Design and synthesis of endoperoxide antimalarial prodrug models

Article abstract of DOI:10.1002/anie.200453859

A masked combination chemotherapy which relies on the embedding of a number of active components, in a latent form, within a single endoperoxidic chemical entity is the aim of the research presented. The approach is illustrated by means of purposely designed bicyclic endoperoxide prodrug prototypes 1 and subsequently validated through the study of model compounds 2 (Ar= Ph, p-FC ₆H₄, p-ClC₆H₄.

Full text of DOI:10.1002/anie.200453859

Angewandte
Chemie
Cysteine Protease Inhibitors
Design and Synthesis of Endoperoxide
Antimalarial Prodrug Models**
Paul M. OꢀNeill,* Paul A. Stocks, Matthew D. Pugh,
Nuna C. Araujo, Edward E. Korshin, Jamie F. Bickley,
Stephen A. Ward, Patrick G. Bray, Erica Pasini,
Jill Davies, Edite Verissimo, and Mario D. Bachi*
There has been an increase in support for combination
chemotherapy as a rational strategy to combat malaria.[1] It is
anticipated that, in addition to pharmacodynamic benefits
such as the synergistic effect of drugs, combination therapy
will delay the development of drug resistance in the malaria
parasite P. falciparum. For malaria chemotherapy it was
suggested that one component of such a drug combination
should be a 1,2,4-trioxane-containing artemisinin derivative,
as these compounds show fast antiparasitic action.[2,3] Very
recently, an extension of this approach resulted in the
elaboration of new potent modular antimalarial agents.
These active compounds each contain two antimalarial
pharmacophores, such as 1,2,4-trioxane and aminoquino-
line[4,5] or an aliphatic diamine,[6] within the same molecule.
Herein, we describe a paradigm for a masked combination
chemotherapy which relies on the embedding of a number of
active components, in a latent form, within a single endoper-
oxidic chemical entity. Following penetration as a “Trojan
horse” into the ferrous-rich food vacuole (FV) of the malaria
parasite, these endoperoxidic prodrugs will be unmasked by
in situ iron(ii)-mediated fragmentation thus releasing multiple
parasiticidal entities.[7]
Our approach is illustrated by means of the purposely
designed bicyclic endoperoxide prodrug prototypes 1 and
subsequently proved through the study of model compounds
2. The substituents at position 4 in 1 should secure the in situ
generation of chalcones of type 3 alongside additional
noxious species as shown in Scheme 1. Some of these active
[*] Dr. P. M. O’Neill, Dr. P. A. Stocks, Dr. M. D. Pugh, N. C. Araujo,
J. F. Bickley, J. Davies, E. Verissimo
Department of Chemistry
The Robert Robinson Laboratories
Universityof Liverpool
Liverpool L697ZD (UK)
Fax: (+44)151-794-3588
E-mail: p.m.oneill01@liv.ac.uk
Dr. E. E. Korshin, Prof. Dr. M. D. Bachi
Department of Organic Chemistry
The Weizmann Institute of Science
Rehovot 76100 (Israel)
Fax: (+972)8-9344142
E-mail: mario.bachi@weizmann.ac.il
Prof. Dr. S. A. Ward, Dr. P. G. Bray, E. Pasini
Liverpool School of Tropical Medicine
Pembroke Place, Liverpool L35QA (UK)
[**] This work was supported bygrants from the BBSRC (UK) for P.A.S.,
P.O’N., and S.A.W. (26/B13581) and from the EPSRC (UK) for
M.D.P.
Angew. Chem. Int. Ed. 2004, 43, 4193 –4197
DOI: 10.1002/anie.200453859
ꢀ 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
4193

Communications
The designed prodrugs 1 are new representatives of an
emerging class of promising antimalarial endoperoxides
which contain the 2,3-dioxabicyclo[3.3.1]nonane framework
5 and are structurally related to naturally occurring ying-
zhaosu A (6).[14,15] Synthetic endoperoxides, such as arteflene
(7, Ar= 2,4-bis(trifluoromethyl)phenyl) and its analogues,[16]
as well as the b-sulfonyl endoperoxides 8a and 8b and related
compounds,[15,17,18] were found to be potent and nontoxic
antimalarial agents in vivo. In vitro antimalarial activity was
reported for 4-acetal, 1,4-diacetal, and 1- or 4-iodomethyl
derivatives of 8.[19–21]
Biomimetic FeII-induced degradation reactions of arte-
flene (7) provided some clues on the mode of action of these
endoperoxides.[22,23] Thus, on being subjected to ferrous-
mediated fragmentation in water/MeCN, arteflene (7) gave
the stable enone 10 and the transient carbon-centered
cyclohexyl radical 11 (Scheme 2).[22] This latter species was
Scheme 2. FeII-catalyzed degradation of arteflene (7).
