Biological activities of α-mangostin derivatives against acidic sphingomyelinase

Article abstract of DOI:10.1016/S0960-894X(03)00719-4

Deprenyl and benzofenone-type congeners of α-mangostin 1 have been synthesized to understand their role for the inhibitory activity against sphingomyelinase (SMase). While removal of the prenyl group of the right side (11 and 12) caused loss of the selectivity between ASMase (acidic sphingomyelinase) and NSMase (neutral sphingomyelinase), the prenyl group of the left side appeared to increase the inhibitory activities (16 and 17).

Full text of DOI:10.1016/S0960-894X(03)00719-4

Bioorganic & Medicinal Chemistry Letters 13 (2003) 3151–3153
Biological Activities of ꢀ-Mangostin Derivatives
against Acidic Sphingomyelinase
Motoko Hamada,a Kazuhiko Iikubo,a Yuichi Ishikawa,a Aya Ikeda,b
Kazuo Umezawab and Shigeru Nishiyamaa,*
aDepartment of Chemistry, Faculty of Science and Technology, Keio University, Hiyoshi 3-14-1,
Kohoku-ku, Yokohama 223-8522, Japan
bDepartment of Applied Chemistry, Faculty of Science and Technology, Keio University, Hiyoshi 3-14-1,
Kohoku-ku, Yokohama 223-8522, Japan
Received 31 May 2003; accepted 4 July 2003
Abstract—Deprenyl and benzofenone-type congeners of a-mangostin 1 have been synthesized to understand their role for the
inhibitory activity against sphingomyelinase (SMase). While removal of the prenyl group of the right side (11 and 12) caused loss of
the selectivity between ASMase (acidic sphingomyelinase) and NSMase (neutral sphingomyelinase), the prenyl group of the left side
appeared to increase the inhibitory activities (16 and 17).
# 2003 Elsevier Ltd. All rights reserved.
a-Mangostin 1, isolated from Garcinia mangostana L.
(Guttiferae)1 as a representative xanthone-class natural
products of plant origin, revealed highly selective inhi-
bitory activity against acidic sphingomyelinase,2 in
addition to diverse biological activities of this mol-
ecule.3 Despite such intriguing biological activities, to
our knowledge, there was only one formal synthesis of 1
by Lee: the chroman precursor was converted into b-
mangostin,4 demethylation of which was reported to
provide 1.5 In this context, we reported a new efficient
total synthesis of 1 by using the diaryl ether construc-
At the outset, the deprenyl derivatives of the corre-
sponding aromatic moieties 5 and 7, were synthesized.
Thus, 2,4-dihydrobenzaldehyde 4 was benzylated, fol-
lowed by the Baeyer–Villiger oxidation and acidic
hydrolysis to give the corresponding phenol, which on
regioselective bromination and methylation provided 5
in good overall yield (Scheme 1). Compound 7 was
synthesized by the known procedure8 using the Vilsme-
ier–Haack–Viehe reaction of 1,3,5-trihydroxybenzene 6,
followed by exhaustive methoxymethylation.
6
tion under mild dehydration conditions, developed by
our group.7 Fortunately, the benzophenone derivative 2
obtained as a synthetic intermediate, was observed to
possess inhibitory activity against ASMase comparable
to that of 1, while its cytotoxicity was 1/10-fold less than
that of 1. In addition, Umezawa reported that the tet-
rahydro derivative 3 exhibited reduction of the selective
inhibition against ASMase and NSMase: the NSMase
activity was two times stronger than that of 1.2 These
findings prompted us to acquire further information on
the structure- activity relationship (SAR) of SMase. We
describe herein our investigation-process, in particular
related to the effect of the diaryl ether moieties, as well
as the prenyl side chains (Fig. 1).
*Corresponding author. Tel./fax: +81-45-566-1717; e-mail:
nisiyama@chem.keio.ac.jp
Figure 1. Structures of mangostins and its derivatives.
0960-894X/$ - see front matter # 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/S0960-894X(03)00719-4

