RCAI-61, the 6′-O-methylated analog of KRN7000: its synthesis and potent bioactivity for mouse lymphocytes to produce interferon-γ in vivo

Article abstract of DOI:10.1016/j.tetlet.2008.09.074

RCAI-61, the 6′-O-methylated analog of KRN7000, and six other analogs with modified 6′-position of the galactose moiety of KRN7000 were synthesized to examine their bioactivity for mouse lymphocytes. Methyl α-d-galactopyranoside was the starting material

Full text of DOI:10.1016/j.tetlet.2008.09.074

Tetrahedron Letters 49 (2008) 6827–6830
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
RCAI-61, the 60-O-methylated analog of KRN7000: its synthesis and potent
bioactivity for mouse lymphocytes to produce interferon-c in vivo
Takuya Tashiro a, Ryusuke Nakagawa b, Sayo Inoue b, Masao Shiozaki a, Hiroshi Watarai b,
Masaru Taniguchi a,b, Kenji Mori a,
*
a Glycosphingolipid Synthesis Group, Laboratory for Immune Regulation, Research Center for Allergy and Immunology, RIKEN, Hirosawa 2-1, Wako-shi, Saitama 351-0198, Japan
b Laboratory for Immune Regulation, Research Center for Allergy and Immunology, RIKEN Yokohama Institute, Suehiro-cho 1-7-22, Tsurumi-ku, Yokohama-shi,
Kanagawa 230-0045, Japan
a r t i c l e i n f o
a b s t r a c t
RCAI-61, the 60-O-methylated analog of KRN7000, and six other analogs with modified 60-position of the
Article history:
Received 11 August 2008
Revised 8 September 2008
Accepted 12 September 2008
Available online 17 September 2008
galactose moiety of KRN7000 were synthesized to examine their bioactivity for mouse lymphocytes.
Methyl
RCAI-87 was prepared from methyl b-
potent stimulant of mouse lymphocytes than KRN7000 and RCAI-56 to induce the production of a large
amount of IFN- in vivo.
a
-
D-galactopyranoside was the starting material for RCAI-58, 61, 64, 83, 85, and 86, while
L
-arabinopyranoside. Bioassay showed RCAI-61 to be a much more
c
Keywords:
CD1d
Ó 2008 Elsevier Ltd. All rights reserved.
a-Galactosylceramides
IFN-c
KRN7000
1. Introduction
problem, use of 1 for clinical therapy has been limited. To solve
the problem, many research groups attempt to develop a novel
In 1995, KRN7000 (1,
a-GalCer, Fig. 1) was developed by
researchers at Kirin Brewery Co. as an anticancer drug candidate.1
It was obtained through the modification of the structure of agelas-
phins (main component is agelasphin-9b, 2), which had been iso-
lated in 1993 from the extract of an Okinawan marine sponge,
Agelas mauritianus, as anticancer glycosphingolipids.2,3 They are
HO
HO
OH
O
OH
HO
O
(CH2)12Me
HN
OH
(CH2)23Me
structurally characteristic
immunostimulating agents to induce antitumor activity in vivo in
mice and humans. In 1997, it was shown that -glycosphingolipids
can be a ligand to make a complex with CD1d protein, the major gly-
colipid presentation protein on the surface of the antigen presenting
cells of immune system.4 Natural killer (NK) T cells recognize this
CD1d-glycosphingolipid complex with their invariant (mouse:
a-galactosylceramides, and act as the
O
KRN7000 (α-GalCer, 1)
a
HO
HO
OH
O
OH
HO
O
(CH2)10CHMe2
HN
OH
(CH2)21Me
Va14, human: Va24) T cell receptor (TCR), and then they are acti-
O
vated to release both helper T(Th)1- and Th2-types of cytokines at
OH
the same time in large quantities.5
agelasphin-9b (2)
Th1 cytokines [interferon(IFN)-c, etc.] can induce protective
HO
HO
OMe
O
immune response against pathogen infections or mediate tumor
rejection, whereas Th2 cytokines [interleukin(IL)-4, etc.] mediate
regulatory immune functions to ameliorate autoimmune disease
or transplantation tolerance. These Th1 and Th2 cytokines can
antagonize each other’s biological functions.6 Because of this
OH
HO
O
(CH2)12Me
HN
OH
(CH2)23Me
O
RCAI-61 (3a)
* Corresponding author. Tel.: +81 3 3816 6889; fax: +81 48 467 9381.