directly detected by EPR[23] and trapped with TEMPO
(2,2,6,6-tetramethylpiperidinyloxy) in a degradation induced
by MnII–tetraphenylporphyrin (TPP).[24] (Parallel biomimetic
studies with the sulfonyl endoperoxide 8a demonstrated that
secondary C-centred radicals, related to 11, can also readily
undergo oxidation by FeIII to potentially toxic carbocat-
ions.[25]) Whereas the enone 10 liberated from arteflene is
inactive against Plasmodium falciparum,[22] the prodrugs
described herein have the capacity to liberate an enone of
the chalcone class with antimalarial activity.[10,11,26]
Scheme 1. The designed ferrous-catalyzed degradation of the generic
prodrug 1.
The synthesis of the model endoperoxides 2 is depicted in
Schemes 3 and 5. Ozonolysis of commercially available (R)-
limonene oxide (12) followed by in situ reduction and
transformation of the internal epoxide into the corresponding
alkene[27] afforded the unsaturated ketone 13 (50%;
Scheme 3). The subsequent formation of the kinetic enol
triflate 14 was initially attempted with trifluoromethanesul-
species are reminiscent of those generated by artemisinin and
related trioxanes and presumably kill the parasite through a
similar mode of action.[7–9] In contrast, chalcones 3 cannot be
formed by ferrous-mediated degradation of the currently
known 1,2,4-trioxanes. On the other hand, a series of
chalcones have been found to be effective antimalarial
cysteine protease (CP) inhibitors.[10] Moreover, natural lico-
chalcone A (4) was reported to provide efficacious protection
against P. berghei malaria in mice.[11] Falcipain 2, a CP of the
papain family, is a P. falciparum FV hemoglobinase; it acts in
concert with some aspartic proteases to degrade hemoglobin,
thus enabling the malaria parasite to acquire amino acids for
its protein biosynthesis.[12] Therefore, plasmodium CPs con-
stitute an attractive target for antimalarial drug
research.[1,12,13]
fonic anhydride. However, the unsatisfactory yield (8%)
[28]
prompted us to use PhNTf2
as the triflating agent and
KHMDS as the base, which provided the triflate 14 in 64%
yield. The triflate 14 was then subjected to a nickel-catalyzed
cross-coupling[29] with phenyl magnesium bromide to give 15,
a phenyl analogue of (R)-limonene (75%; Scheme 3).
Recently we applied the free-radical, four-component,
sequential thiol–olefin co-oxygenation (TOCO) reaction to
limonene and similar monoterpenes, thus providing an
efficient tool for the construction of the 2,3-dioxabicy-
clo[3.3.1]nonane system 5.[30,31] This reaction was found to
4194
ꢀ 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
Angew. Chem. Int. Ed. 2004, 43, 4193 –4197

Angewandte
Chemie
to the right and accelerating the whole chain process. As a
result, the TOCO reaction gave the hydroperoxy endoper-
oxides 16 in high yield, even in a more concentrated solution,
in shorter reaction times, and with close to stochiometric
ratios of the reagents.
The configuration of the diastereomeric sulfides 17a and
17b was assigned based on their NMR spectra in accordance
with the previously formulated empirical rules.[30,31] Some
relevant 1H NMR data are shown in Figure 1. The assignment
for 17a by NMR spectroscopy was corroborated by the crystal
structure of the corresponding crystalline acetoxy sulfone 17c
(Figure 1),[32] which was obtained in a silylation, acetylation,
and oxidation process.[18,31]
Scheme 3. a) O3, ꢀ788C, CH2Cl2; b) NaI, AcOH, AcONa, Zn (50%
from 12); c) KHMDS (1.5 equiv, 1.0m in THF), PhNTf2 (1.5 equiv),
THF, ꢀ78!ꢀ408C, 64%; d) PhMgBr (2 equiv), [Ni(acac)2] (0.1 equiv),
Et2O, room temperature, 75%; e) PhSH (1.2 equiv), AIBN (0.07 equiv),
O2 (excess), hn, 08C, CH3CN; f) Ph3P (1.6 equiv), CH3CN, CH2Cl2, 08C
to room temperature (70% from 16; 17a/17b ca. 4:3). KHMDS=
potassium hexamethyldisilazane; PhNTf2 =N-phenyltrifluoromethane-
sulfonimide; acac=acetylacetonate; AIBN=azabisisobutyronitrile.