3152
M. Hamada et al. / Bioorg. Med. Chem. Lett. 13 (2003) 3151–3153
Table 1. Inhibitory activities of a-mangostin 1 and its derivatives
against sphingomyelinase (SMase)
Synthesis of 11 and 12
Exposure of bromide 86 to s-BuLi gave the corresponding
lithio derivative, which on coupling with 7 provided 9
(Scheme 2). Oxidation of the benzyl alcohol by IBX9 and
transacetalization afforded benzofenone 10, which was
hydrogenolized to give 11. Treatment of 10 with silica gel9
effected the desired cyclization to give xanthone 12.
Compd
IC50 (mg/mL)
ASMase
NSMase
11
12
16
17
5.3
5.25
24.0
34.5
10.2
8.9
72.5
>100
Synthesis of 16 and 17
2
16.5
5.15
48.5
46.5
Compound 5 was lithiated and coupled with 136 to give
the corresponding benzyl alcohol 14, which on oxidation
with IBX9 and hydrogenolysis gave benzophenone 15
(Scheme 3). While deprotection under acidic conditions
provided 16, treatment of 15 with the PPh3–CCl4 pro-
tocol,7,10 afforded xanthone 17 in moderate yield.
a-Mangostin 1
Biological Activity
Procedure
A mixture of NBD-sphingomyelin, sphingomyelinase
and a sample was incubated at 37 ꢀC for 30 min. Enzy-
matic activity in the mixture was determined by mea-
suring the fluorescence intensity of ceramide produced.
Compounds 11 and 12, carrying no prenyl group at the
right residue, maintained comparable activity to that of
1, although selectivity between ASMase and NSMase
was diminished by increase of their activities against
NSMase (Table 1). This property was similar to the case
of saturation of the olefinic bonds of the prenyl groups.2
When compared with 1 and 2, the right prenyl group
might be responsible for the selectivity against ASMase
and NSMase. In contrast, benzophenone 16 and xan-
thone 17 without the left-prenyl group, kept the selec-
tivity, while the ASMase activities reduced to ca. 1/10 of
that of 1. These observations indicated each prenyl
group might be required to express the highly selective
inhibitory activity against ASMase.
Scheme 1. (a) BnBr, K2CO3/DMF, 96%; (b) mCPBA/CH2Cl2, then
6 M HCl/MeOH, 95%; (c) Br2/CHCl3, 84%; (d) MeI, K2CO3/DMF,
97%; (e) POCl3/DMF, then MOMCl, NaH/DMF, 54%.
Acknowledgements
This work was supported by Grant-in-Aid for the 21st
Century COE program ‘KEIO Life Conjugate Chem-
istry’ from the Ministry of Education, Culture, Sports,
Science, and Technology, Japan, as well as Keio Gijyuku
Fund for the Advancement of Education and Research.
Scheme 2. (a) s-BuLi/THF, then 7, 49%; (b) IBX/PhMe–DMSO (1:1),
82%; (c) CSA/MeOH, 81%; (d) 10% Pd/C, cyclohexene/EtOH, 97%;
(e) silica gel, 74%.
References and Notes
1. Isolation: Schmid, W. Liebigs Ann. Chem. 1855, 93, 83.
Dragendorff, O. Liebigs Ann. Chem. 1930, 482, 280. Structural
determination: Yates, P.; Stout, G. H. J. Am. Chem. Soc.
1958, 80, 1691. Scheinmann, F. Chem. Commun. 1967, 1015.
Stout, G. H.; Krahn, M. M.; Yates, P.; Bhat, H. B. Chem.
Commun. 1968, 211.
2. Okudaira, C.; Ikeda, Y.; komdo, S.; Furuya, S.; Hirabaya-
shi, Y.; Koyano, T.; Saito, Y.; Umezawa, K. J. Enzym. Inhib.
2000, 15, 129.
3. (a) Chairungsrilerd, N.; Furukawa, K.; Ohta, T.; Nozoe, S.;
Ohizumi, Y. Eur. J. Pharmacol. 1996, 314, 351. (b) Tosa, H.;
Iinuma, M.; Tanaka, T.; Nozaki, H.; Ikeda, S.; Tsutsui, K.;
Scheme 3. (a) s-BuLi/THF, then 13, 41%; (b) IBX/PhMe–DMSO
(1:1), 100%; (c) 10% Pd/C, HCO2NH4/acetone, 88%; (d) TsOH/
MeOH, 94%; (e) Ph3P, CCl4/THF, then silica gel, 61%.

M. Hamada et al. / Bioorg. Med. Chem. Lett. 13 (2003) 3151–3153
3153
Tsutsui, K.; Yamada, M.; Fujimori, S. Chem. Pharm. Bull.
1997, 45, 418. (c) Hasegawa, H.; Sasaki, S.; Aimi, N.;
Takayama, H.; Koyana, T. Jpn. Patent 08231396, 1996. (d)
Shankarayan, D.; Gopalakrishnan, C.; Kameswaran, L. Arch.
Int. Pharmacodyn. Ther. 1979, 239, 257. (e) Williams, P.;
Ongsakul, M.; Proudfoot, J.; Croft, K.; Beilin, L. Free Rad.
Res. 1995, 23, 175.
4. Lee, H.-H. J. Chem. Soc., Perkin Trans. 1 1981, 3205.
5. Jefferson, A.; Quillinan, A. J.; Scheinmann, F.; Sim, K. Y.
Aust. J. Chem. 1970, 23, 2539.
Lett. 1990, 31, 5619. (b) Yamamura, S.; Nishiyama, S. Bull.
Chem. Soc. Jpn. 1997, 70, 2025.
8. Graybill, T. L.; Casillas, E. G.; Pal, K.; Townsend, C. A. J.
Am. Chem. Soc. 1999, 121, 7729.
9. (a) Frigerio, M.; Santagostino, M.; Sputore, S. J. Org.
Chem. 1999, 64, 4537. (b) Nicolaou, K. C.; Zhong, Y.-L.;
Baran, P. S. J. Am. Chem. Soc. 2000, 122, 7596. (c) Wirth, T.
Angew. Chem. Int. Ed. 2001, 40, 2812.
10. The substutution pattern of the aromatic moiety might
affect the difficulty of the diaryl ether production. Treatment
with PPh3–CCl4, followed by silica gel, was required in the
cases of 1 and 17, whereas 12 was produced only by exposure
to silica gel. The detailed reactivity profile is still unclear.
6. Iikubo, K.; Ishikawa, Y.; Ando, N.; Umezawa, K.; Nish-
iyama, S. Tetrahedron Lett. 2002, 43, 291.
7. (a) Arimoto, H.; Nishiyama, S.; Yamamura, S. Tetrahedron