2,5-Anhydro sugar diacid and 2,5-anhydro sugar diamine based C2 symmetric peptidomimetics as potential HIV-1 protease inhibitors

Article abstract of DOI:10.1016/S0040-4039(00)01803-7

Conformationally constrained molecular frameworks of the 2,5-anhydro sugar diacid (9) and 2,5-anhydro sugar diamines (10, 11) were used to construct architecturally beautiful novel C₂ symmetric peptidomimetics 1-8. Although none of these compou

Full text of DOI:10.1016/S0040-4039(00)01803-7

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 10121–10125
2,5-Anhydro sugar diacid and 2,5-anhydro sugar diamine
based C2 symmetric peptidomimetics as potential HIV-1
protease inhibitors
T. K. Chakraborty,a,* Subhash Ghosh,a M. H. V. Ramana Rao,a A. C. Kunwar,a H. Chob
and A. K. Ghoshb
aIndian Institute of Chemical Technology, Hyderabad 500 007, India
bDepartment of Chemistry, University of Illinois at Chicago, 845 West Taylor Street, Chicago, IL 60607, USA
Received 15 August 2000; revised 2 October 2000; accepted 11 October 2000
Abstract
Conformationally constrained molecular frameworks of the 2,5-anhydro sugar diacid (9) and 2,5-anhy-
dro sugar diamines (10, 11) were used to construct architecturally beautiful novel C2 symmetric
peptidomimetics 1–8. Although none of these compounds showed any significant HIV-1 protease
inhibitory activity, further refinements in design may lead to protease inhibitors based on these rigid
carbohydrate-derived scaffolds. © 2000 Elsevier Science Ltd. All rights reserved.
Among the several specific targets in the cell cycle of the human immunodeficiency virus
(HIV), the virally encoded homodimeric HIV-1 protease, which is an aspartyl protease required
for maturation of the infectious virion, has emerged as a promising target leading to the design
and evaluation of a vast array of compounds with diverse structural motifs as possible
inhibitors, some of which have already been approved for the treatment of AIDS.1–6
We describe herein the development of a new class of compounds 1–8 as potential HIV-1
protease inhibitors that are based on carbohydrate–peptide hybrid structures. In this approach,
identical peptide chains are anchored on both sides of a core carbohydrate motif—a C2
symmetric 2,5-anhydro sugar diacid or sugar diamine—leading to the formation of C2 symmet-
ric peptidomimetics.7 Carbohydrate-based molecular designs are increasingly drawing chemists’
attention.8,9 Detailed studies on the development of new HIV-1 protease inhibitors based on
acyclic carbohydrates have recently been reported.10–12 It is also being increasingly felt that small
molecule protease inhibitors need to have restricted degrees of freedom. The success of cyclic
urea based inhibitors supports this feeling.13,14 This has prompted us to look for cyclic
carbohydrate based core foundations as conformationally rigid scaffolds to build a new class of
molecular frameworks as potential protease inhibitors.
* Corresponding author.
0040-4039/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)01803-7

10122
Two different types of cyclic carbohydrate framework—sugar diacid and sugar diamine—are
employed in our designs. These molecules are 2,5-anhydro- -idaric acid (9), 1,6-diamino-2,5-
anhydro-1,6-dideoxy- -iditol (10) and 1,6-diamino-2,5-anhydro-1,6-dideoxy- -mannitol (11).
D
D
D
The sugar diacid 9, to the best of our knowledge, was reported for the first time by us along with
the synthesis of the first sugar diacid based peptidomimetic 1.15 The twofold symmetry of the
1
molecule was evident in its H and 13C NMR spectra which showed peaks for only half of the
molecule. Two-dimensional NMR studies in combination with constrained molecular dynamics
(MD) simulations revealed a very ordered C2 symmetric structure for 1, consisting of identical
intramolecular H bonds at the two ends between the LeuNH“sugar-OH. A very small
temperature coefficient for the LeuNH chemical shift (Dl/DT=−1.2 ppb K−1) was observed in
DMSO-d6. The presence of two ‘cis-b-hydroxycarboxyl’ moieties, the core structural motif
believed to be responsible for such intramolecular H bonds,16 on two sides of the tetra-
hydrofuran ring nucleated identical b-turn-like structures in 1 at both ends.
To further these studies, we decided to prepare a few more C2 symmetric peptidomimetics and
examine their structures and properties, especially HIV-1 protease inhibition activities, as these
compounds structurally resemble many well-established C2 symmetric HIV-1 protease inhibitors.
In this paper we describe the results of that investigation.
Compounds 2 and 4 were prepared in 60 and 70% yields, respectively, from 1 in two steps:
saponification followed by the reaction with p-bromoaniline (for 2) or H2NꢀAlaꢀOMe (for 417)
under standard solution phase peptide synthesis conditions using 1-hydroxybenzotriazole
(HOBt) and 1-ethyl-3-(3-(dimethylamino)propyl)carbodiimide hydrochloride (EDCI) as cou-
pling agents and amine-free dry DMF and/or dry CH2Cl2 as solvents. The synthesis of 3 was
carried out following the same procedure described earlier for the synthesis of 1.15 The