E-mail address: kjk-mori@arion.ocn.ne.jp (K. Mori).
Figure 1. Structures of KRN7000 (a-GalCer, 1), agelasphin-9b (2), and RCAI-61 (3a).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.09.074

6828
T. Tashiro et al. / Tetrahedron Letters 49 (2008) 6827–6830
HO
HO
analog of 1, which induces the production of either Th1 or Th2
cytokines.7
Recently, the X-ray crystallographic analyses revealed the struc-
tures of mouse and human CD1d-18,9 and human CD1d-1-V
24TCR
OH
O
HO
OMe
a
Methyl α-D-
galactopyranoside
(4)
complexes.10 According to the X-ray analysis of human CD1d-1-TCR
complex, the galactose head group of 1 on the surface of CD1d is pre-
sented to TCR. The TCR makes a rigid network of hydrogen bondings
withthe 20-, 30-, and 40-hydroxygroups of the galactosepart andwith
the 3-hydroxy group of the sphingosine chain of 1, whereas 60-hy-
droxy group does not make a hydrogen bonding with any residue
of neither CD1d nor TCR. Modification of these hydroxy groups of
the galactose moiety were examined in the past to some extent with
no remarkable result.7 The 20-, 30-, or 40-hydroxy groups of KRN7000
(1) seem to play critical roles in TCR recognition, enabling the forma-
tion of hydrogen bondings which must be important for the expres-
sion of bioactivity. Any modification of these hydroxy groups
weakened or abolished the bioactivities of KRN7000 (1) except for
lit. 16
BnO
OH
BnO
BnO
OR
O
a
O
BnO
BnO
OMe
BnO
OMe
5
6a R = Me
6b R = Et
6c R =
n
-Pr
BnO
BnO
Me
Br
O
b
c
O
BnO
BnO
BnO
BnO
OMe
OMe
3-O-sulfo-a
-GalCer, which shows almost comparable activity.11
7
6d
We, therefore, decided to investigate the structure–activity relation-
ships focused on the 60-hydroxy group of the galactose part. As de-
BnO
BnO
BnO
Me
O
e
d
O
BnO
8
scribed below, we synthesized seven analogs of 1, which have a-D-
BnO
galactose moiety modified at 60-position. Among them, especially
the 60-O-methylated galactose derivative 3a (RCAI-61) was found
to be a potent stimulant of NKT cells to induce a large amount of
BnO
OMe
OMe
6e
IFN-c in mice in vivo. It should be added that D
-galacturonic,12,13
BnO
BnO
F
O
f
60-amino,14 and 60-acetamidogalactose analogs15 show activity
O
O
OMe
+
BnO
BnO
comparable to 1.
OBn
OMe
6f
9
2. Results and discussion
Scheme 1. Synthesis of the analogs of D-galactose modified at 6-position 6a–f.
Reagents and conditions: (a) NaH, MeI or EtBr or n-PrBr, (n-Bu)4NI (when the alkyl
bromide was used), DMF, THF, rt, 12–16 h (78–98%); (b) Ph3P, CBr4, pyridine, 65 °C,
13 h (87%); (c) (n-Bu)3SnH, AIBN, toluene, 95 °C, 17 h (94%); (d) (i) (COCl)2, DMSO,
CH2Cl2, ꢀ78 °C, 40 min; then Et3N (quant.); (ii) Ph3PMeBr, n-BuLi, THF, rt, 30 min
(85%, two steps); (e) H2NNH2ꢁH2O, 30% H2O2 aq, EtOH, rt, 18 h (87%); (f) DAST, Et3N,
CH2Cl2, reflux, 1 h (34%).
