Pyrrolidinyl peptide nucleic acid homologues: Effect of ring size on hybridization properties

Article abstract of DOI:10.1021/ol300190u

The effect of ring size of four- to six-membered cyclic β-amino acid on the hybridization properties of pyrrolidinyl peptide nucleic acid with an alternating α/β peptide backbone is reported. The cyclobutane derivatives (acbcPNA) show the highest T_m and excellent specificity with cDNA and RNA.

Full text of DOI:10.1021/ol300190u

ORGANIC
LETTERS
2012
Vol. 14, No. 6
1440–1443
Pyrrolidinyl Peptide Nucleic Acid
Homologues: Effect of Ring Size on
Hybridization Properties
†
†
‡
‡
ꢀ
ꢀ
ꢀ
Woraluk Mansawat, Chotima Vilaivan, Arpad Balazs, David J. Aitken, and
Tirayut Vilaivan*,†
Organic Synthesis Research Unit, Department of Chemistry, Faculty of Science,
Chulalongkorn University, Phayathai Road, Patumwan, Bangkok 10330, Thailand, and
ꢁ
ꢀ
Laboratoire de Synthese Organique & Methodologie, ICMMO ꢀ CNRS UMR 8182,
ꢀ
Universite Paris-Sud, 15 rue Georges Clemenceau, 91405 Orsay cedex, France
vtirayut@chula.ac.th
Received January 23, 2012
ABSTRACT
The effect of ring size of four- to six-membered cyclic β-amino acid on the hybridization properties of pyrrolidinyl peptide nucleic acid with an alternating
R/β peptide backbone is reported. The cyclobutane derivatives (acbcPNA) show the highest Tm and excellent specificity with cDNA and RNA.
Nucleic acids form higher order structures in a predictable
fashion as a result of the highly specific WatsonꢀCrick type
base pairing. This property is essential for the function of
nucleic acids in the storage and transfer of genetic informa-
tion in all living organisms. It is also the basis of various
applications, ranging from biomedical sciences through bio-
technologies to material sciences.1 In recent years, there has
been considerable interest in the design of alternative nucleic
acid recognition systems that may offer advantages over
DNA or RNA in terms of chemical stability, binding affin-
ities, and/or specificities toward different types of nucleic
acids. Peptide nucleic acid (PNA) is a class of nucleic acid
analogues in which a peptide-like backbone replaces the
deoxyribose-phosphate backbone of DNA. In addition to
being able to recognize its cDNA/RNA with high affinity and
sequence specificity, the electrostatically neutral nonphos-
phate backbone of PNA gives rise to a number of unique
properties not observed in other classes of DNA analogues,
such as complete resistance to nucleases and the relative
insensitivity of PNA DNA hybrids to ionic strength.2
3
Conformational restriction of the N-aminoethylglycyl
backbone of the original PNA (now known as aegPNA),
for example, by incorporation of a cyclic moiety or
one or more substituents along the PNA backbone, can
provide PNA with an improved binding affinity as well as
specificity.3ꢀ5
(2) (a) Nielsen, P. E. Chem. Biodiversity 2010, 7, 796–804. (b) Lundin,
€
€
K. E.; Good, L.; Stromberg, R.; Graslund, A.; Smith, C. I. E. Adv. Genet.
2006, 56, 1–51. (c) Egholm, M.; Buchardt, O.; Christensen, L.; Behrens, C.;
Freier, S. M.; Driver, D. A.; Berg, R. H.; Kim, S. K.; Norden, B.;
Nielsen, P. E. Nature 1993, 365, 566–568.
(3) Reviews: (a) Corradini, R.; Sforza, S.; Tedeschi, T.; Totsingan, F.;
Manicardi, A.; Marchelli, R. Curr. Top. Med. Chem. 2011, 11, 1535–
1554. (b) Efimov, V. A.; Aralov, A. V.; Chakhmakhcheva, O. G. Russ. J.
Bioorg. Chem. 2010, 36, 663–683. (c) Kumar, V. A.; Ganesh, K. N. Acc.
Chem. Res. 2005, 38, 404–412.
(4) Selected examples of PNA incorporating cyclic structures in the
backbone: (a) Pokorski, J. K.; Witschi, M. A.; Purnell, B. L.; Appella,
D. H. J. Am. Chem. Soc. 2004, 126, 15067–15073. (b) Govindaraju, T.;
Kumar, V. A.; Ganesh, K. N. J. Am. Chem. Soc. 2005, 127, 4144–4145.
(5) Selected examples of PNA with backbone substituents: (a)
Dragulescu-Andrasi, A.; Rapireddy, S.; Frezza, B. M.; Gayathri, C.;
Gil, R. G.; Ly, D. H. J. Am. Chem. Soc. 2006, 128, 10258–10267. (b)
Englund, E. A.; Appella, D. H. Angew. Chem., Int. Ed. 2007, 46, 1414–
1418. (c) Manicardi, A.; Calabretta, A.; Bencivenni, M.; Tedeschi, T.;
Sforza, S.; Corradini, R.; Marchelli, R. Chirality 2010, 22, E161–E172.
† Chulalongkorn University.
‡
ꢀ
Universite Paris-Sud.
(1) Reviews: (a) Silverman, S. K. Angew. Chem., Int. Ed. 2010, 49,
7180–7201. (b) Aldaye, F. A.; Palmer, A. L.; Sleiman, H. F. Science
2008, 321, 1795–1799. (c) Seeman, N. C. Mol. Biotechnol. 2007, 37, 246–
257. (d) Leumann, C. J. Bioorg. Med. Chem. 2002, 10, 841–854.
r
10.1021/ol300190u
Published on Web 02/29/2012
2012 American Chemical Society

