Synthesis and conformational studies of 3,4-di-O-acylated furanoid sugar amino acid-containing analogs of the receptor binding inhibitor of vasoactive intestinal peptide

Article abstract of DOI:10.1016/j.tetlet.2007.07.158

Structural analysis of the di-O-caprylated Gaa-containing analog of the receptor binding inhibitors of vasoactive intestinal peptide by various NMR techniques and constrained molecular dynamics (MD) simulation studies established a well-defined β-turn str

Full text of DOI:10.1016/j.tetlet.2007.07.158

Tetrahedron Letters 48 (2007) 6945–6950
Synthesis and conformational studies of 3,4-di-O-acylated
furanoid sugar amino acid-containing analogs of the
receptor binding inhibitor of vasoactive intestinal peptideI
T. K. Chakraborty,* S. Uday Kumar, B. Krishna Mohan, G. Dattatreya Sarma,
M. Udaya Kiran and B. Jagadeesh*
Indian Institute of Chemical Technology, Hyderabad 500 007, India
Received 11 June 2007; revised 17 July 2007; accepted 25 July 2007
Available online 28 July 2007
Abstract—Structural analysis of the di-O-caprylated Gaa-containing analog of the receptor binding inhibitors of vasoactive intes-
tinal peptide by various NMR techniques and constrained molecular dynamics (MD) simulation studies established a well-defined
b-turn structure in DMSO-d6 with an intramolecular hydrogen bond between TyrNH ! MetCO.
Ó 2007 Elsevier Ltd. All rights reserved.
Receptors for vasoactive intestinal peptide (VIP),1
a
However, for the development of peptides as novel ther-
apeutic agents, it is essential to have them delivered effi-
ciently to their specific sites of action.10 To achieve this,
many peptides have been modified covalently by attach-
ing fatty acid moieties to their C- or N-termini.11 As part
of our ongoing project on sugar amino acid based mole-
cular designs,12 we were interested in developing 3,4-di-O-
acylated derivatives of the peptide 2 for improved thera-
peutic applications. It was also essential for us to ensure
that the acylated analogs do not deviate from the bio-
active conformation of the native peptide. In this connec-
tion, we have studied earlier the acylated derivatives of
the Gaa-containing analogs of Leu-enkephalin.13 Here-
in, we describe the synthesis of acylated derivatives 3–5
of the VIP receptor binding inhibitor 2 and the detailed
conformational analysis of the di-O-caprylated analog
4 by various NMR techniques and constrained molecu-
lar dynamics (MD) simulation studies that established
a well-defined b-turn structure in DMSO-d6, similar to
that seen earlier in 2,8 with an intramolecular hydrogen
bond between TyrNH ! MetCO.
widely distributed naturally occurring neuropeptide,
are over-expressed in a variety of malignant tumor cells
that are also associated with the synthesis and secretion
of detectable levels of VIP by the malignant cells them-
selves.2 VIP acts as a growth factor and plays a domi-
nant role in the sustained or indefinite proliferation of
cancer cells. Therefore, VIP receptor binding inhibitors
have the potential to arrest the growth of malignant
cells.3 The peptide sequence Leu1-Met2-Tyr3-Pro4-
Thr5-Tyr6-Leu7-Lys8 1 is known to be one such VIP
receptor binding inhibitor.4 The role of this octapeptide
as a VIP receptor binding inhibitor5 and its anti cancer
activities in combination with other neuropeptide ana-
logs6 have been well established. Several novel analogs
of this peptide containing a,a-dialkylated amino acids
and its lipoconjugates have been synthesized and tested
for their anti cancer activities.7 We have earlier devel-
oped several analogs of octapeptide 1 by replacing some
of its amino acids by dideoxy furanoid sugar amino
acids.8 Many of these analogs, such as the tetrapeptide
2, showed either retention or enhancement of biological
activities.9
Scheme 1 outlines the synthesis of the 3,4-di-O-acylated
peptides 3–5. The acylated sugar amino acids14 were
synthesized following a new route which gave improved
yields of the target molecules compared with our earlier
methods.13,15
Keywords: Di-O-acylated furanoid sugar amino acids; Vasoactive int-
estinal peptide; Conformation; NMR.
q IICT Communication No. 070606.