2.1. Syntheses of RCAI-58, 61, 64, 83, 85, and 86: the
analogs modified at 6-position (3a–f) and RCAI-87: the
D-galactose
L-arabinose analog (3g) of KRN7000
To investigate the importance of the 60-hydroxy group of 1, we
planned to synthesize five types of the analogs. Syntheses of the
HO
HO
O
HO
OMe
Methyl β-L-arabinopyranoside
(12)
lit. 20,21
OTBS
BnO
BnO
BnO
R'
R
R
a
b
c
HO
(CH2)12Me
OTBS
(CH2)23Me
O
O
O
+
BnO
BnO
BnO
HN
BnO
BnO OH
BnO
F
OMe
O
10a-f
11a-g
R' = CH2OMe
R' = CH2OEt
6a
6b
6c
6d
6e
6f
13
R' = CH2On-Pr
R' = Me
R' = Et
R' = CH2F
HO
R
O
BnO
R'
BnO
R'
OH
HO
O
O
HO
OH
OTBS
BnO
BnO
O
(CH2)12Me
d
e
BnO
BnO
HN
OH
(CH2)23Me
O
(CH2)12Me
O
(CH2)12Me
OTBS
(CH2)23Me
HN
OH
(CH2)23Me
HN
O
3a R' = CH2OMe (RCAI-61)
3b R' = CH2OEt (RCAI-85)
O
O
3c R' = CH2O
3d R' = Me
3e R' = Et
3f R' = CH2F
3g R' = H
n
-Pr (RCAI-86)
(RCAI-58)
(RCAI-64)
(RCAI-83)
(RCAI-87)
15a-g
14a-g
Scheme 2. Synthesis of RCAI-58, 61, 64, 83, 85–87 (3a–g). Reagents and conditions: (a) concd H2SO4, Ac2O, 0 °C, 30 min; NaOMe, MeOH, rt, 40 min (64–94%); (b) DAST,
CH2Cl2, rt, 40 min (84–96%); (c) 13, SnCl2, AgClO4, powdered MS 4 Å, THF, ꢀ18 to 5 °C, 1–2 h; (d) TBAF, THF, rt, 13–18 h (48–73%, two steps); (e) H2, 20% Pd(OH)2–C, EtOH–
CHCl3–THF (8:2:5), rt, 11–24 h (32–85%).

T. Tashiro et al. / Tetrahedron Letters 49 (2008) 6827–6830
6829
galactose derivatives (6a–f) modified at 6-position are summarized
in Scheme 1. The 6-O-alkylated galactose derivatives 6a–c were
synthesized from alcohol 5, which was prepared from methyl
-galactopyranoside (4) in three steps.16 Williamson’s etherifica-
tion of the 6-hydroxy group of 5 gave 6a–c in 78–98% yield. The
6-deoxy- -galactose ( -fucose) derivative (6d) was also synthe-
IFN-γ in sera (2µg/mouse, in vivo)
(ng/mL)
800
a
-
D
600
400
200
0
D
D
sized from alcohol 5. The alcohol 5 was converted to bromide 7
(87%), which was then reduced with tri-n-butyltin hydride to give
D
-fucose derivative 6d in 82% yield.17 The 6-deoxy-6-methyl-
D-gal-
actose derivative 6e was prepared from the known alkene 8,18
which could be derived from 5 via Swern oxidation followed by
Wittig reaction (85%, two steps). The alkene 8 was reduced with
diimide to afford the saturated derivative 6e in 87% yield. Treat-
ment of alcohol 5 with (diethylamino)sulfur trifluoride (DAST) in
the presence of Et3N afforded 6-deoxy-6-fluoro-
D-galactose deriva-
tive 6f (34%) together with a cyclized by-product 9.19 When this
reaction was performed without Et3N, only cyclized
obtained.