10123
di-O-benzyl derivative of 2,5-anhydro-
D
-idaric acid15 (9) was treated with an excess of amino-
terminal free peptide molecule to furnish 3 in 55% yield.
Structural studies of these molecules (2–4) did not reveal significant turn structures in solution
as seen in 1. While compounds 3 and 4 still maintained C2 symmetric structures as shown by
their NMR studies in DMSO-d6, the p-bromoanilide derivative 2 lost its symmetry with each of
its amide protons showing two peaks in the same solvent. Its LeuNH chemical shifts, however,
exhibited low temperature coefficients of −2.1 and −2.4 ppb K−1 maintaining their participation
in intramolecular H bonding, similar to the one observed in 1, albeit weaker. Hydrogenation of
3 gave a complex mixture of products and its structure and properties were studied in the
Bn-protected form, which showed high temperature coefficients for the amide proton chemical
shifts. The temperature coefficient of the LeuNH peak in 4 was −2.8 ppb K−1, indicating gradual
loss in its ability to nucleate the desired secondary structure, probably due to the increased steric
hindrance.
Next, we turned our attention to the remaining peptidomimetics, 5–8, based on sugar
diamines 10 and 11. Syntheses of 5 and 6 were accomplished according to Scheme 1. The
starting material 12, prepared from 1,3:4,6-di-O-benzylidene-
-mannitol,15 was converted to 14
D
in four steps—ditosylation, azidination and selective azide reduction, followed by protection in
situ using Boc2O for purification purposes giving the di-N-Boc-protected intermediate 14 in 50%
overall yield from 12. Purified 14 was treated with TFA in CH2Cl2 and peptide chains were
attached at both ends using EDCIꢀHOBt as coupling reagents. Finally, debenzylation using
H2ꢀPdꢀC (10%) in MeOH furnished the final product 5 (and 6) in ꢀ70% overall yield.18
Scheme 1. Synthesis of 5 and 6
Syntheses of 7 and 8 from 3,4-di-O-benzyl-1,2:5,6-diisopropylidene- -mannitol (15) are
D
depicted in Scheme 2. Monodeprotection gave a diol intermediate whose primary hydroxyl was
selectively acylated to get a 55% yield of acetate 16. Conversion of 16 to the terminal epoxide
17 was achieved in two steps in 86% yield. Acid-catalyzed cycloetherification of 17 went
smoothly to furnish the 2,5-anhydro- -mannitol framework 18, which was converted to the
D
Scheme 2. Synthesis of 7 and 8

