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Pergamon Bioorganic & Medicinal Chemistry Letters, Vol. 5, No. 7, pp. 699-704, 1995
Copyright © 1995 Elsevier Science Ltd Printed in Great Britain. All rights reserved
0960-894X/95 $9.50+0.00 0960-894X(95)00097-6
SYNTHESES OF ¢x-, I3-MONOGLYCOSYLCERAMIDES AND FOUR DIASTEREOMERS OF AN cx-GALACTOSYLCERAMIDE
Masahiro Morita, Takenori Natori, Kohji Akimoto, Tatsushi Osawa, Hideaki Fukushima,
and Yasuhiko Koezuka*
Pharmaceutical Research Laboratory, Kirin Brewery Co., Ltd.
3 Miyahara-cho, Takasaki-stu', Gunma 370-12, Japan
A b s t r a c t : To examine antitumor activities of monoglycosylceramide, we synthesized ~-, ~- galactosylceramides and ct-, I~-glucosylceramides which have the same ceramide portion, and four kinds of diastereomers of the ceramide portion in an ct-galactosylceramide.
Agelasphines (AGLs) have been isolated from an extract of the marine sponge, Agelas mauritianus, as
active substances in the course of screening of antitumor agents. 1,2 Since sufficient amounts of the four kinds
of AGLs (AGL-7a, AGL-9b , AGL.11, and AGL-13, Fig. 1) having ct-galactosylceramide (ct-GalCer)
structures and AGL-10 which has a 13-glucosylceramide (l~-GluCer) structure were obtained, we examined the
biological activities of five compounds using several assay systems, and found that ct-GalCers showed stronger
antitumor activities against B 16-bearing mice and stirnulatory effects of lymphocyte proliferation on allogeneic
mixed lymphocyte reaction (MLR) than 13-GluCer.
HO - - O H OH OH 0 ~ 0
HO ~ (CH2)x-CH 3 / OH ~ (CH2h-CH 3
HO! ~ QH H ~ O ~ - ' ~ . , s ~ R
OH HO OH
X R X R
AGL-7a 21 -(CH2)I 1-CH3 AGL-10 21 , . , ~ . ~ j (CH2)6-CH 3 AGL-9b 21 -(CH2)I 1-CH(CH3)2 AGL-11 21 -(CH2)n-CH(CH3)-C2H5 CH 3 AGL-13 22 -(CH2)11-CH(CH3)-C2H5
Fig. 1. Structures of AGL-7a , AGL-9b , A G L - I I , AGL-13, and AGL-10.
699
700 M. MORITA et al.
These findings suggested that not only the manner of combination between sugar and ceramide but also
the type of sugar combining to ceramide greatly affects the biological activities of monoglycosylated ceramides
(MonoCers). To confirm this possibility, we synthesized four kinds of MonoCers (AGL-517, 3 AGL-562, 4
AGL-563, 5 and AGL-564, 6) which have the same ceramide and their structures are shown in Fig. 2.
R I • . . . . OH 0 0
R1 OH R 2 H O ~ ~ HN,¢~ (CH2) 12CH3 f ~ . - v ~ (CH2) 12CH3
HOo ~ (CH2)I3CH 3 R2 ~ O ~ ' ~ (CH2) 13CH3 OH HO OH
AGL-517; RI=OH, R2=H AGL-564; RI=OH, R2=H AGL-563; RI=H, R2=OH AGL-562; RI=H, R2=OH
O O H.O ~ . OH II
[ ~ 0 x HN I ' ~ (CH2)24CH3 HN " ~ (CH2)24CH3 - o . -
HO, " - o -7 -
O ¢ ~ " ~ (CH2) 13CH3 H O ~ O ~ (CH2) 13CH3 OH HO OH
KRN7000 AGL-583
Fig. 2 Structures of AGL-517, AGL-564, AGL-563, AGL°562, KRN7000,
and AGL-583.
As shown in Scheme 1, AGL-517 (a-GalCer) and AGL-563 (u-GluCer) were synthesized from a
ceramide (1) 7 under Mukaiyama's ct-glycosidation condition 8 and following hydrogenolysis.
