Abstract
This thesis entitled “Design and synthesis of non natural peptides with helices,
turns and super secondary structures” is divided into three chapters. First chapter
mainly described the generalization of the three residue turns (-- and --) by using
different -amino acids such as L-Val, Aib, L-Pro, D-Pro, Gly and β-amino acids (S)-Clinked carbo-β-amino acid, -D-hAla and -hGly. Further, the HT motifs were efficiently
converted into peptides with novel helix-turn-helix (HTH) tertiary structures. Second
chapter dealt with the synthesis of new type of /-hybrid peptides. Based on the earlier
findings the peptides were designed to study a series of new turns and /-peptides using
Glycine (Gly) as -amino acid to understand the formation and stability of helix and
helix-turn conformation, in the absence of alternating chirality. Third chapter explored
the new concept of ‘hybrid helices’, using several helices obtained by us in different
peptide foldamer families as building blocks. Hybrid helices were realized by a
combination of two or more different types of homologous and hybrid peptides.
Chapter I: Synthesis of α/β-peptides with three residue turns and
tertiary structures: study on the impact of α- and β-amino acids on the
turns
An overview on peptides
A brief review is presented on -, -, -peptides and peptides with heterogeneous
backbones. The discussion represents the details of conformational analysis and protein
structure. -Peptides and most of the foldamers1 reported so far have homogeneous
backbones. Peptides with heterogeneous backbones were also recently found to display
well-defined folding behavior, resulting in helical and skeletal diversity.
β-Amino acids are part structures of several natural products and their importance
and nonavailability from ‘chiral pool’ prompted the development of new and efficient
strategies2 for their synthesis, enroute` to peptidomimetics. Seebach et al.3 and Gellman
et al.4 were the first to report β-peptides with novel helical structures, followed by
subsequent reports5 on a variety of novel secondary structures in β-peptides with different
designs.6
The research studies revealed that the attachment of carbohydrate7 to peptides
improves bioavailability and water solubility, while increasing the resistance to proteases.
Based on the structures of nikkomycins8, our group has reported the synthesis of C-linked
1
Abstract
carbo-β-amino acids9 (β-Caa), with carbohydrate moieties as side chains. Making use of
these monomers, earlier our group has reported β-peptides with novel helical patterns.10a,b
The β-Caa residues were made from the known11 D-glucose derived aldehyde 1.
Accordingly, the Michael acceptor 2, prepared (Scheme 1) from the corresponding
aldehyde,11 on reaction with benzyl amine12 at room temperature gave epimeric (at the
amine stereocentre) esters 3 (46%) and 4 (22%).
Scheme 1
O
OHC
H3CO
O
PPh3=CHCOOCH3
O
O
Benzene, reflux
5 h, 69%
O
H3CO
1
O
2
NHR
O
+
O
H3CO
O
H3CO
O
H3CO
O
O
H3CO
3 R = Bn
5 R=H
7 R = Boc
4 R = Bn
6 R=H
8 R = Boc
O
NHBoc
MeOH
O
HO
H3CO
NHBoc
O
O
4N NaOH
2 h, 85%
2. 10% Pd-C, MeOH, 12 h
(Boc)2O, Et3N, THF, 2 h
O
O
NHR
O
MeOH
1. BnNH 2, 12 h
O
H3CO
4N NaOH
2 h, 86%
O
9
O
HO
H3CO
11
O
8
7
O
TFA
CH 2Cl 2
TFA
NH 2.CF3COOH
O
CH 2Cl 2
O
H3CO
H3CO
O
O
NH 2.CF3COOH
O
O
H3CO
H3CO
10
O
12
Esters 3 and 4 on hydrogenolysis (10% Pd-C) in methanol under hydrogen
atmosphere gave amines 5 and 6 respectively, which on reaction with (Boc)2O and Et3N
in THF gave 7 (72%) and 8 (72%) respectively. Further, hydrolysis of 7 and 8 with 4N
NaOH in methanol afforded respective acids 9 (85%) and 11 (86%), while, treatment
with trifluroacetic acid (TFA) in CH2Cl2 furnished the respective TFA salts 10 and 12.
Based on the earlier findings on /-peptides10c,d from (S)-β-Caa and L-Ala
resulting in right-handed 9/11-mixed helices and new three residue ‘turn motifs’, a
further study was undertaken on the generalization of three residue turns by using
different - and -amino acids. In this study -amino acids such as L-Val, Aib, Gly, L-
2
Abstract
Pro and D-Pro where used, while (S)-β-Caa, -D-hAla and -hGly used as -amino acid
residues (Figure 1). The peptides were prepared using standard peptide coupling13
conditions in the presence of water soluble EDCI and HOBt with DIPEA as a base in dry
CH2Cl2.