10124
diamine and finally to the desired products 7 and 8,19 following the procedure described above
in Scheme 1.
All the sugar diamine based mimetics, 5–8, had C2 symmetric structures in solution, as
1
determined by their H NMR studies in DMSO-d6, which showed peaks for only half of the
molecule. However, very high temperature coefficients for all of their amide proton chemical
shifts indicated the absence of any intramolecular H bonding in these molecules.
The potential of the peptidomimetics 1–8 as HIV protease inhibitors were evaluated using an
assay protocol developed by Toth and Marshall.20 Unfortunately, none of these compounds
showed any enzyme inhibitory activities up to 2 mM inhibitor concentration. The large distances
between the phenyl rings of the P1/P1% positions are probably responsible for their low activities.
Efforts are now underway to improve our designs and to prepare active HIV-1 protease
inhibitors from conformationally constrained 2,5-anhydro sugar-based scaffolds.
Acknowledgements
Authors wish to thank the CSIR, New Delhi for research fellowships (to S.G. and
M.H.V.R.R.) and a Young Scientist Award Research Grant (to T.K.C.).
References
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10125
1
17. Selected physical data of 4. Rf=0.4 (silica, EtOAc); [h]2D0 −12.8 (c 0.52, CHCl3); H NMR (500 MHz, DMSO-d6):
l 8.09 (d, J=6.8 Hz, 2H, AlaNH), 8.07 (d, J=8.5 Hz, 2H, PheNH), 7.72 (d, J=8.2 Hz, 2H, LeuNH), 7.28–7.19
(m, 10H, aromatic), 5.96 (d, J=2.8 Hz, 2H, OH), 4.56 (d, J=2.8 Hz, 2H, C2- and C5-H), 4.50 (ddd, J=10.4,
8.5, 3.4 Hz, 2H, PheaH), 4.28 (ddd, J=9.8, 8.2, 5.1 Hz, 2H, LeuaH), 4.23 (m, 2H, AlaaH), 4.16 (t, J=2.8 Hz,
2H, C3- and C4-H), 3.60 (s, 6H, OCH3), 3.19 (dd, J=14.1, 3.4 Hz, 2H, PhebH), 2.96 (dd, J=14.1, 10.4 Hz, 2H,
PhebH%), 1.63 (m, 2H, LeugH), 1.44 (ddd, J=13.7, 8.6, 5.1 Hz, 2H, LeubH), 1.38 (ddd, J=13.7, 9.8, 5.6 Hz, 2H
LeubH%), 1.29 (d, J=7.3 Hz, 6H, AlabH), 0.89 (d, J=7.2 Hz, 6H, LeudH), 0.8 (d, J=7.2 Hz, 6H, LeudH%); 13C
NMR (125 MHz, CDCl3): l 172.92, 172.25, 170.51, 169.47, 135.79, 128.94, 128.91, 127.51, 83.26, 77.92, 54.19,
52.43, 51.35, 48.46, 40.39, 36.55, 24.48, 22.89, 21.72, 17.49.
1
18. Selected physical data of 6. Rf=0.3 (silica, EtOAc); [h]2D0 −23.3 (c 0.5, CHCl3); H NMR (500 MHz, DMSO-d6):
l 8.04 (t, J=5.6 Hz, 2H, sugarNH), 7.85 (d, J=8.4 Hz, 2H, PheNH), 7.24–7.14 (m, 10H, aromatic), 6.64 (d,
J=9.0 Hz, 2H, ValNH), 5.05 (d, J=3.6 Hz, 2H, OH), 4.56 (ddd, J=9.2, 8.4, 5.1 Hz, 2H, PheaH), 3.91 (dt,
J=6.8, 2.8 Hz, 2H, C2- and C5-H), 3.82 (dd, J=3.6, 2.8 Hz, 2H, C3- and C4-H), 3.70 (dd, J=9.0, 7.0 Hz, 2H,
ValaH), 3.24 (ddd, J=13.6, 6.8, 5.8 Hz, 2H, C1- and C6-H), 3.12 (ddd, J=13.6, 6.8, 5.6 Hz, 2H, C1- and
C6-H%), 2.94 (dd, J=13.7, 5.1 Hz, 2H, PhebH), 2.79 (dd, J=13.7, 9.2 Hz, 2H, PhebH%), 1.81 (m, 2H, ValbH),
1.37 (s, 18H, Boc), 0.71 (d, J=6.6 Hz, 6H, ValgH), 0.67 (d, J=6.6 Hz, 6H, ValgH%); 13C NMR (125 MHz,
DMSO-d6): l 171.38, 170.87, 155.27, 137.47, 129.11, 127.91, 126.15, 78.53, 78.06, 75.84, 59.99, 53.48, 38.29, 37.92,
30.36, 28.11, 19.02, 18.05.
1
19. Selected physical data of 8. Rf=0.45 (silica, 10% MeOH in CHCl3); [h]2D0 +29.5 (c 0.55, CHCl3); H NMR (500
MHz, DMSO-d6): l 8.07 (dd, J=6.3, 5.2 Hz, 2H, sugarNH), 7.81 (d, J=8.7 Hz, 2H, PheNH), 7.23–7.14 (m,
10H, aromatic), 6.65 (d, J=9.2 Hz, 2H, ValNH), 5.17 (d, J=3.9 Hz, 2H, OH), 4.60 (ddd, J=9.7, 8.7, 4.3 Hz,
2H, PheaH), 3.77–3.70 (m, 4H, C2-, C3-, C4- and C5-H), 3.69 (dd, J=9.2, 6.8, 1H, ValaH), 3.27 (dt, J=13.2,
5.2 Hz, 2H, C1- and C6-H), 3.19 (dt, J=13.2, 6.3 Hz, 2H, C1- and C6-H%), 2.97 (dd, J=13.7, 4.3 Hz, 2H,
PhebH), 2.77 (dd, J=13.7, 9.7 Hz, 2H, PhebH%), 1.79 (m, 2H, ValbH), 1.37 (s, 18H, Boc), 0.69 (d, J=6.8 Hz,
6H, ValgH), 0.64 (d, J=6.8 Hz, 6H, ValgH%); 13C NMR (125 MHz, DMSO-d6): l 171.10, 170.86, 155.27, 137.64,
129.18, 127.87, 126.11, 82.12, 78.81, 78.08, 60.10, 53.41, 41.10, 38.13, 30.41, 28.13, 19.04, 18.08.
20. Toth, M. V.; Marshall, G. R. Int. J. Pep. Prot. Res. 1990, 36, 544–550.
.
.