S c h e m e 1
0
R 2 ~ O + .= BnO ~ F H O ¢ , , ~ (CH2) 13CH 3
BnO OH
2; RI=OBn, R2=H 1 3; RI=H, R2=OBn
RI .....- OBn
B n O ~ - ~ HN f ~. (CHz) 12CH3 BnO ! .---
O @ ~ ~'~ (Ctt2) 13CH 3 OH
4; RI=OBn, R2=H 5; RI=H, R2=OBn
RIj.- OH
H O ~ HN_ ~ (CH2)I2CH3 HO ! -
O , ~ (CH2) 13CH3 OH
AGL-517; RI=OH, R2=H AGL-563; R1--H, R2--OH
(a) SnC12, AgC104, MS4A / THF; (b) H 2, Pd-BaSO 4 / THF
0c-, [~-Monoglycosylceramides 701
Scheme 2
l • l ~ OAc 0
AcO x - - " ~ " " ~ "" OAc HO " (CH2) 13CH3 AcO
OH
a
O R I ~ R 3 ] \ ,-, HN- "(CH2)12CH3
R3 OH
6; R1--OAc, R2=H 1 7; RI=H, R2--OAc
["-" 8 ; RI=R3=OAc, R2=H h AGL-564; RI=R3=OH, R2=H
b ~ 9 ; RI=H, R2=R3--OAc AGL-562; R I=H, R2=R3--OH
(a) TMSOTf, MS4A / CH2C12 ; (b) NaOMe / MeOH-THF
AGL-564 (13-GalCer) and AGL-562 (13-GluCer) were synthesized as follows: the same ceramide (1)
was treated with penta-O-acetyl sugars (6, 7) in the presence of trimethylsilyltrifrate (TMSOTf) and
molecularsives 4A 9 to afford the desired 13-glycosides (8, 9). Deacetylation of 8 and 9 by treatment with
sodium methoxide to give AGL-564 and AGL-562 (Scheme 2).
Futhermore we synthesized KRN700010 (a-GalCer) and AGL-58311 (13-GalCer) which have the
different ceramide portion 7 from AGL-517 using the same glycosidation methods as described for AGL-517
and AGL-564, and their structures are shown in Fig. 2.
Scheme 3
NH2
H O ~ , ~ , , ~ (CH2)I 1CH3 OH
lOa; (2S, 3S) lOb; (2R, 3R) Ilk:; (2S, 3R) lOd; (2R, 3S)
HN L (CH2)12CH 3 --- H O ~ (
a CH2)11CH3 b OH
l la; (2S, 3S) l ib; (2R, 3R) lle; (2S, 3R) lld; (2R, 3S)
BnO ~ OBn o
BnO , ~ HN (CH2)12CH 3
O ~ J ~ "~ (CH2)I 1CH3 OH
12a; (2S, 3S) 12b; (2R, 3R) 12c; (2S, 3R) 12d; (2R, 3S)
HO ~ OH o
~, HO HN,~,,,~ (CH2) 12CH3
O ~ (CH2) 11CH3 OH
AGL-555; (2S, 3S ) AGL-556; (2R, 3R) AGL-558; (2S, 3R ) AGL-559; (2R, 3S)
(a) p-nitrophenyl tetradecanoate, DMAP / THF; (b) 2, SnC12, AgC104, MS4A / THF; (c) H 2, Pd-BaSO4 / THF
702 M. MORITA et al.
H~ ~ OH
e o . ~ HN.J~ ca cx ~ 0
~ (CH2)I 1CH3 OH
AGL-555; (2S, 3S)
HO ~ OH
o 0 -
~ " ' ~ (CH2)I 1CH3 OH
AGL-558; (2S, 3R)
- -~O [ 1 1 (C 2)12CH3
O , , , ~ " - (CH2hICH3 OH
AGL-556; (2R, 3R) HO OH
~0 I H~I" "(CH2)12CH3
O ~ , , , , " ~ (CH2)I 1CH3 OH
AGL-559; (2R, 3S)
Fig. 3. Structures of AGL-555, AGL-556, AGL558, and AGL-559.
