Syntheses and biological activities of KRN7000 analogues having aromatic residues in the acyl and backbone chains with varying stereochemistry

Article abstract of DOI:10.1016/j.bmcl.2009.12.103

KRN7000 is an important ligand identified for CD1d protein of APC, and KRN7000/CD1d complex can stimulate NKT cells to release a broad range of bioactive cytokines. In an effort to understand the structure-activity relationships, we have carried out synth

Full text of DOI:10.1016/j.bmcl.2009.12.103

Bioorganic & Medicinal Chemistry Letters 20 (2010) 814–818
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Syntheses and biological activities of KRN7000 analogues having aromatic
residues in the acyl and backbone chains with varying stereochemistry
Jeong-Ju Park a, Ji Hyung Lee a, Kyung-Chang Seo a, Gabriel Bricard b, Manjunatha M. Venkataswamy b,
Steven A. Porcelli b,c, Sung-Kee Chung a,
*
a Department of Chemistry, Pohang University of Science and Technology, Pohang 790-784, Republic of Korea
b Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, NY 10461, USA
c Department of Medicine, Albert Einstein College of Medicine, Bronx, NY 10461, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
KRN7000 is an important ligand identified for CD1d protein of APC, and KRN7000/CD1d complex can
stimulate NKT cells to release a broad range of bioactive cytokines. In an effort to understand the struc-
ture–activity relationships, we have carried out syntheses of 26 new KRN7000 analogues incorporating
aromatic residues in either or both side chains. Structural variations of the phytosphingosine moiety also
include varying stereochemistry at C3 and C4, and 4-deoxy and 3,4-dideoxy versions. Their biological
activities are described.
Received 19 October 2009
Revised 23 December 2009
Accepted 25 December 2009
Available online 4 January 2010
Dedicated to the fond memory of the late
Professor Chi Sun Hahn of Yonsei University,
Korea
Ó 2009 Elsevier Ltd. All rights reserved.
Keywords:
Glycolipids
KRN7000
a-GalCer
NKT cell
CD1d
In the early 1990s potent antitumor activity was found with
agelasphins, the glycolipids extracted from Okinawan sponge Age-
ral and antibacterial activities, whereas Th2 cytokine are believed
to promote immune tolerance and modulate the onset of autoim-
mune diseases such as type-1 diabetes.4 However, the opposing
las mauritianus by Kirin Pharmaceuticals, and synthetic
a-galacto-
syl ceramide ( -GalCer) named KRN7000 was identified to have
a
activities displayed by Th1 and Th2 cytokines induced by
limits its value as a potential therapeutic agent.
a-GalCer
the best antitumor activity in a series of structurally modified gly-
colipids.1 Subsequent studies have shown that T cell receptors
(TCRs) of NKT cells recognize the KRN7000 molecule presented
by CD1d of antigen presenting cells (APC). The CD1 family of the
antigen presenting glycoproteins mediates T-cell responses
through the presentation of foreign lipids, glycolipids, lipoproteins
and amphiphilic small molecules to TCR in a manner analogous to
the peptide presentation by major histocompatibility complex
(MHC) class 1 and ll molecules. Various CD1 isoforms (CD1a, -b, -c,
-d, and -e) have been identified in humans, and their crystal struc-
tures have been studied.2 Upon recognition of KRN7000/CD1d
complex, NKT cells release a number of cytokines, including pro-
A number of KRN7000 (
their biological properties evaluated in order to shed some light on
the binding interaction between -GalCer and CD1d, and also to
a-GalCer) analogues were prepared and
a
selectively control the cytokine release profile by NKT cells either
toward Th1 or Th2. Modification studies focused on the sugar moi-
ety of
critical for
their TCR.5 The equatorial C2–OH group of the galactose was also
a-GalCer suggested that the
a-anomeric galactose group is
a-GalCer to bind CD1d and to active NKT cells through
found to be crucial for the activity of
a-GalCer; any modification
at this position largely abolished activity.6 Modifications at the
C3- and C6–OH groups of the galactose was found to be tolerated.7
The structure–activity relationship (SAR) studies centered on the
inflammatory T helper 1 (Th1) cytokines such as interferon-
c
IFN-
c
and tumor necrosis factor-
a
, and anti-inflammatory Th2
ceramide moiety of a-GalCer may be grouped into modifications
of the acyl and phytosphingosine chains, and of the polar portion
of the ceramide. It was found that truncations of either the phyto-
cytokines such as interleukin-4, -10, and -13 (IL-4, -10, and -13).3
Th1 cytokines are thought to correlate with the antitumor, antivi-
sphingosine or acyl chain resulted in
cells toward release of Th2 cytokines (IL-4),8 and insertion of dou-
ble bonds into the acyl chain of -GalCer (C20:2) also biased
a-GalCer that biased NKT
* Corresponding author. Tel./fax: +82 54 279 2103.
E-mail address: skchung@postech.ac.kr (S.-K. Chung).
a
0960-894X/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2009.12.103