(S)--Caa-L-Ala-(S)--Caa
-D-hAla  L-Val-D-hAla
-hGlyAib -hGly
Gly
L-Pro 
D-Pro
O
H3CO
NHBoc
C C
O
C4 C1 O
O
BocHN
OH
C3
H3CO
Boc-Aib-OH 14
Boc-L-Val-OH 13
O
O
O
OH
Boc-L-Ala-OH 15
TFA.H2N
OCH3
HCl. NH2--D-hAla-OMe 16
H
O
BocHN
OH
C2 O
(S)--Caa 7
BocHN
O
BocHN
ClH.H 2N
HCl. NH2--hGly-OMe 17
H
OH
OH
OH
N
N
Boc-Gly-OH 18
OCH3
O
Boc
Boc-L-Pro-OH 19
Boc
O
Boc-D-Pro-OH 20
Figure 1: (S)-β-Caa [(S)-C-linked carbo-β-amino acid], Boc-L-Val, Boc-Aib, Boc-L-Ala,
TFA.NH2-β-D-hAla-OMe (β-Alanine methyl ester trifluoroacetic acid salt), HCl.NH2-hGly-OMe (-Alanine methyl ester hydrochloride salt), Boc-Gly, Boc-L-Pro, Boc-D-Pro.
In the initial studies, the attention was focussed to understand the generality of residue in turn (--) region, wherein L-Val and Aib were independently used as residues at the C-terminus of ‘-Caa-L-Ala--Caa’ (--). Accordingly, pentapeptides
21 and 22 were prepared under standard peptide coupling conditions (EDCI, HOBt and
DIPEA) in CH2Cl2. NMR, MD and CD studies clearly indicated that /-hybrid peptides
21 and 22 fold into helix-turn super secondary structural motifs, with an 11/9-mixed
helical pattern at N-terminus and 7/13-turn at C-terminus (Figure 2). This inferred that the
bulky side chain and increased steric strain in the -residue as well as removal of the
chirality in the -residue has no effect on the ‘turn’ formation.
3
Abstract
2
R1 R
H
11
O
Sugar
N
N
7
O H
13 O
N H
Sugar
H
O
O
OMe
7
N
MeO
H N
O
H N 3
O
O
O
O
13
Sugar
H
6
N H
O
Sugar
H
4
9
O
O
O
O
CH3
5
N
(CH3)2
OMe
O
Sugar =
O
H3CO
21 pentapeptide
(R1 = iso propyl, R2 = H)
22 pentapeptide
(R1, R2 = methyl)
Figure 2: Characteristic nOes and H-bonds defining the turn in 21 (Dotted lines indicate
the nOes, dark lines indicate the H-bonds and italic represents residue number)
In a further study, hexapeptides 23 and 24 [-Caa in the turn (--) region is
replaced with -D-hAla and -hGly at the C-terminus] were prepared in the presence of
EDCI, HOBt and DIPEA in CH2Cl2. NMR and MD studies demonstrated the peptides 23
and 24 with -D-hAla and -hGly at the C-terminus in resulting the helix-turn motif
(Figure 3). The study amply indicates that a bulky carbohydrate side chain or less bulky
methyl group or no side chain, the last three -- residues form a stable ‘turn’.
11
O
O
N
H
9
7
H
H
N
N
O
O
O
O
R
O
H
N
N
H
H
N
R
O
OCH3
11
H3CO
O
O
13
O
23 hexapeptide
(R = methyl)
24 hexapeptide
(R = H)
4
Abstract
(A)
(B)
Figure 3: (A) Circular dichroism spectrum of 24 in CH3OH (C = 0.2 Mm) (B)
Stereoview (bundle of the twenty five conformers lowest in energy determined by
restrained molecular dynamics. Sugars are replaced with methyl groups and protons have
been removed for clarity)
Having successfully generalized - and β-residues in the turn region of --,
subsequently the study was then extended to replacement of -residue (L-Ala) with
constrained -amino acid such as L-Pro and D-Pro.
Accordingly, hexapeptides 25 and 27 (R = carbohydrate side chain) were prepared
in the presence of EDCI, HOBt and DIPEA in CH2Cl2. NMR and MD studies on 25 and
27 (Figure 4) did not show the formation of any turn. Assuming the bulky carbohydrate
side chain is responsible for the above results, peptides 26 and 28 (R = H) were prepared
using -hGly as -residue to relieve the steric strain and provide conformational freedom
in the turn region. However 26 and 28 were also found to be with no turn in the Cterminus region. This study further proves that the constrained -residues are not
compatable for the formation of turns.