be particularly suitable for the formation of the bicyclic
endoperoxidic backbone of model compounds 2. Optimiza-
tion of this reaction led to the following protocol: a solution of
PhSH was added during 30 min to a solution of the 1,5-diene
15 and AIBN in acetonitrile at 08C under small positive
pressure of pure oxygen and under UV irradiation, to afford
the hydroperoxy endoperoxides 16. The reactive hydroperoxy
group was reduced selectively in the same vessel with Ph3P to
give the rather stable hydroxy endoperoxides 17. The
diastereomeric compounds 17a,b (a/b ca. 4:3) were isolated
after flash chromatography in 70% yield (average yield per
newly formed bond: > 93%). The mechanism of the sequen-
tial TOCO reaction is illustrated in Scheme 4.
Figure 1. Distinctive 1H NMR data for sulfides 17a and 17b, and syn-
thesis and X-raycrystal structure of the sulfone 17c (ORTEP).[32]
The completion of the synthesis of the model prodrugs 2 is
described in Scheme 5. The acetylation of the sterically
hindered tertiary hydroxy group in 17a to give the sulfide
18 was achieved by 1) silylation with TMSOTf, and 2) acyla-
tion of the crude TMS derivative with neat AcCl.[18,31] The key
aldehyde intermediate 20 was obtained by a Pummerer-type
oxidative desulfurization as reported for similar endoperoxi-
dic sulfoxides:[15] selective oxidation of 18 with mCPBA
afforded a mixture of the epimeric sulfoxides 19; treatment of
19 with TFAA[33] afforded the desired aldehyde 20 (40%).
Finally, this aldehyde was converted into the prototypic
prodrugs 2a–c through a Wittig cis olefination.[16a,b]
The endoperoxidic prodrug prototypes 2a–c were assayed
for in vitro antimalarial activity against the chloroquine-
resistant K1 strain of Plasmodium falciparum (Table 1). The
data are encouraging in the sense that all of the prepared
analogues 2 have superior activity to the Hoffmann LaRoche
antimalarial drug candidate arteflene (7).
Scheme 4. Mechanism of the TOCO reaction.
It has been noted for the case of the parent limonene that
it is necessary to maintain a low concentration of PhSH and a
high monoterpene/PhSH ratio throughout the TOCO reac-
tion to obtain the bridged bicyclic endoperoxides in good
yield.[31] However, because of the supporting effect of the
phenyl group in the phenyl analogue 15, addition of the
sulfanyl radical to the terminus of the exocyclic C C bond in
15 to generate radical A is faster (Scheme 4). The phenyl
group stabilizes radical A, thus shifting the equilibrium 15QA
A biomimetic FeII-mediated degradation of the model
endoperoxide 2a in H2O/MeCN at room temperature accord-
ing to the previously described protocol[22,23] afforded the
expected trans chalcone 3a (45%) as the major product
(Scheme 6),[34] along with a smaller amount of the diol 21
=
Angew. Chem. Int. Ed. 2004, 43, 4193 –4197
www.angewandte.org
ꢀ 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
4195

Communications
analysis of ethyl acetate extracts of isolated FVs of mid-term
trophozoites exposed to 50 mm prodrug clearly demonstrated
the presence of parent chalcone 3a. Quantification was
achieved by LC–MS monitoring of [M+H] at m/z 209.3. The
chalcone 3a was identified by matching the MS/MS spectrum
of the parent ion and by comparing the retention times with
those of an authentic sample.
In conclusion, we have developed a general synthetic
route for the preparation of a promising class of antimalarial
prodrug candidates of the general structure 1. Compound 2a
was chosen as a prototype. It was expected that for a variety of
substituents R1 and R2 at C8 of the bridged bicyclic frame-
work 5, different compounds of type 1 (Ar1 = Ar2 = Ph) would
act as precursors to the chalcone 3a, which is the prototype of
the known CP inhibitors 3 and 4. Indeed, it was proved that
the endoperoxide 2a liberates, through iron(ii) mediation, the
chalcone 3a and additional potential parasiticidal species. Not
only did all three model compounds 2 exhibit significant
antimalarial activity but definitive proof that these systems
are capable of liberating a chalcone in the living parasite was
provided by LC–MS analysis of prodrug-exposed parasites. It
is planned to extend the present work by studying compounds
of type 1 with masked chalcone units endowed with varying
CP-inhibition potential and antimalarial potencies.