9 was
12 h
24 h
Scheme 2 summarizes the completion of the synthesis of the
desired analogs (3a–g) of KRN7000 (1). Acetolysis of 6a–f with
IFN-γ in sera (in vivo)
(ng/mL)
800
acetic anhydride in the presence of
a catalytic amount of
H2SO4 was followed by O-deacetylation with NaOMe in MeOH
to afford hemiacetals 10a–f (64–94%, two steps). These hemiace-
tals 10a–f were treated with DAST to give fluorides 11a–f in 48–
600
400
200
0
73% yield. The
methyl b-
L-arabinose derivative 11g was prepared from
L
-arabinopyranoside 12 according to the reported pro-
cedures.20,21 The obtained fluorides 11a–g were coupled with
the ceramide 1322 under Mukaiyama conditions23 to give pro-
tected
a-galactosylceramides 14a–g. Two tert-butyldimethylsilyl
(TBS) groups of 14a–g were removed with tetra-n-butylammo-
nium fluoride (TBAF) to give alcohols 15a–g (27–56%, two
steps). Finally, hydrogenolysis of all of the benzyl groups of
15a–g gave the desired analogs 3a–g in 32–85% yield as color-
less solids.24
12 h
24 h
12 h
24 h
RCAI-61(3a)
(1)
KRN7000
Figure 2. The concentrations of IFN-
c
in sera in mice (i.v.).26
2.2. Results of bioassay
Figure 2 shows the results of bioassay.25 Concentrations of
cytokines in sera of mice were measured after their intravenous
injection of KRN7000 (1) or synthetic analogs.26 As can be seen,
HO
HO
OH
HO
OH
all of the new analogs induced potent IFN-
in mice. These new analogs induced maximum production of
IFN- at 24 h after injection, while in the case of KRN7000 (1),
c production in vivo
O
(CH2)12Me
c
HN
OH
(CH2)23Me
the maximum was observed at 12 h. These analogs lack their
60-hydroxy group, which makes intramolecular hydrogen bond-
ing with 40-hydroxy groups. The enhanced activity of these ana-
logs might be attributed to the increased stability of the CD1d-
ligand-TCR complex by increasing the electron density at 40-hy-
droxy group. Because of its ready availability and intensity of
bioactivity, we chose RCAI-61 (3a) as the lead compound. As
for RCAI-61 (3a), the dose dependence of its activity was also
investigated. Indeed in comparison with KRN7000 (1), RCAI-61
(3a) brought about highly remarkable increase (ꢂ8.2 times, total
O
RCAI-56 (16)
Figure 3. The structures of RCAI-56 (16).
the comparison of bioactivities in vivo of 3a with 16 will be re-
ported elsewhere in due course.28 RCAI-61 (3a) seems to show
stronger bioactivity than RCAI-56 (16).
amount of the produced IFN-c at 2 lg/mouse in vivo) in the pro-
3. Conclusion
duction of IFN- even at low concentration. In another experi-
c
ment, it has also been found that RCAI-61 (3a) induces the
production of a large amount of IL-12, which is one of the cyto-
In conclusion, we synthesized RCAI-58, 61, 64, 83, 85, and 86:
the analogs with modified 60-position (3a–f) and RCAI-87:
L-arabi-
nose analog (3g) of KRN7000 (1). Among them, the 60-O-methyl-
ated analog of 1, RCAI-61 (3a) is a remarkably potent inducer of
kines causing IFN-
production of a very large amount of IFN-
c
production, in mice in vivo. Accordingly, the
upon injection of
c
RCAI-61 (3a) might be partly due to its ability to induce the pro-
IFN-c in mice in vivo. From the pharmaceutical point of view,
duction of IL-12.
The overall yield of RCAI-61 (3a) was 23% based on methyl
galactopyranoside (4) through 10 steps. In 2007, we reported the
RCAI-61 (3a) may be the most hopeful analog due to its ready
availability and strong bioactivity. So-called ‘structure-based de-
sign of ligands’ considering the X-ray results was successful in
a-D-
synthesis of RCAI-56 (16, Fig. 3) as the potent inducer of IFN-c in
our case to make unusually potent ligands to induce IFN-c produc-
tion. Computational docking models are now being calculated, and
mice and humans.27 It was also synthesized from 4, and its overall
yield was only 6.7% (20 steps). Detailed bioassay results including
the result will be reported shortly.