J.-J. Park et al. / Bioorg. Med. Chem. Lett. 20 (2010) 814–818
815
toward Th2 responses.9 On the other hand, introduction of an aro-
OH
OH
OH OH
O
R
O
R
O
O
matic residue into either the acyl or phytosphingosine chain en-
HO
HO
NH OH
NH OH
hanced the Th1 cytokine profiles.10 The C-glycoside variant of
HO
HO
O
O
(CH2)3Ph
(CH2)3Ph
KRN7000 (a-C-GalCer, in which the glycosidic oxygen was re-
OH
OH
placed by a methylene group) stimulated strong Th1 responses
in vivo from NKT cells.11a–c The carbasugar analogues of
KRN7000, in which the oxygen in the sugar ring was replaced by
methylene, also showed to release Th1-biased cytokines, that is,
1a: R = (CH2)5Ph
1b: R = (CH2)7Ph
1c: R = (CH2)9Ph
1d: R = (CH2)24CH3
2a: R = (CH2)5Ph
2b: R = (CH2)7Ph
2c: R = (CH2)9Ph
2d: R = (CH2)24CH3
IFN-
sine were reported to contribute to the activity of
c
in mice.11d The C3- and C4-OH groups of the phytosphingo-
OH OH
OH OH
O
R
O
R
a-GalCer,
O
O
HO
HO
NH OH
NH OH
although the C3–OH group appeared to be more important than
the C4–OH group.5 The observed results have been rationalized
in relation to the structures of the binding domains of the CD1d
and NKT cell TCR proteins as determined by X-ray crystallography.
HO
HO
O
O
(CH2)3Ph
(CH2)3Ph
OH
OH
3a: R = (CH2)5Ph
3b: R = (CH2)7Ph
3c: R = (CH2)9Ph
3d: R = (CH2)24CH3
4a: R = (CH2)5Ph
4b: R = (CH2)7Ph
4c: R = (CH2)9Ph
4d: R = (CH2)24CH3
Two X-ray studies of the CD1d/
that the lipid chains of -GalCer fit tightly into the CD1d binding
groove (A0 and F0 pockets). In addition, hydrogen-bonding interac-
tions were indicated between CD1d and -GalCer [2-OH group of
a-GalCer complexes have shown
a
a
OH OH
OH OH
O
R
O
R
O
O
the galactose group and Asp151 (mouse Asp153) of the CD1d; 3-
OH group of the phytosphingosine and Asp80 of CD1d]. These
HO
HO
NH OH
NH
HO
HO
O
O
C14H29
C14H29
bonds serve to anchor
tion it in the lipid binding groove.12,13 The recent crystal structure
of human NKT TCR-CD1d- -GalCer complex showed that -GalCer
a-GalCer in a distinct orientation and posi-
OH
OH
5a: R = (CH2)5Ph
5b: R = (CH2)9Ph
5c: R = (CH2)24CH3
6a: R = (CH2)5Ph
6b: R = (CH2)9Ph
6c: R = (CH2)24CH3
a
a
protrudes minimally from the CD1d cleft with only the galactose
group and portions of the proximal polar head of the phytosphin-
gosine exposed for recognition by the NKT TCR.14
In the related efforts we have previously carried out synthesis of
a complete set of the eight KRN7000 stereoisomers, and examined
their biological activities, since a systematic study of phytosphin-
gosine core-modified KRN7000 stereoisomers had not been carried
out before. With both mouse and human iNKT cells, the stereoiso-
OH OH
O
R
OH OH
O
R
O
O
HO
NH
HO
NH
HO
O
HO
O
C14H29
C14H29
OH
7a: R = (CH2)5Ph
7b: R = (CH2)9Ph
7c: R = (CH2)24CH3
8a: R = (CH2)9Ph
8b: R = (CH2)24CH3
mers with 2S (derived from
er potency (IFN- , IL-4/IL-13 production) than the isomers with 2R