Scheme 5. a) TMSOTf (2 equiv), 2,6-lutidine (2.75 equiv), CH2Cl2, 95%;
b) neat AcCl (60% from 17a); c) mCPBA (1.1 equiv), CH2Cl2, 08C,
85%; d) TFAA (2 equiv), morpholine, CH3CN, 40%;
e) (ArCH2)Ph3P+Brꢀ (1.4 equiv), KHMDS (1.4 equiv), THF, ꢀ10!
258C, 2 h. TMSOTf=trimethylsilyl triflate; TFAA=trifluoroacetic anhy-
dride.
Table 1: In vitro antimalarial activityof prototpye endoperoxides 2a–c
against the K1 strain of P. falciparum.
Received: January 27, 2004 [Z53859]
Compound
IC50 [nm]
SDꢁ
Keywords: antimalarial agents · chalcones · combination
chemotherapy· cysteine protease inhibitors · endoperoxides
.
2a
2b
2c
34
29
23
47
15
4
5
4
8
4
arteflene (7)
artemisinin
[1] P. J. Guerin, P. Olliaro, F. Nosten, P. Druilhe, R. Laxminarayan,
F. Binka, W. L. Kilama, N. Ford, N. J. White, Lancet Infect. Dis.
2002, 2, 564 – 573.
[2] M. Frederich, J. M. Dogne, L. Angenot, P. De Mol, Curr. Med.
Chem. 2002, 9, 1435 – 1456.
[3] S. Pukrittayakamee, N. J. White, Pharm. News 2001, 8, 21 – 26.
[4] a) A. Robert, O. Dechy-Cabaret, J. Cazelles, B. Meunier, Acc.
Chem. Res. 2002, 35, 167 – 174; b) O. Dechy-Cabaret, F. Benoit-
Vical, A. Robert, B. Meunier, ChemBioChem 2000, 1, 281 – 283;
c) L. K. Basco, O. Dechy-Cabaret, M. Ndounga, F. S. Meche, A.
Robert, B. Meunier, Antimicrob. Agents Chemother. 2001, 45,
1886 – 1888.
(33%), the product of a two-electron reduction.[22] (The
chalcone 3a is a surrogate marker for the generation of the
secondary C-centered radical 22.) More significantly, LC–MS
[5] O. Dechy-Cabaret, A. Robert, B. Meunier, C. R. Chim. 2002, 5,
297 – 302.
[6] S. Hindley, S. A. Ward, R. C. Storr, N. L. Searle, P. G. Bray, B. K.
Park, J. Davies, P. M. OꢀNeill, J. Med. Chem. 2002, 45, 1052 –
1063.
[7] a) G. H. Posner, S. B. Park, L. Gonzalez, D. Wang, J. N. Cum-
ming, D. Klinedinst, T. A. Shapiro, M. D. Bachi, J. Am. Chem.
Soc. 1996, 118, 3537 – 3538; b) J. N. Cumming, P. Ploypradith,
G. H. Posner, Adv. Pharmacol. 1997, 37, 253 – 297; c) G. H.
Posner, J. N. Cumming, M. Krasavin in Biomedicinal Chemistry:
Applying Chemical Principles to the Understanding and Treat-
ment of Disease (Ed.: P. F. Torrence), Wiley-Interscience, New
York, 2000, pp. 289 – 309; d) K. Borstnik, I.-H. Paik, G. H.
Posner, Mini-Rev. Med. Chem. 2002, 2, 573 – 583.
[8] a) A. Robert, J. Cazelles, B. Meunier, Angew. Chem. 2001, 113,
2008 – 2011; Angew. Chem. Int. Ed. 2001, 40, 1954 – 1957; b) A.
Robert, B. Meunier, J. Am. Chem. Soc. 1997, 119, 5968 – 5969;
c) Y. Wu, Acc. Chem. Res. 2002, 35, 255 – 259; d) Y. Wu, Z.-Y.
Yue, Y.-L. Wu, Angew. Chem. 1999, 111, 2730 – 2733; Angew.
Scheme 6. a) FeCl2·4H2O (1 equiv), CH3CN/H2O (1:1), room tempera-
ture.
4196
ꢀ 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
Angew. Chem. Int. Ed. 2004, 43, 4193 –4197

Angewandte
Chemie
Chem. Int. Ed. 1999, 38, 2580 – 2583; e) C. W. Jefford, Curr. Med.