In addition, we previously reported 7 that, the structure of the ceramide portion in a-GalCer greatly affects
their biological activities, i.e., (1) the longer fatty acid in ceramide moiety shows more marked antitumor
activity in the range of C14 - C26, (2) the optimal length of long chain base in ceramide is C18 in the range of
Cll - C20, and (3) 3-hydroxyl group plays an important role in biological activities. However, the biological
activities of the diastereomers of the ceramide portion have not been reported yet. To examine their biological
activities, we synthesized four kinds of diastereomers having ct-GalCer structures starting from
dihydrosphingosines (10a-d) 12 by previously reported method 2, 7 (Scheme 3). Fig. 3 shows the structures of
four diasteromers which are AGL-555 (2S, 3S) 13, AGL-556 (2R, 3R) 14, AGL-558 (2S, 3R) 15, and
AGL-559 (2R, 3S) 16.
Acknowledgement: We thank Dr. Hiroyuki Matsuda, Central Research Laboratory, Takasago International
Corporation, for generous gift of four kinds of dihydrosphingosines.
0~-, ~-Monoglycosylceramides 703
References and Notes
1. Natori, T.; Koezuka, Y.; I-Iiga, T. Tetrahedron Lett. 1993, 34, 5591-5592.
2. Natori, T.; Morita, M.; Akimoto, K.; Ko~zuka, Y. Tetrahedron, 1994, 50, 2771-2784.
3. AGL-517 physical data: [aiD24 = +57.8 ° (c 1.0, pyridine); m.p. 159.0-161.0 °C; FDMS m/z 674 M+; 1H NMR (500 MI-Iz, CsDsN) 8 (ppm) 8.52 (IH, d, J = 8.6 Hz), 5.45 (1H, d, J = 3.7 I-Iz), 4.69-4.76 (1H, m), 4.63-4.68 (lI-I, m), 4.40-4.58 (6I-I, m), 4.36 (1H, dd, J = 5.5, 10.0 Hz), 4.25-4.31 (1H, m), 2.48 (2H, t, J = 7.0 Hz), 1.80-1.95 (4H, m), 1.52-1.62 (1H, m), 1.18-1.43 (45H, m), 0.88 (6H, t, J = 6.7 Hz): Anal. C38H75NO 8 (C, H, N). calcd. 67.72, 11.22, 2.08, found. 67.41, 11.28, 2.03.
4. AGL-562 physical data: [a]D 23 = -3.1 ° (c 0.85, pyridinc); m.p. 159.0-162.5 °C; FDMS m/z 675 (M+I)+; 1H NMR (500 MHz, C5D5N) 8 (ppm) 8.40 (1H, d, J = 8.5 I-Iz), 4.97 (1H, d, J = 7.9 Hz), 4.78 (1H, dd, J --4.9, 10.4 Hz), 4.68-4.75 (1H, m), 4.55 (1H, d, J = 11.6 Hz), 4.36 (1H, dd, J = 5.5, 11.6 Hz), 4.18-4.30 (4H, m), 4.06 (1H, t, J =7.9 Hz), 3.94-3.98 (1H, m), 2.47 (2H, t, J = 7.3 Hz), 1.78- 1.99 (4H, m), 1.52-1.61 (lI-I, m), 1.06-1.44 (45H, m), 0.88 (6H, t, J = 7.0 Hz): Anal. C38H75NO8 (C, H, N). calcd. 67.72, 11.22, 2.08, found. 67.88, 11.39, 1.92.
5. AGL-563 physical data: let]D23 = +57.4 ° (c 0.46, pyridinc); m.p. 162.0-163.0 °C; FDMS m/z 675 (M+I)+; 1H NMR (500 MI-Iz, CsDsN) 6 (ppm) 8.43 (1H, d, J = 8.6 Hz), 5.40 (1H, d, J = 3.1 Hz), 4.65-4.72 (lI-I, m), 4.22-4.60 (TH, m), 4.10-4.21 (2H, m), 2.43 (2H, t, J = 7.3 Hz), 1.76-1.93 (4H, m), 1.48-1.56 (1H, m), 1.10-1.42 (45H, m), 0.88 (6H, t, J = 6.7 Hz): Anal. C38H75NO8 (C, H, N). calcd. 67.72, 11.22, 2.08, found. 67.84, 11.27, 1.96.
