on the overall reactions and on strand transfer,
respectively.31 The difference between the two assays indicated
that caffeic acid is more likely to be active at either the viral
DNA binding or 30 processing steps. The correlation observed be-
tween relative drug potency in the presence of Mg2+ and relative
potency in the wild-type enzyme suggests that assays performed
using wild-type enzyme and Mg2+ represent the most stringent
conditions with respect to drug inhibition.32 Since the caffeic acid
assays were conducted using Mn2+, caffeic acid would be expected
to show lower activity using Mg2+ and greater IC50 values. Our re-
sults showed that 1 has higher anti-IN activities than 14 and caffeic
acid. The presence of the two acidic functions has a synergistic ef-
fect on the anti-IN activity of 1 and 2, and a second catechol func-
tion slightly improves the anti-IN activities (2 and rac-12)
comparable to those of lithospermic acids.13 The best results were
obtained with the unexpectedly obtained rigid and folded struc-
ture of rac-12 and strand transfer inhibition assays also indicate
that these compounds are active inhibitors at that point in the viral
replication cycle.
Attempts to limit the cyclization process to the furan ring by
modifying reaction time (from 1 h to 15 h) and quenching process
(pouring the reaction mixture into cold water or NaH2PO4
saturated solution) failed, leading to variable mixtures of 2 and
rac-12. Whatever the quenching conditions, rac-12 was always ob-
tained in the same amount suggesting that the Friedel–Crafts cycli-
zation occurred during the reaction process with BBr3. Since
Detterbeck et al. reported that aldehyde 7 cyclized when treated
by BBr3, the same reaction conditions (12 h, room temperature)
were used. Surprisingly, the aldehyde 7 did not cyclize and led to
13 in 75% yield. Knoevenagel reaction of 13 gave 2 in 95% yield.
This alternative pathway furnished a substantial yield improve-
ment (7–2: 21% yield via 10 and 71% yield via 13). Attempts to pro-
mote the cyclization of 11 or 13 using HBr22 also failed. Compound
13 was almost quantitatively recovered, whereas 11 was totally
degraded.
1, 2, rac-12 and 2,3-dihydroxyphenylacetic acid 1427 were
tested in IN inhibition assays which have been recently re-
viewed28,29 and data are summarized in Table 1. The overall IN
enzymatic activity has been evaluated in two independent labora-
tories using two different protocols (see Supporting Information)
with two different preparations of the enzyme and magnesium
ions as co-factor (protocol 1, Table 1, column 4 and protocol 2, Ta-
ble 1, column 6). The strand transfer reaction inhibition was eval-
uated using protocol 1 (Table 1, column 5). The overall HIV-1 IN
inhibition assays show that higher IC50 values were obtained with
protocol 1 when compared to protocol 2. Similar discrepancies
were already observed for rosmarinic acid derivatives.30 But the
same general hierarchy between 1, 2 and rac-12 was observed in
both assays.
The antiviral activity of our compounds on HIV-1-induced CPE
in human lymphocyte MT-4 cell culture was determined by the
MT-4/MTT-assay33 and cytotoxicity was also evaluated in MT-4
cells (Table 1). The three tested molecules were found to be toxic
in cell cultures, and it was not possible to determine their antiviral
activities.
Numerous polyhydroxylated aromatic compounds had been
previously identified as HIV-1 IN. The main disadvantages of these
compounds are the lack of significant activity against replicating
virus, cell toxicity, lack of selectivity or a combination of these fac-
tors. But few have met the criterion for ‘‘lead” compounds. This
was the case for L-chicoric acid, lithospermic acid, lithospermic
acid B and 3,5-dicaffeoyl quinic acid.6,12 Herein the high cell toxic-
ity displayed by our compounds renders them unsuitable as poten-

C. Queffélec et al. / Bioorg. Med. Chem. Lett. 18 (2008) 4736–4740
4739
Table 1
Inhibition of HIV-1 IN catalytic activities, antiviral activity, and cytotoxicity of test compounds
Compound
MT-4 cells
HIV-1 integrase inhibition
a
b
c
c
d
EC50
(l
M)
CC50
(l
M)
Overall IC50
(l
M)
ST IC50
(l
M)
overall IC50 (lM)
OH
OH
1
>44
44
>77.9
77.9
1.34
1.09
0.32
COOH
COOH
OH
OH
OH
OH
>6.4
>4.5
6.4
4.5
0.56
0.73
0.22
COOH
2
COOH
OH
O
OH
OH
>23.3
>27.4
23.3
27.4
0.15
0.30
0.05
O
rac-12
COOH
OH
OH
NTe
NTe
NTe
NTe
>100
14
COOH
a
b
c
Effective concentration required to reduce HIV-1-induced cytopathic effect by 50% in MT-4 cells.
Cytotoxic concentration to reduce MT-4 cell viability by 50%.
Concentration required to inhibit by 50% the in vitro integrase activity using protocol 1.
Concentration required to inhibit by 50% the in vitro integrase activity using protocol 2.