6830
T. Tashiro et al. / Tetrahedron Letters 49 (2008) 6827–6830
10. Borg, N. A.; Wun, K. S.; Kjer-Nielsen, L.; Wilce, M. C. J.; Pellicci, D. G.; Koh, R.;
HO
Me
Besra, G. S.; Bharadwaj, M.; Godfrey, D. I.; McCluskey, J.; Rossjohn, J. Nature
2007, 448, 44–49.
O
OH
HO
HO
11. Xing, G.-W.; Wu, D.; Poles, M. A.; Horowitz, A.; Tsuji, M.; Ho, D. D.; Wong, C.-H.
Bioorg. Med. Chem. 2005, 13, 2907–2916.
O
(CH2)12Me
(CH2)11Me
HN
12. Kinjo, Y.; Wu, D.; Kim, G.; Xing, G.-W.; Poles, M. A.; Ho, D. D.; Tsuji, M.;
Kawahara, K.; Wong, C.-H.; Kronenberg, M. Nature 2005, 434, 520–525.
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14. Zhou, X.-T.; Forestier, C.; Goff, R. D.; Li, C.; Teyton, L.; Bendelac, A.; Savage, P. B.
Org. Lett. 2002, 4, 1267–1270.
O
AGL-571 (17)
HO
HO
O
OH
HN
15. Liu, Y.; Goff, R. D.; Zhou, D.; Mattner, J.; Sullivan, B. A.; Khurana, A.; Cantu, C.,
III; Ravkov, E. V.; Ibegbu, C. C.; Altman, J. D.; Teyton, L.; Bendelac, A.; Savage, P.
B. J. Immunol. Methods 2006, 312, 34–39.
16. Bernotas, R. C.; Pezzone, M. A.; Ganem, B. Carbohydr. Res. 1987, 167, 305–311.
17. Koto, S.; Kusunoki, A.; Hirooka, M. Bull. Chem. Soc. Jpn. 2000, 73, 967–976.
18. Tatsuta, K.; Niwata, Y.; Umezawa, K.; Toshima, K.; Nakata, M. Carbohydr. Res.
1991, 222, 189–203.
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Kojiro, S.; Nakamura, T.; Kawase, T.; Zen, S. Bull. Chem. Soc. Jpn. 1989, 62, 3549–
3566.
HO
O
(CH2)12Me
(CH2)11Me
O
AGL-577 (18)
Figure 4. The structures of AGL-571 (17) and AGL-577 (18).
Acknowledgments
21. Motoki, K.; Morita, M.; Kobayashi, E.; Uchida, T.; Akimoto, K.; Fukushima, H.;
Koezuka, Y. Biol. Pharm. Bull. 1995, 18, 1487–1491.
We thank Professor H. Watanabe and Dr. K. Ishigami (the
Unversity of Tokyo) for their helpful comments. T.T. is grateful to
Professor T. Nakata (Science University of Tokyo) for his encour-
agement. This work was supported partly by Grant-in-Aid for
Young Scientists (B) (No. 20790108) from the Ministry of Educa-
tion, Culture, Sports, Science, and Technology (MEXT), Japan.