O
O
N
H
H
N
O
H
N
O
O
R
O
H
N
N
N
H
H
H3CO
O
O
OCH3
R
O
O
O
25 R = Su
26 R = H
O
Su =
H3CO
O
O
N
H
H
N
O
H
N
O
H3CO
O
O
O
O
R
N
H
O
H
N
N
H
O
27 R = Su
28 R = H
Figure 4: Structures of peptides 25, 26, 27 and 28.
5
OCH3
R
O
O
O
Abstract
To understand the above results, peptide 29 (L-Ala--Caa-L-Ala--hGly-Gly-hGly) with an ‘achiral turn region’ (-hGly-Gly--hGly) was synthesized. The studies on
29, however revealed the presence of a three residue turn in 29.
This study resulted in novel three residue turns such as ‘-Caa-L-Val/Aib--Caa’.
A literature survey revealed that the three-residue turns are the second most frequently
observed class of hairpin forming loops after two-residue loops. Unlike the D-Pro-L-ProD-Ala turn14 (Figure 5B), the new ‘-Caa-L-Val/Aib--Caa’ turn (Figure 5C), is devoid
of any constrained amino acids and differs in the directionality of the 13-membered Hbond. Further, both these turns differ from the -turns15 (Figure 5A) observed in proteins.
(A)
(B)
(C)
(D)
Figure 5: Ball and stick models of turns (A) -helix; (B) D-Pro-L-Pro-D-Ala; (C) -CaaL-Val/Aib--Caa (D) L-Val/Aib--Caa--Caa
The study was then extended to understand the generality of the HTH motif.
Accordingly, higher oligomers 30 and 31 were prepared by the extension of 21 and 22 at
the C-termini, The NMR studies on 30 and 31 though indicated the presence of stable
helices at the two termini, with the characteristic H-bonding and the nOe patterns three
residue turn, imparts an angle of about 90º between the two helices.
The H-bonding in the new ‘L-Val/Aib--Caa--Caa’ turn (Figure 5D) differs
from the ‘-Caa-L-Val/Aib--Caa’ turn (Figure 5C), wherein ‘L-Val/Aib--Caa--Caa’
is a new three-centered turn with bifurcated H-bonding.16 Thus, the Helix-Turn-Helix
(HTH) peptides 30 and 31 have been identified with three centered (bifurcated) hydrogen
bonding between two donar N-H groups and one acceptor C=O.
6
Abstract
O
O
9
OCH3
O
11
O
Sugar
H
N
R1
11
R2
O
9
O
N
H
N
H
N
H
15
O
Sugar
H
N
N
H
O
O
O
O
O
OCH3
9
OMe
O
9
O
Sugar
Sugar
H N
11
O
H
N H
9
O
Sugar
N H
O
Sugar =
H3CO
6
O
N 5
O
H
CH3
30: nonapeptide
(R1 = iso propyl, R2 = H)
31: nonapeptide
(R1, R2 = methyl)
11
4
H
O
N 7
H
O
O
O
O
N
15
N
O
A
13
Figure 6: (A) Characteristic nOes and H-bonds defining the turn in 30 (Dotted lines
indicate the nOes, dark lines indicate the H-bonds in the turn region and italic represents
residue number) (B) Circular dichroism spectrum of 30 in CH3OH at (C = 0.2 Mm). (C)
Stereoview (bundle of the twenty conformers lowest in energy determined by restrained
molecular dynamics. Sugars are replaced with methyl groups and protons have been
removed for clarity except that of residue-6)
A general study on the /-peptides, wherein both the - and -amino acids were
replaced in the turn region to understand the impact. Except for cyclic constrained amino acids (D-Pro/L-Pro), the turn was found to be compatable to a veriety of - and amino acids.
7
Abstract
Chapter II: Synthesis of /-hybrid peptides from alternating Gly and
(S)-C-linked carbo--amino acids and novel three residue turns
The preceding chapter described the synthesis of a new class of /-hybrid
peptides demonstrated the use of the concept of ‘alternating chirality’ for the realization
of robust 11/9- and 9/11-helices, novel three residue turns and helix turn (HT) motifs.
Based on the above observations /-peptides were designed and synthesized using
achiral ‘Glycine’ (Gly) alternatingly with (S)-β-Caa 7. This study is aimed to understand
the impact of the absence ‘alternating chirality’ in the back bone on the helix and turn
formation.