(derived from -serine). However, the 2S isomer having the in-
verted C4–OH group stereochemistry ( -lyxo based on phytosphin-
L-serine) generally showed much high-
c
D
Figure 1. Structures of KRN7000 analogues.
D
gosine) displayed comparable potency (proliferation and cytokine
secretion) with those of KRN7000.15 These data suggest that the
spatial orientations of C2–NH2 group and C3–OH group of phyto-
sphingosine are both important for the activity, with the configura-
tion of C2–NH2 group having a greater impact than that of C3–OH
group. In contrast, stereochemical variation of the C4–OH group
seems to have at most a minor effect which is less significant than
what was suggested in some earlier studies.5 Based on our stereo-
chemical studies of the phytosphingosine backbone and the earlier
results obtained by Wong et al. from the analogues having an aro-
matic residue in the acyl or phytosphingosine chain,10 we have
now prepared a series of compounds in which various combina-
tions of the aromatic residue in both chains and the backbone ste-
reochemistry have been made, and examined their biological
properties (Fig. 1).
OH
(CH2)3Ph
HO
NH OH
Boc
11
OH
HO
HO
(CH2)3Ph
(CH2)3Ph
NHBoc
HO
Boc
9
NH OH
O
12
O
H
NBoc
OH
Garner's aldehyde
(CH2)3Ph
HO
Boc
(CH2)3Ph
NH OH
NHBoc
13
10
Our syntheses of new KRN7000 analogues commenced with the
Garner’s aldehyde, which was readily prepared from L-serine. The
OH
(CH2)3Ph
HO
Boc
Wittig reaction with tripheny-(4-phenylbutyl)-phosphonium bro-
mide in the presence of n-BuLi provided predominantly the (Z)-ole-
fin (Z/E = 22/1) in 88% yield. Removal of the oxazoline protecting
group in aq acetic acid gave 9 in 95%. On the other hand, the Wittig
reaction in the presence of KHMDS followed by quenching with ex-
cess methanol at ꢀ78 °C gave the corresponding (E)-olefin (10) in
93%. The Sharpless dihydroxylation16 of 9 and 10 each with the
NH OH
14
Scheme 1. Preparation of truncated phytosphingosine skeletons.
CuSO4 and K2CO3 for diazo transfer reaction (ca. 90% over two
steps), in which the amino group was converted to azido function-
ality.17 The 1°-OH group was protected with trityl chloride and
Et3N, and the 2°-OH with benzyl bromide and NaH, respectively.
Removal of the trityl group followed by glycosylation with perben-
zylated galactosyl iodide with TBAI as promoter exclusively pro-
AD-mix-
four diastereomers corresponding to
-lyxo (13), and -xylo (14) configurations (Scheme 1). The stere-
a
and AD-mix-b conditions provided in good yields all
D
-arabino (11), -ribo (12),
D
D
D
oselectivities observed in the dihydroxylation were found to be
about 10:1 for products 11 and 13, and about 5:1 for 12 and 14;
they were separated to pure diastereomers. Each of compounds
11–14, after removal of the Boc group, was treated with TfN3,
vided the desired
a
-glycoside in better than 90%.18 The azide
group was reduced under the Staudinger conditions,19 and the