Chem. 2001, 8, 1803 – 1826.
[22] P. M. OꢀNeill, L. P. Bishop, N. L. Searle, J. L. Maggs, S. A. Ward,
P. G. Bray, R. C. Storr, B. K. Park, Tetrahedron Lett. 1997, 38,
4263 – 4266.
[23] P. M. OꢀNeill, L. P. Bishop, N. L. Searle, J. L. Maggs, R. C. Storr,
S. A. Ward, B. K. Park, F. Mabbs, J. Org. Chem. 2000, 65, 1578 –
1582.
[24] J. Cazelles, A. Robert, B. Meunier, J. Org. Chem. 1999, 64, 6776 –
6781.
[25] A. M. Szpilman, E. E. Korshin, R. Hoos, G. H. Posner, M. D.
Bachi, J. Org. Chem. 2001, 66, 6531 – 6540.
[26] Avariety of peptidyl aldehydes are also potent in vitro inhibitors
of protozoan CP; see: K. A. Scheidt, W. R. Roush, J. H.
McKerrow, P. M. Selzer, E. Hansell, P. J. Rosenthal, Bioorg.
Med. Chem. 1998, 6, 2477 – 2494, and references therein.
[27] H. Takikawa, Y. Yamazaki, K. Mori, Eur. J. Org. Chem. 1998,
229.
[9] a) S. R. Meshnick, T. E. Taylor, S. Kamchonwongpaisan, Micro-
biol. Rev. 1996, 60, 301 – 315; b) S. R. Meshnick, Int. J. Parasitol.
2002, 32, 1655 – 1660; c) Y.-L. Hong, Y.-Z. Yang, S. R. Meshnick,
Mol. Biochem. Parasitol. 1994, 63, 121 – 128; d) W. Asawamaha-
sakda, I. Ittarat, Y.-M. Pu, H. Ziffer, S. R. Meshnick, Antimicrob.
Agents Chemother. 1994, 38, 1854 – 1858; e) J. Bhisutthibhan, X.-
Q. Pan, P. A. Hossler, D. J. Walker, C. A. Yowell, J. Carlton, J. B.
Dame, S. R. Meshnick, J. Biol. Chem. 1998, 273, 16192 – 16198;
f) A. V. Pandey, B. L. Tekwani, R. L. Singh, V. S. Chauhan, J.
Biol. Chem. 1999, 274, 19383 – 19388; g) U. Eckstein-Ludwig,
R. J. Webb, I. D. A. van Goethem, J. M. East, A. G. Lee, M.
Kimura, P. M. OꢀNeill, P. G. Bray, S. A. Ward, S. Krishna, Nature
2003, 424, 957 – 961.
[10] R. Li, G. L. Kenyon, F. E. Cohen, X. Chen, B. Gong, J. N.
Dominguez, E. Davidson, G. Kurzban, R. E. Miller, E. O.
Nuzum, P. J. Rosenthal, J. H. McKerrow, J. Med. Chem. 1995,
38, 5031 – 5037.
[11] a) M. Chen, T. G. Theander, S. B. Christensen, L. Hviid, L. Zhai,
A. Kharazmi, Antimicrob. Agents Chemother. 1994, 38, 1470 –
1475; b) L. Nadelmann, J. Tjornelund, S. H. Hanse, C. Cornetti,
U. G. Sidelmann, Xenobiotica 1997, 27, 667 – 680.
[12] a) P. J. Rosenthal, Emerging Infect. Dis. 1998, 4, 49 – 57; b) P. J.
Rosenthal, Adv. Parasitol. 1999, 43, 105 – 159; c) P. J. Rosenthal,
J. H. McKerrow, M. Aikawa, H. Nagasawa, J. H. Leech, J. Clin.
Invest. 1988, 82, 1560 – 1566; d) D. E. Goldberg, A. F. G. Slater,
R. Beavis, B. Chait, A. Cerami, G. B. Henderson, J. Exp. Med.
1991, 173, 961 – 969; e) N. D. Gamboa de Dominguez, P. J.
Rosenthal, Blood 1996, 87, 4448 – 4454; f) M. Dua, P. Raphael,
P. S. Sijwali, P. J. Rosenthal, M. Hanspal, Mol. Biochem. Para-
sitol. 2001, 116, 95 – 99.