Non-tested.
d
e
tial therapeutic drugs. This shortcoming may be overcome by
introducing a tartaric acid moiety on the caffeoyl carboxylic acids
(IC50 = 640 nM) and HIV replication (ED50 = 1.9
300
M) with a favourable selectivity index.35
lM; LD50 =
l
of our compounds. Indeed
the most potent and selective anti-HIV agent amongst the family of
polyhydroxylated aromatic compounds. -CA is a dicaffeoyl deriva-
L
-chicoric acid (
L
-CA) represents to date
In summary, the substituted caffeic acid moieties of natural sal-
vianolic acids D and E revealed very strong activities against IN,
amongst the best reported in this family of IN inhibitors. But these
compounds, like many other polyhydroxylated ones, were devoid
of any anti-HIV activity due to a high cell toxicity. Their structures
need to be modified as previously described in order to improve
their antiviral activities and to lower their cytotoxicities. The dihy-
drobenzofuran ring of rac-12 could represent a potential new hit
in the field of HIV-1 IN inhibitors and structure–activity relation-
ships are worth being investigated for this compound.
L
tive in which two caffeoyl moieties are bridged by a tartaric acid. It
is active against HIV-1 IN at submicromolar range and against HIV-
1 replication at micromolar range.34,35 The results concerning its
cellular toxicity are controversial. Whereas Robinson et al. revealed
the lack of cell toxicity for L-CA (LD50 = 700 l
M),35 further studies
were in favour of selectivity indexes around 10.34,36–38 Based upon
its structure, several dicaffeoyltartaric acid analogues were elabo-
rated and inhibited HIV-1 IN and HIV-1 replication at non-toxic
concentrations.34 So the bridging of two salvianolic acid fragments
by a tartaric acid may lead to compounds with increased anti-HIV
activity. These derivatives would of course not be devoid of cell
toxicity since the potential toxicity is generally associated with
the presence of catechol groups. But the latter ones are necessary
for HIV-1 IN inhibitory and anti-HIV properties, which were in
most cases correlated to the presence of at least one catechol
group. However these new compounds are expected to present lar-
gely more favourable selectivity indexes than their parent ones. An
alternative solution may consist in a same manner in bridging two
molecules by a quinic acid since 3,5-dicaffeoylquinic acid was
found to be very active against HIV-1 IN catalyzed reactions
Acknowledgments
This work was financially supported by grants from le Centre
National de la Recherche Scientifique (CNRS), l’Agence Nationale
de la Recherche contre le Sida (ANRS) and the European Commis-
sion (Grant LSHB-CT-2003-503480). The European TRIoH Consor-
tium is gratefully acknowledged. The mass spectrometry facility
used in this study was funded by the European Community (FED-
ER), the Région Nord-Pas de Calais (France), the CNRS and the Uni-
versité des Sciences et Technologies de Lille. We are grateful to
Martine Michiels, Nam Joo Vanderveken and Barbara Van Remoor-
tel for excellent technical assistance.

4740
C. Queffélec et al. / Bioorg. Med. Chem. Lett. 18 (2008) 4736–4740
19. Dupont, R.; Jeanson, L.; Mouscadet, J. F.; Cotelle, P. Bioorg. Med. Chem. Lett.
Supplementary data
2001, 11, 3175.
20. Queffélec, C.; Bailly, F.; Cotelle, P. Synthesis 2006, 768.
21. Ai, C. B.; Li, L. N. Planta Med. 1992, 58, 197.
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.bmcl.2008.06.063.
22. Jacobson, R. M.; Raths, R. A. J. Org. Chem. 1979, 44, 4013.
23. Detterbeck, R.; Hesse, M. Helv. Chim. Acta 2003, 86, 343.
24. Meyer, M.; Deschamps, C.; Molho, D. Bull. Soc. Chim. Fr. 1991, 127, 91.
25. Negishi, E.; Coperet, C.; Ma, S.; Mita, T.; Sugihara, T.; Tour, J. M. J. Am. Chem. Soc.
1996, 118, 5904.
References and notes
26. Amman, W. Q.; Ganter, C. Helv. Chim. Acta 1981, 64, 996.
27. Snook, M. E.; Mason, P. F.; Arrendale, R. F.; Chortyk, O. T. J. Chromatogr. A 1985,
324, 141.
28. Witvrouw, M.; Van Maele, B.; Vercammen, J.; Hantson, A.; Engelborghs, Y.; De
Clercq, E.; Pannecouque, C.; Debyser, Z. Curr. Drug Metab. 2004, 5, 291.
29. Debyser, Z.; Cherepanov, P.; Pluymers, W.; De Clercq, E. Methods Mol. Biol.
2001, 160, 139.
30. Dubois, M.; Bailly, F.; Mbemba, G.; Mouscadet, J. F.; Debyser, Z.; Witvrouw, M.;
Cotelle, P. J. Med. Chem. 2008, 51, 2575.
31. Singh, S. B.; Jayasuriya, H.; Dewey, R.; Polishook, J. D.; Dombrowski, A. W.; Zink,
D. L.; Guan, Z.; Collado, J.; Platas, G.; Pelaez, F.; Felock, P. J.; Hazuda, D. J. J. Ind.
Microbiol. Biotechnol. 2003, 30, 721.