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J.-J. Park et al. / Bioorg. Med. Chem. Lett. 20 (2010) 814–818
BnO OBn
O
Reaction of the Garner’s aldehyde with tripheny-pentadecyl-
OBn
1a-d
2a-d
3a-d
4a-d
phosphonium bromide in the presence of KHMDS, followed by
quenching with excess methanol at ꢀ78 °C gave the (E)-olefin
product in a good yield, and the subsequent hydrolysis of the oxaz-
oline ring provided 23. The Sharpless dihydroxylation of 23 with
BnO
BnO
NH2 OBn
(CH2)3Ph
OBn
19-22
(CH2)3Ph
HO
O
N3 OBn
15 (D-arabino)
16 (D-ribo)
17 (D-lyxo)
18 (D-xylo)
Ad-mix-a provided two diastereomeric products in 4:1 ratio. The
major product was separated and the Boc group was removed,
and the amino functionality was converted to the azido group.
Selective manipulations of the 1° and 2° hydroxyl groups as de-
scribed in the previous series yielded compound 24. The terminal
OH group was glycosylated, and the azide was reduced to amino
functionality with trimethylphosphine to give 25. Compound 25
was acylated with three different N-hydroxysuccinimide activated
esters, and all benzyl groups were removed to yield 3 analogues
Scheme 2.
a
-Glycosylation and N-acylation to analogues 1–4.
BnO OBn
OBn
O
C14H29
NHBoc
BnO
BnO
NH2 OBn
C14H29
HO
5a-c
HO
O
C14H29
N3 OBn
OBn
23
24
25
(5a–c) of
pared as follows.
a
-GalCer. (Scheme 3) The remaining analogues were pre-
Scheme 3. Synthesis of analogues 5.
D
-erythro- and
L
-threo-sphingosine21 were sepa-
rately converted to the corresponding azide with N3Tf and CuSO4,
and the 2°-OH group in the products was protected as benzyl ether
(26 and 27). The terminal OH group was glycosylated, and the
azide reduced to the amino group to give 28 and 29. The amino
group was acylated with three different N-hydroxysuccinimide
activated esters, and removal of all benzyl groups together with
saturation of the double bond were accomplished by using H2
and Pd(OH)2/C in MeOH and CH2Cl2 to yield 3 analogues each (6
BnO OBn
O
OBn
BnO
NH2
6a-c
7a-c
HO
C13H27
BnO
O
C13H27
N3
OBn
26 (D-erythro)
27 (L-threo)
28 (D-erythro)
29 (L-threo)
and 7) of a-GalCer (Scheme 4). A second product was obtained in
Scheme 4. Synthesis of analogues 6 and 7.
the last reduction step with H2 over Pd(OH)2 catalyst, and it turned
out to be the hydrogenolysis product of the benzyl ether at the
allylic position, namely compound 8.
resulting amine (19–22) was efficiently acylated with four differ-
ent N-hydroxysuccinimide activated esters.20 In the final step all
benzyl protecting groups were removed with H2 over Pd(OH)2/C
The biological activity of these phenyl-containing
logues for stimulation of human NKT cells was evaluated by induc-
tion of cytokines such as INF- , IL-4 and IL-13 (Figs. 2 and 3). Fig. 2
a-GalCer ana-
c
to yield 16 analogues (1–4) of a-GalCer (Scheme 2).
Figure 2. IL-13 production by human iNKT cell clones as primary screen for activity. Panel A shows IL-13 production by cultures in which a CD4+ NKT cell clone (HDD11) was
cultured with antigen presenting cells (CD1d-transfected HeLa cells) and the indicated glycolipids at a concentration of 400 nM. Panel B shows the same analysis using a
CD4ꢀ NKT cell clone (HDA7). Cultures were done in 96 well microtiter plates, and medium was RPMI-1640 supplemented with 10% fetal bovine serum. 2.5 ꢁ 104 CD1d-
transfected HeLa cells per well in 0.2 ml medium with the indicated glycolipids were cultured for 18 h at 37 °C, followed by removal of the medium, a brief wash with
medium and then replacement with 0.3 ml fresh medium (without glycolipids) containing 2.5 ꢁ 104 cloned human iNKT cells. IL-13 levels were determined by standard
capture ELISA in culture supernatants harvested after 18 h of incubation at 37 °C.

J.-J. Park et al. / Bioorg. Med. Chem. Lett. 20 (2010) 814–818
817
Acknowledgments
This work was supported by the Korea Research Foundation
grant funded from the Korean Government (MOEHRD: KRF-2005-
070-C00078), and by a grant from the NIH/NIAID (RO1 AI45889).
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.bmcl.2009.12.103.
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of compounds 8a and 8b, which have a simple
a-amino alcohol
skeleton, indicating that the C3–OH group of the sphingosine skel-
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