*
The primary hydroxyl group of the common starting
material 6, synthesized from D-mannitol following the
Corresponding authors. Tel.: +91 40 2719 3154/2716 0048; fax: +91
40 2719 3275/2719 3108 (T.K.C.); e-mail: chakraborty@iict.res.in
0040-4039/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.07.158

6946
T. K. Chakraborty et al. / Tetrahedron Letters 48 (2007) 6945–6950
i) Et3N, TsCl, DMAP
i) HCl, MeOH, 0 oC to rt, 2 h
OBn
OBn
O
CH2Cl2, 0 oC to rt, 5 h
O
O
O
N3
OH
ii) TsCl, Py, DMAP, 0 oC to rt, 3 h
iii) K2CO3, MeOH, rt, 10 h
90%
ii) NaN3, DMF, 80 oC, 4 h
86%
OH
OBn
OBn OH
7
6
BnO
OBn
O
BnO
OBn
i) TPP, MeOH, 2 h then (Boc)2O
i) H2-Pd(OH)2, EtOAc, rt
BocHN
OtBu
N3
OH
ii) CrO3, Py, Ac2O, tBuOH,
CH2Cl2:DMF (4:1), rt, 12 h
65%
O
O
ii) DCC, RCOOH, DMAP,
0 oC to rt, 2 h
8
9
63 - 70%
[R = CH3(CH2)2, CH3(CH2)6, CH3(CH2)12
]
i) TFA, CH2Cl2, 0 oC to rt, 2 h
ROCO
FmocHN
OCOR
OH
ROCO
BocHN
OCOR
OtBu
ii) CH2Cl2, DIPEA, Fmoc-OSu
82 - 85%
O
O
O
O
11
10
i) 20% Piperidine, CH2Cl2,
0 oC to rt, 20 min
ROCO
FmocHN
OCOR
EDCI, HOBt, then
O
H2N-Tyr(tBu)-Leu-OMe,
H
3-5
N
OMe
DIPEA, CH2Cl2, 0 oC to rt, 2 h
N
H
ii) EDCI, HOBt,
O
O
O
Boc-Met-OH, DIPEA,
CH2Cl2, 0 oC to rt, 2 h
72 - 80%
70 - 75%
12
tBuO
Scheme 1. Synthesis of peptides 3–5.
HO
OH
O
O
O
O
O
H
H
H
N
N
N
N
H2N
N
N
N
OH
H
H
H
O
O
H
O
SMe
NH2
1
OH
SCH3
SCH3
OCOR
ROCO
O
O
H
N
H
H
H
N
N
N
BocHN
O
N
CO2Me
H2N
O
N
CO2H
H
H
O
O
O
O
3: R = CH3(CH2)2-
4: R = CH3(CH2)6-
5: R = CH3(CH2)12
2
-
OtBu
OH
reported procedure,16 was converted to an azide in two
steps, tosylation followed by reaction with sodium azide,
to provide 7 in 86% overall yield. Next, deprotection of
the acetonide was accomplished using concd HCl in
MeOH followed by selective tosylation using TsCl in
pyridine and treatment of the resulting tosyl intermedi-
ate with K2CO3 generated the tetrahydrofuran 8 in
90% overall yield. Reduction of the azide group using
Ph3P, in situ protection of the resulting amine using
(Boc)2O and oxidation of the free hydroxyl with
CrO3–Py in the presence of acetic anhydride and t-buta-
nol provided the t-butyl ester of the D-gluconic acid 9 in
65% yield.17 Removal of the Bn-protective groups was
achieved by hydrogenation using Pd(OH)2–C as catalyst
to afford a diol intermediate. The diol was acylated by
reacting with n-alkanoic acid in the presence of 1,3-dic-
yclohexylcarbodiimide (DCC) and a catalytic amount of
4-dimethylaminopyridine (DMAP) to give the diacy-

T. K. Chakraborty et al. / Tetrahedron Letters 48 (2007) 6945–6950
6947
lated product 10 in 63–70% yields. Treatment of 10 with
trifluoroacetic acid (TFA) deprotected both the C- and
N-termini, and the N-terminus was protected using
Fmoc-OSu to furnish Fmoc-Gaa(OCOR)2-OH 11 in
82–85% yields.