6. AGL-564 physical data: [Ct]D24 = +7.3 ° (c 0.93, pyridine); m.p. 175.0-177.0 °C; FDMS m/z 675 (M+I)+; 1H NMR (500 MHz, CsD5N) 8 (ppm) 8.31 (1H, d, J = 9.2 Hz), 4.88 (1H, d, J = 7.3 Hz), 4.80 (1H, dd, J = 4.9, 10.4 I-Iz), 4.64-4.70 (1H, m), 4.55 (1H, d, J = 3.1 Hz), 4.49 (1H, dd, J = 7.9, 9.2 Hz), 4.40-4.45(2H, m), 4.10-4.25 (3H, m), 4.06 (1H, t, J = 5.8 Hz), 2.44 (2H, t, J = 7.3 Hz), 1.76- 1.92 (4H, m), 1.48-1.57 (lI-I, m), 1.10-1.42 (45H, m), 0.88 (6H, t, J = 6.7 Hz): Anal. C38H75NO8 (C, H, N). calcd. 67.72, 11.22, 2.08, found. 67.94, 11.37, 1.90.
7. Morita, M.; Motoki, K.; Akimoto, K.; Natori, T.; Sakai, T.; Sawa, E.; Yamaji, K.; Kobayashi, E.; Fukushima, H.; Koezuka, Y. Manuscript submitted for publication.
8. Mukaiyama, T.; Mural, Y.; Shoda, S. Chem. Lett., 1981, 431-432.
9. Ogawa, T.; Beppu, K.; Nakabayashi, S. Carbohydr. Res. 1981, 93, C6-C9.
10. KRN7000 physical data: [CC]D 23 = +43.6 ° (c 1.0, pyridine); m.p. 189.5-190.5 °C; negative FABMS m/z 857 (M-H)- ; 1H NMR (500 MHz, C5D5N) 8(ppm) 8.47 (1H, d, J = 8.5 Hz), 5.58 (1H, d, J = 3.7 Hz), 5.27 (1H, m), 4.63-4.70 (2H, m), 4.56 (1H, m), 4.52 (1H, t, J = 6.1 Hz), 4.37-4.47 (4H, m), 4.33 (2H, m), 2.45 (2H, t, J =7.3 Hz), 2.25-2.34 (1H, m), 1.87-1.97 (2H, m), 1.78-1.85 (2H, m), 1.62-1.72 (1H, m), 1.26-1.45 (66H, m), 0.88 (6H, t, J = 6.7 I-Iz); Anal. C50H99NO9 (C, H, N). calcd. 69.97, 11.63, 1.63, found. 69.77, 11.65, 1.53.
11. AGL-583 physical data: [C~]D24 -- -3.5 ° (c 0.81, pyridinc); m.p. 152.0-154.0 °C; negative FABMS m/z 857 (M-H)- ; 1H NMR (500 MHz, C5D5N) 8(ppm) 8.44 (1H, d, J = 8.5 Hz), 5.11-5.17 (1H, m), 4.91 (1H, d, J = 7.3Hz), 4.81 (1H, dd, J = 5.5, 10.4 Hz), 4.54 (1H, d, J = 3.1 Hz), 4.35-4.50 (6H, m), 4.17-4.24 (1H, m), 4.14 (1H, dd, J = 3.7, 9.8 Hz), 4.04 (1H, t, J = 6.1 Hz), 2.42 (2H, t, J =7.3 Hz), 2.17-2.21 (1H, m), 1.63-1.92 (6H, m), 1.05-1.50 (64H, m) 0.86-0.89 [6H, (0.881, t, J = 6.7 Hz), (0.876, t, J = 6.7Hz)]; Anal. C50H99NO9 (C, H, N). calcd. 69.97, 11.63, 1.63, found. 70.12, 11.70, 1.51.