Accordingly, the /β-hybrid peptides 32 to 35 were prepared from (S)-β-Caa 7
and Gly in the presence of EDCI, HOBt and DIPEA in CH2Cl2. The NMR, CD and MD
studies on peptides 32 to 35 (Figure 7) clearly indicated the presence of right-handed
9/11-mixed helical patterns. These peptides thus, demonstrated that the absence of
‘alternating chirality’ does not effect the formation of stable 9/11-helices.
H
N
O
O
O
H3CO
O
O
O
H
N
O
OCH 3
H
N
N
H
O
H
N
O
O
H3CO
O
n
O
32 n = 2 tetrapeptide
33 n = 3 hexapeptide
O
O
11
O
9
H3CO
H
N
O
O
H3CO
O
H
N
O
O
O
O
O
H
N
O
N
H
N
H
9
11
33 hexapeptide
8
O
H3CO
O
H
N
O
O
O
OCH3
O
34 n = 1 tripeptide
35 n = 2 pentapeptide
9
O
O
OCH3
n
Abstract
(A)
(B)
Figure 7: Structures of peptides 32 to 35 (A) Circular dichroism spectrum of 33 in
CH3OH (C = 0.2 Mm) (B) Superimposed 20 minimum energy structures of 33.
In a further study to understand the impact of the absence of ‘alternating chirality’
in turn formation (at the C-terminus), /β-hybrid peptides 36-39 were prepared from (S)β-Caa 7 and Gly in the presence of EDCI, HOBt and DIPEA in CH2Cl2. A prominent
three residue turn pattern at C-terminus in peptides 36 to 39 (Figure 8) was indicated
along with the presence of right-handed 9/11-mixed helices. Unlike in the case of earlier
/β-peptides with ‘alternating chirality’ which have shown a 7/13-mr turn in the Cterminus region, the new designs have shown a ‘novel turn’, which was stabilized by a
13-membered hydrogen bonding between NH(i-2) – CO (i). This 13-mr turn is in contrast
to -helix, where, a backward hydrogen bonding is formed between CO(i) – NH(i+4)
residue. Thus, the turn in the present design is entirely different from the turn (7/13-mr)
that was realized in the earlier design.
O
H3CO
H
N
O
O
H3CO
O
H
N
O
O
O
O
O
O
N
H
O
O
OCH3
O
N
H
H
N
O
H3CO
O
n
36 n = 1 tripeptide
37 n = 2 pentapeptide
OCH3
O
O
O
n
38 n = 2 tetrapeptide
39 n = 3 hexapeptide
9
Abstract
13
O
11
O
O
H3CO
H
N
O
O
O
O
H
N
O
N
H
N
H
O
O
H3CO
11
9
H
N
O
O
O
OCH3
O
N
H
O
H3CO
O
O
39 hexapeptide
(A)
(B)
13
(C)
(D)
Figure 8: Structures of peptides 36 to 39 (A) Circular dichroism spectrum of 39 in
CH3OH (C = 0.2 Mm). (B) Superimposed 20 minimum energy structures of 39. Ball and
stick models of turns (C) α-helix (D) -Caa-Gly--Caa.
Further, the study was extended to the design and synthesis of /β-hybrid
peptides with ‘new three residue turns’ -- and -- at the C-terminus. The peptides
40 and 41 were synthesized by standard peptide coupling methods.
10
Abstract
O
9
O
H
H
N
N
O
O
H3CO
7
O
O
O
O
H
N
N
H
H
N
O
O
O
H3CO
OCH3
7
12
O
11
O
12
40
A
O
O
H3CO
H
O
O
N
O
O
O
7
O
7
H
N
N
H
H
O
N
14
O
O
11
O
H3CO
14
OCH3
B
41
Figure 9: Structures of peptides 40 and 41. Ball and stick models of turns A) -- and
B) --.
The NMR and MD studies on peptides 40 and 41, with -- (-Caa-L-Ala-LAla) and -- (-Caa-L-Ala--Caa) at the C-terminus respectively showed 7/12- and
7/14-membered turns. Thus, the new designs resulted in a new class of three residue
turns.
Chapter III: Design and synthesis of peptides with ‘hybrid helices’ as
novel motifs for foldamers
The preceding two chapters discussed about peptides with heterogeneous
backbones in producing 9/11-helix and new ‘turns’. In a further study to explore the
peptides with heterogeneous backbone with helical diversity, a new design was envisaged
based on the concept of ‘hybrid helices’. Hybrid helices were designed based on a
combination of two or more different types of homologous and hybrid peptides, e.g. peptides and /- and /-hybrid peptides10,17 within the same oligomer.