Fmoc-Gaa(OCOR)2-OH 11 was used in the synthesis of
VIP receptor inhibitor analogs 3–5 via standard solution
phase peptide synthesis methods18 using 1-ethyl-3-(3-
(dimethylamino)propyl)carbodiimide
hydrochloride
(EDCI) and 1-hydroxybenzotriazole (HOBt) as cou-
pling agents and dry CH2Cl2 as solvent. The tripeptide
Fmoc-Gaa(OCOR)2-Tyr(tBu)-Leu-OMe 12 was pre-
pared by the condensation of Fmoc protected free acid
11 with the dipeptide H-Tyr(tBu)-Leu-OMe following
the above protocol in 70–75% yield. Deprotection of
the N-terminus of tripeptide 12 with 20% piperidine in
dry CH2Cl2 and coupling of the resulting free amine
with Boc-Met-OH gave the required peptides 3–5 in
72–80% yields.19 The final products were purified by sil-
ica gel column chromatography and fully characterized
by spectroscopic methods before using them in the con-
formational studies.
Peptide 4 was completely characterized by 1D and
homonuclear 1H–1H 2D experiments, gDQCOSY,
TOCSY,20 and ROESY.21 The corresponding resonance
assignments of 4 are shown in Table 1. Variable temper-
ature studies were carried out to measure the tempera-
ture coefficients of the amide proton chemical shifts
(Dd/DT), which provided information about their
involvement in intramolecular hydrogen bonding22 and
the relative strength of the hydrogen bonds. The intensi-
ties of the cross-peaks in the ROESY spectrum, shown
in Figure 1, were used to obtain the restraints in the
simulated molecular dynamics (MD) calculations. A
portion of the ROESY spectrum is shown in Figure 2.
3
The JNH–CaH values were large (>8 Hz) for Leu and
Gaa indicating that the values of / for these residues
were in the vicinity of ꢀ137°. The populations of the
side-chain conformations about Ca–Cb (v1) for all the
C H7OCO
3
H
3
4
OCOC H7
3
H
H
O
H
H
N
2
5
6
O
O
H
H
N
H
6'
b
O
O
H
H
O
N
H
c
d
O
O
N
H
H
a
H
H
S
H
O
Figure 1. Schematic representation of the ROE cross peaks in the
peptide 4.

6948
T. K. Chakraborty et al. / Tetrahedron Letters 48 (2007) 6945–6950
amide protons could be estimated from the Ja–b values
shown in Table 1. Ja–b(pro-R) and Ja–b(pro-S) are 9.2 and
4.6 Hz, respectively, for Tyr, whereas these values are
3
8.14 and 4.24 Hz, respectively, for Met. The J values
for both these residues suggest the gꢀ rotamer popula-
tions about v1 to be more than 70%. The predominance
of the gꢀ rotamers about Ca–Cb is further supported by
strong ROESY cross-peaks between NH M CbH(pro-R)
and NH M CbH(pro-S) in these residues. The values of
J2,3 = 4.6, J3,4 = 1.4 and J4,5 = 6.7 Hz in Gaa and the
ROESY cross peak between GaaC2H M C5H support
an envelope (C2-exo or C3-endo) conformer for the sugar
ring.
The NOE between TyrNH M GaaC6H(pro-R) and the
magnitude of the temperature coefficient (Dd/DT) =
ꢀ4.88 ppb/K measured over a range of 25–70 °C, for
Tyr-NH, strongly support the presence of a b-turn-like
ring structure bridged by a 10-membered intramolecular
hydrogen bond between TyrNH ! MetCO, similar to
that observed earlier by us and others.13 The molecular
structure was further supported by the observed ROE
cross-peaks between,TyrNH M GaaC2H, GaaNH M
GaaC5H, GaaNH M GaaC4H and TyrPhe M MetCaH.