12. Matsuda, H.; Yamamoto, T.; Sato, T. Japanease Patent Laid-Open Publication No. 80617/1994.
704 M. MOR1TA et al.
13.
14.
15.
16.
AGL-555 physical data: [Ct]D23 +52.5 ° (c 0.75, pyridine); m.p. 148.5-152.5 °C; FDMS m/z 646 M+; IH NMR (500MHz, CsD5N) 8 (ppm) 8.10 (IH, d, J = 8.5 Hz), 5.46 (1H, d, J = 3.7 Hz), 4.75-4.82 (1H, m), 4.66 (1H, dd, J = 3.7, 9.8 Hz), 4.34-4.56 (7H, m), 4.12 (1H, t, J = 6.1 Hz), 4.07 (1H, dd, J = 6.1, 9.8 Hz), 2.49 (2H, t, J = 6.5 Hz), 1.63-1.92 (4H, m), 1.50-1.60 (1H, m), 1.20-1.42 (41H, m), 0.88 (6H, t, J = 6.7 Hz): Anal. C36HT1NO8 (C, H, N). calcd. 66.94, 11.08, 2.17, found. 67.01, 11.28, 1.93.
AGL-556 physical data: [Or]D24 +80.7 ° (c 0.27, pyridine); m.p. 149.0-150.5 °C; FDMS m/z 646 M+; 1H NMR (500MHz, CsDsN) 8 (ppm) 8.04 (1H, d, J = 8.6 Hz), 5.49 (1H, d, J = 3.7 Hz), 4.77-4.82 (1H, m), 4.68 (1H, dd, J = 3.7, 9.8 Hz), 4.65 (IH, bd, J = 2.4 Hz), 4.36-4.58 (6H, m), 4.16 (1H, dd, J = 6.7, 10.4 Hz), 2.50 (2H, t, J = 7.3 Hz), 1.64-1.92 (4H, m), 1.47-1.57 (1H, m), 1.20-1.42 (41H, m), 0.88 (6H, t, J -- 7.0 Hz): Anal. C36H71NO8 (C, H, N). calcd. 66.94, 11.08, 2.17, found. 67.12, 11.34, 2.09.
AGL-558 physical data: [a]D24 +74.3 ° (c 0.35, pyridine); m.p. 153.5-156.0 °C; FDMS m/z 646 M+; 1H NMR (500MHz, C5D5N ) 8 (ppm) 8.52 (1H, d, J = 8.6 Hz), 5.47 (1H, d, J -- 3.7 Hz), 4.71-4.78 (1H, m), 4.67 (IH, dd, J = 3.7, 9.8 Hz), 4.34-4.60 (7H, m), 4.26-4.32 (1H, m), 2.48 (2H, dt, J = 1.2, 7.3 Hz), 1.80-1.95 (4H, m), 1.52-1.62 (1H, m), 1.20-1.42 (41H, m), 0.87 (6H, t, J = 6.8 Hz): Anal. C36HT1NO8 (C, H, N). calcd. 66.94, 11.08, 2.17, found. 66.99, 11.24, 2.01.
AGL-559 physical data: [~t]D24 +62.0 ° (c 0.50, pyridine); m.p. 145.0-147.0 °C; FDMS m/z 646 M+; 1H NMR (500MHz, CsDsN) 8 (ppm) 8.40 (1H, d, J = 8.5 Hz), 5.47 (1H, d, J = 3.7 Hz), 4.66-4.76 (3H, m), 4.10-4.62 (7H, m), 2.48 (2H, dt, J = 1.8, 7.3 Hz), 1.73-2.00 (4H, m), 1.52-1.62 (1H, m), 1.20- 1.42 (41H, m), 0.88 (6H, t, J = 6.7 Hz): Anal. C36H71NO8 (C, H, N). calcd. 66.94, 11.08, 2.17, found. 67.01, 11.30, 2.13.
(Received in Japan 19 January 1995; accepted 16 February 1995)
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