Based on the above design, peptides 42 to 44 were prepared, from two or three
types of peptides with mixed helical patterns, in the presence of water soluble EDCI,
HOBt and DIPEA in CH2Cl2.
11
Abstract
Figure 10: (R)-β-Caa (R -C-linked carbo-β-amino acid), (S)--Caa (S-C-linked carbo-amino acid).
The peptides 42 and 43 are prepared by the combination of peptides of two
different helical types, the 10/12- and 11/9-helices derived from -peptides and /hybrid peptides. There are two such helices in the peptide 42, three in the peptide 43.
O
10
10
10
9
12 H
H
N
O
O
O
H3CO
O
H3CO
O
O
O
H3CO
O
O
H
N
N
O
O
H3CO
O
O
12 H
H
N
N
O
O
H3CO
O
O
O
O
H3CO
O
O
H
N
12
12
O
O
O
O
H
N
N
O
O
O
H3CO
O
O
O
12
H
H
N
N
O
OH CO
3
O
O
12
O
O
H3CO
O
O
H
H
O
N
N
O
O
H3CO
O
O
O
O
N
H
O
12
N
H
9
O
H
N
O
OCH3
O
O
H3CO
O
42
O
O
N
H
H
9
10
11
H
H
N
N
O
H3CO
O
O
H
N
O
N
11
9
O
O
O
O
11
11
O
H3CO
9
H
O
H3CO
H
N
O
10
10
O
H
N
O
O
H3CO
O
O
H3CO
O
O
H
N
O
H3CO
O
O
H3CO
O
O
10
12
H
H
N
O
OH CO
3
O
O
N
OCH3
O
O
H3CO
O
O
O
O
O
43
Abstract
Likewise, the peptide 44, consisting of three different helices representing three
different folding patterns, 12/10-, 9/11- and 10/12-helices derived from -,/-peptides
and γ/-hybrid peptides. The NMR studies on the above new hybrid peptides amply
indicated the presence of H-bonding representing the constituent helical structures.
O
H
O
H3CO
O
H
12 H
N
N
O
O
H3CO
O
O
12
N
O
O
H3CO
O
O
H
H
N
N
O
O
H3CO
O
O
10
H3CO
9
O
12
12
O
10
10
O
O
O
H
9
O
H
N
N
O
O
H
11
N
O
H3CO
O
O
N
O
O
O
H
H
N
O
H3CO
O
OCH3
N
O
O
H
O
44
θ/ deg cm2 dmol-1
47
50
Figure 11: Structures of peptides 42 to 44 (arrows indicate the H-bonds of the preferred
mixed helix types) and Stereoview of superimposed 15 minimum energy structures for
peptides 43 and 44 (Sugars are replaced with methyls for clarity)
42
43
44
λ /nm
Figure 12: CD spectra of the peptides 42, 43 and 44 in MeOH
13
Abstract
Further, the two or three helix types are well accommodated within the oligomers
with negligible deviations in the hinge region. The conformational analysis demonstrates
that the two or three different helix types can be realized in a hybrid helix with a
continuous propagation along the sequence of the oligomer. In comparison to the other
hybrid helices, in peptide 44, there is a more distinct kink in the hinge region between the
/- and /-parts (~ 15-20°). Such ‘kinks’ impart subtle variations in the direction of
helix propagation.18
Conclusion
Thus, the work reported in the thesis resulted in the design and synthesis of a new
class of peptides having -amino acids such as L-Ala, L-Val, Aib, L-Pro, D-Pro and Gly
and β-amino acids such as (S)-β-Caa, (R)-β-Caa, β-D-hAla and β-hGly and (S)-γ-Caa.
Which presented a study on the generalization at the new three residue turns (-- and
--) by the use of different - and -amino acids. Similarly, the /-peptides prepared
from (S)-β-Caa and Gly, devoid of alternating chirality, have shown the presence of 9/11mixed helix. However, three residue ‘--’ region at the C-terminus, have showed a 13membered turn supported by a helix, unlike in the earlier design. In a further study,
peptides with new turn structures in -- and -- with 7/12- and 7/14-membered
hydrogen bonded rings nucleated with a helix respectively, we also realized. In
continuation, based on the concept of ‘hybrid helices’, peptides were prepared with more
than one type of backbones and secondary structures. The transition from one helix type
to another was found to be rather smooth with high compatibility and change in the
direction of the helix propagation was in a subtle manner enabling to control the
orientation of the side chains.
14
Abstract
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