[13] a) R. G. Ridley, Nature 2002, 415, 686 – 693; b) G. H. Coombs,
D. E. Goldberg, M. Klemba, C. Berry, J. Kay, J. Mottram, Trends
Parasitol. 2001, 17, 532 – 537; c) P. Olliaro, J. Cattani, D. Wirth,
JAMA 1996, 275, 230 – 233.
[28] T. Hayashi, Y. Katsuro, M. Kumada, Tetrahedron Lett. 1980, 21,
3915.
[29] P. M. OꢀNeill, M. D. Pugh, A. V. Stachulski, S. A. Ward, J.
Davies, B. K. Park, J. Chem. Soc. Perkin Trans. 1 2001, 2682.
[30] M. D. Bachi, E. E. Korshin, Synlett 1998, 122 – 124.
[31] E. E. Korshin, R. Hoos, A. M. Szpilman, L. Konstantinovski,
G. H. Posner, M. D. Bachi, Tetrahedron 2002, 58, 2449 – 2469.
[32] CCDC 228984 (17c) contains the supplementary crystallo-
graphic data for this paper. These data can be obtained free of
charge via www.ccdc.cam.ac.uk/conts/retrieving.html (or from
the Cambridge Crystallographic Data Centre, 12, Union Road,
Cambridge CB21EZ, UK; fax: (+ 44)1223-336-033; or deposit@
ccdc.cam.ac.uk).
[33] For these modified Pummerer reaction conditions, see: Y.
Arroyo-Gomez, J. F. Rodriguez-Amo, M. Santos-Garcia, M. A.
Sanz-Tejedor, Tetrahedron: Asymmetry 2000, 11, 789 – 796.
[34] A partial cis-to-trans isomerization of enone 10 upon MnIITPP-
induced fragmentation of arteflene (7) has been reported in
reference [24].
[14] a) X. T. Liang, D. Q. Yu, W. L. Wu, H. C. Deng, Acta Chim. Sin.
(Engl. Ed.) 1979, 37, 215 – 230; b) X. Liang in Advances in
Chinese Medicinal Materials (Eds.: H. M. Chang, H. W. Yeung,
W. W. Tso, A. Koo), World Scientific, Singapore, 1985, pp. 427 –
432; c) X. X. Xu, J. Zhu, D.-Z. Huang, W.-S. Zhou, Tetrahedron
Lett. 1991, 32, 5785 – 5788.
[15] M. D. Bachi, E. E. Korshin, R. Hoos, A. M. Szpilman, J.
Heterocycl. Chem. 2000, 37, 639 – 646.
[16] a) W. Hofheinz, G. Schmid, H. Stohler, Eur. Pat. Appl. 311955,
1989 [Chem. Abstr. 1990, 112, 20999]; b) W. Hofheinz, H.
Burgin, E. Gocke, C. Jaquet, R. Masciadri, G. Schmid, H.
Stohler, H. Urwyler, Trop. Med. Parasitol. 1994, 45, 261 – 265;
c) C. Jaquet, H. R. Stohler, J. Chollet, W. Peters, Trop. Med.
Parasitol. 1994, 45, 266 – 271.
[17] M. D. Bachi, E. E. Korshin, P. Ploypradith, J. N. Cumming, S. J.
Xie, T. A. Shapiro, G. H. Posner, Bioorg. Med. Chem. Lett. 1998,
8, 903 – 908.
[18] M. D. Bachi, E. E. Korshin, R. Hoos, A. M. Szpilman, P.
Ploypradith, S. Xie, T. A. Shapiro, G. H. Posner, J. Med. Chem.
2003, 46, 2516 – 2533.
[19] P. M. OꢀNeill, N. L. Searle, K. J. Raynes, J. L. Maggs, S. A. Ward,
R. C. Storr, B. K. Park, G. H. Posner, Tetrahedron Lett. 1998, 39,
6065 – 6068.
[20] a) T. Tokuyasu, A. Masuyama, M. Nojima, H.-S. Kim, Y. Wataya,
Tetrahedron Lett. 2000, 41, 3145 – 3148; b) T. Tokuyasu, A.
Masuyama, M. Nojima, K. J. McCullough, H.-S. Kim, Y. Wataya,
Tetrahedron 2001, 57, 5979 – 5989.
[21] H.-S. Kim, K. Begum, N. Ogura, Y. Wataya, T. Tokuyasu, A.
Masuyama, M. Nojima, K. J. McCullough, J. Med. Chem. 2002,
45, 4732 – 4736.
Angew. Chem. Int. Ed. 2004, 43, 4193 –4197
www.angewandte.org
ꢀ 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
4197