32. Marchand, C.; Johnson, A. A.; Karki, R. G.; Pais, G. C.; Zhang, X.; Cowansage, K.;
Patel, T. A.; Nicklaus, M. C.; Burke, T. R., Jr.; Pommier, Y. Mol. Pharmacol. 2003,
64, 600.
33. Pauwels, R.; Balzarini, J.; Baba, M.; Snoeck, R.; Schols, D.; Herdewijn, P.;
Desmyter, J.; De Clercq, E. J. Virol. Methods 1988, 20, 309.
34. Reinke, R. A.; King, P. J.; Victoria, J. G.; McDougall, B. R.; Ma, G.; Mao, Y.;
Reinecke, M. G.; Robinson, W. E. J. Med. Chem. 2002, 45, 3669.
35. Robinson, W. E., Jr.; Reinecke, M. G.; Abdel-Malek, S.; Jia, Q.; Chow, S. A. Proc.
Natl. Acad. Sci. USA 1996, 93, 6326.
36. King, P. J.; Ma, G.; Miao, W.; Jia, Q.; McDougall, B. R.; Reinecke, M. G.;
Cornell, C.; Kuan, J.; Kim, T. R.; Robinson, W. E., Jr. J. Med. Chem. 1999, 42,
497.
37. Lin, Z.; Neamati, N.; Zhao, H.; Kiryu, Y.; Turpin, J. A.; Aberham, C.; Strebel, K.;
Kohn, K.; Witvrouw, M.; Pannecouque, C.; Debyser, Z.; De Clercq, E.; Rice, W.
G.; Pommier, Y.; Burke, T. R., Jr. J. Med. Chem. 1999, 42, 1401.
38. Charvat, T. T.; Deborah, J. L.; Robinson, W. E., Jr.; Chamberlin, A. R. Bioorg. Med.
Chem. 2006, 14, 4552.
1. Makhija, M. T. Curr. Med. Chem. 2006, 13, 2429.
2. Lataillade, M.; Kozal, M. J. AIDS Patient Care STDS, 2006, 20, 489–501.
3. Dayam, R.; Deng, J.; Neamati, N. Med. Res. Rev. 2006, 26, 271.
4. Pommier, Y.; Johnson, A. A.; Marchand, C. Nat. Rev. Drug Discov. 2005, 4,
236.
5. Johnson, A. A.; Marchand, C.; Pommier, Y. Curr. Top. Med. Chem. 2004, 4, 1059.
6. Maurin, C.; Bailly, F.; Cotelle, P. Curr. Med. Chem. 2003, 10, 1795.
7. Cotelle, P. Recent Patents on Anti-Infective Drug Discovery, 2006, 1, 1.
8. Dejesus, E.; Berger, D.; Markowitz, M.; Cohen, C.; Hawkins, T.; Ruane, P.; Elion,
R.; Farthing, C.; Zhong, L.; Cheng, A. A.; McColl, D.; Kearney, B. P. J. Acquir.
Immune Defic. Syndr. 2006, 43, 1.
9. Grinsztejn, B.; Nguyen, B. Y.; Katlama, C.; Gatell, J. M.; Lazzarin, A.; Vittecoq, D.;
Gonzalez, C. J.; Chen, J.; Harvey, C. M.; Isaacs, R. Lancet 2007, 369, 1261.
10. Markowitz, M.; Morales-Ramires, J. O.; Nguyen, B. Y.; Kovacs, C. M.; Steigbigel,
R. T.; Cooper, D. A.; Liporace, R.; Schwartz, R.; Isaacs, R.; Gilde, L. R.; Wenning,
L.; Zhao, J.; Teppler, H. J. Acquir. Immune Defic. Syndr. 2006, 43, 509.
11. Lataillade, M.; Chiarella, J.; Kozal, M. J. Antivir. Ther. 2007, 12, 563.
12. Bailly, F.; Cotelle, P. Curr. Med. Chem. 2005, 12, 1811.
13. Abd-Elazem, I. S.; Chen, H. S.; Bates, R. B.; Huang, R. C. Antiviral Res. 2002, 55, 91.
14. Han, M. K.; Lee, P. World Patent WO 9966942, 1999.; Han, M. K.; Lee, P. Chem.
Abstr. 1999, 132, 231935.
15. Han, M. K.; Lee, P. US Patent 6043276, 2000.; Han, M. K.; Lee, P. Chem. Abstr.
2000, 132, 69303.
16. Maurin, C.; Bailly, F.; Mbemba, G.; Mouscadet, J. F.; Cotelle, P. Bioorg. Med.
Chem. 2006, 14, 2978.
17. Bailly, F.; Queffélec, C.; Mbemba, G.; Mouscadet, J. F.; Cotelle, P. Bioorg. Med.
Chem. Lett. 2005, 15, 5053.
18. Maurin, C.; Bailly, F.; Buisine, E.; Vezin, H.; Mbemba, G.; Mouscadet, J. F.;
Cotelle, P. J. Med. Chem. 2004, 47, 5583.