A number of interatomic distances derived from intensi-
ties of the ROE cross-peaks were used for obtaining the
restraints in the MD calculations,23 by following a
simulated annealing protocol.24 The long-range distance
restraints (more than three bonds away) were derived
based on a two-spin approximation by taking the dis-
Figure 2. Expansion of some of the important cross peaks in the
ROESY spectrum of 4.
Table 2. The list of distance restraints (more than three bonds away)
used in the MD simulation studies
˚
tance between the Tyr b-protons (1.8 A) as an internal
˚
ROEs
Distance (A)
standard. The long-range distance restraints shown in
1. LeuNH M TyrNH
2. LeuNH M TyrCcH
3. LeuNH M TyrCaH
4. LeuNH M LeuCcH
5. TyrNH M MetCaH
6. TyrNH M GaaCeH
7. TyrNH M GaaCaH
8. GaaNH M MetNH
9. GaaNH M MetCaH
10. GaaC2H M GaaC5H
11. GaaC3H M GaaC5H
2.3–3.0
3.2–3.9
2.0–2.4
2.6–3.2
3.0–3.9
3.0–3.6
2.2–3.0
2.3–2.8
3.0–3.8
2.5–3.2
3.1–3.9
˚
Table 2, and H-bonding restraint (1.3–2.5 A, force
˚
constant 30 kcal/A) were used in the MD calculations.
Twenty structures were sampled during the constrained
MD simulations carried out for a duration of 120 ps
using 20 cycles, each of 6 ps periods, of the simulated
annealing protocol. The sample structures were sub-
sequently energy minimized and the superimposition of
eleven structures from those sampled is shown in Figure
3. The alignment of the hydrogen bonded parts clearly
revealed that the possible conformational arrangement
Figure 3. Stereoview of the eleven backbone-superimposed energy-minimized structures sampled during 20 cycles of the 120 ps constrained MD
simulations following the simulated annealing protocol. For the sake of clarity in viewing, only the backbones are shown here omitting the amino
acid side chains and fatty acid chains.

T. K. Chakraborty et al. / Tetrahedron Letters 48 (2007) 6945–6950
6949
Mathur, A.; Sharma, R.; Gupta, N.; Prasad, S. Tetrahe-
dron 2004, 60, 8329–8339.
9. Prasad, S.; Mathur, A.; Jaggi, M.; Sharma, R.; Gupta, N.;
Reddy, V. R.; Sudhakar, G.; Kumar, S. U.; Kumar, S. K.;
Kunwar, A. C.; Chakraborty, T. K. J. Peptide Res. 2005,
66, 75–84.
of this compound involved an intramolecular hydrogen
bond between TyrNH ! MetCO.
A type II b-turn is generally stabilized by an intramolec-
ular hydrogen bond between the carbonyl group of res-
idue i and the amino group of residue (i + 3) to form a
10-membered b-turn and is believed to be of great
importance for the recognition and activity of peptides
and proteins.25 Our studies show that the acylation of
the ring hydroxyls in the sugar ring did not alter the
overall structure of the sugar amino acid-containing tet-
rapeptide 2 and the side-chain acylated compounds, pre-
pared for improved therapeutic applications, retained
the bioactive conformation of the molecule character-
ized by a b-turn involving an intramolecular hydrogen
bond between TyrNH ! MetCO. Further work is in
progress.
10. (a) Green, I.; Christison, R.; Voyce, C. J.; Bundell, K. R.;
Lindsay, M. A. Trends Pharmacol. Sci. 2003, 24, 213–215;
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Trends Pharmacol. Sci. 2000, 21, 99–103; (e) Schwarze, S.
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M.; Linhardt, J. G.; Adams, P. J. H. M.; van Hest, J. C.
M. Org. Biomol. Chem. 2003, 1, 1827–1829; (b) Foldvari,
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Acknowledgements
The authors wish to thank DST, New Delhi, for finan-
cial support (T.K.C.) and CSIR, New Delhi, for re-
search fellowships (B.K.M., S.U.K., G.D.S. and
M.U.K.).