22. Takikawa, H.; Muto, S.; Mori, K. Tetrahedron 1998, 54, 3141–3150.
23. Mukaiyama, T.; Murai, Y.; Shoda, S. Chem. Lett. 1981, 431–432.
24. All of the spectral data support each structures of synthesized analogs: for
example, RCAI-61 (3a): ½a D28
+46.7 (c 0.31, pyridine); mmax (KBr): 3440 (br s,
ꢃ
OH), 3280 (w, NH), 1640 (br s, C@O), 1540 (br m), 1080 (br s, C–O), 720 (w)
cmꢀ1; dH (400 MHz, pyridine-d5): 8.44 (1H, d, J = 8.8 Hz), 7.05 (1H, br s), 6.74
(1H, br s), 6.45 (1H, d, J = 6.4 Hz), 6.39 (1H, br s), 6.08 (1H, br s), 5.52 (1H, d,
J = 4.0 Hz), 5.28–5.22 (1H, m), 4.64 (1H, dd, J = 10, 5.6 Hz), 4.65–4.58 (1H, m),
4.46 (1H, t, J = 6.4 Hz), 4.40–4.28 (4H, m), 4.14–4.08 (1H, m), 3.97 (1H, dd,
J = 9.6, 5.6 Hz), 3.94 (1H, dd, J = 9.6, 6.4 Hz), 3.33 (3H, s), 2.42 (2H, t, J = 7.2 Hz),
2.33–2.20 (1H, m), 1.95–1.60 (5H, m), 1.48–1.16 (68H, m), 0.84 (6H, t,
J = 6.8 Hz) ppm; dC (100 MHz, pyridine-d5): 173.1, 101.5, 76.6, 73.0, 72.5, 71.4,
70.8, 70.7, 70.1, 68.9, 58.9, 51.2, 36.8, 34.3, 32.1, 30.4, 30.1, 30.04, 30.01, 29.93,
29.88, 29.83, 29.76, 29.6, 26.5, 26.4, 22.9, 14.3 ppm; HR-FABMS calcd for
C51H102NO9 [M+H]+ 872.7555; found, 872.7553.
References and notes
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Koezuka, Y.; Kobayashi, E.; Fukushima, H. J. Med. Chem. 1995, 38, 2176–2187.
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25. We reported the standard protocol for detection, isolation, and culture of
mouse and human invariant NKT cells. See: Watarai, H.; Nakagawa, R.; Omori-
Miyake, M.; Dashtsoodol, N.; Taniguchi, M. Nat. Protocols 2008, 3, 70–78.
26. The serum samples were obtained at indicated time points after injection (i.v.)
of KRN7000 (1) or synthesized analogs (3a–g). Glycolipids: The stock solution
5. Wu, D.; Xing, G.-W.; Poles, M. A.; Horowitz, A.; Kinjo, Y.; Sullivan, B.; Bodmer-
Narkevitch, V.; Plettenburg, O.; Kronenberg, M.; Tsuji, M.; Ho, D. D.; Wong, C.-
H. Proc. Natl. Acad. Sci. U.S.A. 2005, 102, 1351–1356.
of 1 [200
lg/mL in 0.5% polysorbate-20 (MP Biomedicals) or 3a–g [1 mg/mL in
dimethyl sulfoxide (DMSO)] was diluted to 10
lg/mL in Dulbecco’s phosphate
6. Rissoan, M.-C.; Soumelis, V.; Kadowaki, N.; Grouard, G.; Briere, F.; Malefyt, R. de
W.; Liu, Y.-J. Science 1999, 283, 1183–1186.
buffered saline (Sigma, Product No. D8537) just before injection into mice.
Mice: 8–12-week-old female C57BL/6J mice (Charles River Laboratories, Inc.)
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Chem. 2008, 16, 1073–1083.
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Wilson, I. A.; Teyton, L. Nat. Immunol. 2005, 6, 810–818.
Concentration of IFN-c was measured by ELISA (Pierce Biotechnology, Inc.).
27. Tashiro, T.; Nakagawa, R.; Hirokawa, T.; Inoue, S.; Watarai, H.; Taniguchi, M.;
Mori, K. Tetrahedron Lett. 2007, 48, 3343–3347.
28. It should be added that Kirin’s research group reported their synthesis of
9. Koch, M.; Stronge, V. S.; Shepherd, D.; Gadola, S. D.; Mathew, B.; Ritter, G.;
Fersht, A. R.; Besra, G. S.; Schmidt, R. R.; Jones, E. Y.; Cerundolo, V. Nat. Immunol.
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similar analogs,
a-D-fucopyranosyl (AGL-571, 17, Fig. 4) and b-L-
arabinopyranosyl (AGL-577, 18) ceramides, which showed strong
lymphocytic proliferation stimulatory effects in vitro in mice.21