12. For reviews on sugar amino acids see: (a) Gruner, S. A.
W.; Locardi, E.; Lohof, E.; Kessler, H. Chem. Rev. 2002,
102, 491–514; (b) Chakraborty, T. K.; Ghosh, S.; Jayap-
rakash, S. Curr. Med. Chem. 2002, 9, 421–435; (c)
Chakraborty, T. K.; Jayaprakash, S.; Ghosh, S. Comb.
Chem. High Throughput Screening 2002, 5, 373–387; (d)
Schweizer, F. Angew. Chem., Int. Ed. 2002, 41, 230–253;
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13. Chakraborty, T. K.; Mohan, B. K.; Kumar, S. U.;
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5623–5627.
14. Simple di-O-acetyl furanoid sugar amino acids have been
prepared by Fleet’s group earlier: Smith, M. D.; Long, D.
D.; Marquess, D. G.; Claridge, T. D. W.; Fleet, G. W. J.
Chem. Commun. 1998, 2039–2040.
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19. Selected physical data of 3: 1H NMR (CDCl3, 500 MHz) d
7.70 (d, J = 8.8 Hz, 1H), 7.07 (d, J = 8.2 Hz, 2H), 6.95 (t,
J = 6.6 Hz, 1H), 6.84 (d, J = 8.2 Hz, 2H), 6.42 (d,
J = 7.9 Hz, 1H), 5.47 (d, J = 4.6 Hz, 1H), 5.22 (d,
J = 8.7 Hz, 1H), 4.80 (br s, 1H), 4.64 (q, J = 8.1 Hz,
1H), 4.57 (d, J = 4.6 Hz, 1H), 4.46 (dq, J = 8.3, 5.3 Hz,
1H), 4.21 (q, J = 7.5 Hz, 1H), 4.02 (d, J = 4.6 Hz, 1H),
3.62 (m, 4H), 3.01 (dt, J = 7.5, 13.8 Hz, 2H), 2.49 (t,
J = 7.5 Hz, 2H), 2.25 (dt, J = 2.2, 7.8 Hz, 2H), 2.19 (dt,
J = 3.5, 7.8 Hz, 2H), 2.03 (m, 4H), 1.87 (d, J = 7.5 Hz,
1H), 1.77 (br s, 1H), 1.58–1.51 (m, 6H), 1.38 (s, 9H), 1.25
(s, 9H), 0.89 (t, J = 7.5 Hz, 3H), 0.83 (m, 9H); MS
(ESIMS) m/z (%) 895 (30) [M+1]+, 917 (99) [M+Na]+.
Selected physical data of 4: 1H NMR (DMSO-d6,
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6950
T. K. Chakraborty et al. / Tetrahedron Letters 48 (2007) 6945–6950
500 MHz) listed in Table 1; MS (ESI) m/z (%) 1007 (48)
[M+1]+, 1029 (100) [M+Na]+. Selected physical data of
5: 1H NMR (CDCl3, 200 MHz); d 7.75 (d, J = 8.5 Hz,
1H), 7.61 (d, J = 7.4 Hz, 1H), 7.13 (d, J = 8.2 Hz, 3H),
6.87 (d, J = 8.2 Hz, 2H), 6.49 (d, J = 8.9 Hz, 1H), 5.49 (d,
J = 5.3 Hz, 1H), 5.31 (d, J = 8.1 Hz, 1H), 4.82 (s, 1H),
4.68 (m, 1H), 4.61 (d, J = 5.3 Hz, 1H), 4.48 (m, 1H), 4.22
(m, 1H), 4.03 (m, 1H), 3.68 (s, 3H), 3.51 (m, 2H), 3.07 (d,
J = 7.0 Hz, 1H), 2.52 (m, 1H), 2.34–2.22 (m, 4H), 1.98–
1.89 (m, 2H), 1.58 (m, 12H), 1.31–1.25 (m, 56H), 0.88 (m,
12H); MS (ESIMS) m/z (%) 1175 (30) [M+1]+, 1197 (100)
[M+Na]+.
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