Inspired by the discovery that oligomers of cyclic β-
amino acids can adopt well-defined helical conformations,6,7
we previously developed a series of pyrrolidinyl PNA
with an R/β peptide backbone consisting of an alternat-
ing sequence of nucleobase-modified proline and cyclic
β-amino acid “spacer” such as 1-aminopyrrolidinecar-
boxylic acid (dapcPNA)8 or 2-aminocyclopentane-
carboxylic acid (acpcPNA).9 These pyrrolidinyl PNAs bind
to DNA with higher affinity and sequence specificity
compared to aegPNA.10 They also exhibited some un-
usual features, including the preference for binding to
DNA over RNA as well as the inability to form self-
hybrids. The failure of pyrrolidinyl PNA carrying acy-
clic spacers to recognize DNA/RNA targets11 suggested
that the cyclic five-membered ring spacer locks the con-
formation of the PNA into a form that is close to optimal
for DNA binding. The work carried out so far has been
limited to a five-membered ring spacer, and in order to
gain further insight into the structural properties of
these pyrrolidinyl PNA, an investigation of the effect
of the ring size of the spacer part was warranted.
Modification of the ring size should change both
the rigidity and the torsional angle (θ) of the NHꢀ
C2ꢀC1ꢀCO which is an integral part of the PNA
backbone7 and could in turn significantly affect the
hybridization properties of the resulting PNA.
which contains a 2-aminocyclopentanecarboxylic (ACPC)
spacer (Figure 1). Since the (1S,2S) configuration was
previously found to be optimal for the ACPC spacer,9
the same (1S,2S) configuration was a logical starting point
for the new ring systems. Thus, the Fmoc-derivative of
(1S,2S)-ACBC12 was prepared, along with the known
Fmoc-(1S,2S)-ACHC,13 and each of these derivatives
was combined with the (40R)-nucleobase-modified (20R)-
proline employing the Fmoc solid-phase peptide syn-
thesis previously developed14 to give eight new pyrrolidinyl
PNA sequences as shown in Table S1, Supporting Infor-
mation. All of these pyrrolidinyl PNA possess the same
(20R,40R) configuration at the proline part except for epi-
acbcPNA-sCom. This latter PNA, with a (20R,40S) config-
uration, was synthesized in order to investigate the self-pairing
abilities not observed in the (20R,40R) epimer of acpcPNA.15
The PNA was purified by HPLC (>90% purity), and the
identities confirmed by matrix-assisted laser desorption ioni-
zation time-of-flight (MALDI-TOF) mass spectrometry. It is
noteworthy that the intrinsically labile ACBC16 is compatible
with the basic conditions required during Fmoc group re-
moval and nucleobase side chain deprotection procedures.
Table 1. Thermal Stabilities of DNA and RNA Hybrids of
Homologous Pyrrolidinyl PNAa
entry
1
PNA
apDNA pDNA apRNA pRNA
acbcPNA-homoT
73.8
(72.5)
63.2
ꢀ
ꢀ
n.d.
ꢀ
n.d.
ꢀ
2
3
4
5
6
acbcPNA-mixAT
acbcPNA-mix
<20
(<20)
<20
(<20)
34.1
(<20)
ꢀ
50.8
(32.6)
58.2
(42.3)
62.9
(48.0)
n.d.
25.8
(<20)
31.7
(<20)
48.6
(32.9)
n.d.
ꢀ
(54.2)
66.1
(53.3)
69.8
acbcPNA-mixGC
achcPNA-homoT
achcPNA-mix
(54.5)
<20
(72.5)
<20
ꢀ
ꢀ
<20
(<20)
<20
<20
Figure 1. Structures and sequences of PNA.
(53.3)
(42.3)
(<20)
a Tm values of the corresponding acpcPNA hybrids under identical
conditions9 are shown in parentheses, and ap and p are antiparallel and
parallel, respectively. Conditions: 10 mM sodium phosphate buffer pH
7.0, 100 mM NaCl, and [PNA] = [DNA] = 1 μM. Tm values are
accurate to within (0.5 °C.
We now report on the behavior of two new PNA
manifolds, which incorporate 2-aminocyclobutane-
carboxylic acid (ACBC) or2-aminocyclohexanecarboxylic
acid (ACHC) spacers, referred to here as acbcPNA and
achcPNA respectively, and compare them with acpcPNA
The hybridization properties of acbcPNA-homoT and
achcPNA-homoT with cDNA (dA9) were investigated
by thermal denaturation experiments (monitored by
UVꢀvis at 260 nm) (Table 1, entries 1 and 5). A well-
defined thermal denaturation curve was observed only
with acbcPNA-homoT. The melting temperature (Tm) of
(6) (a) Appella, D. H.; Christianson, L. A.; Klein, D. A.; Powell,
D. R.; Huang, X.; Barchi, J. J., Jr.; Gellman, S. H. Nature 1997, 387,
381–382. (b) Cheng, R. P.; Gellman, S. H.; DeGrado, W. F. Chem. Rev.
2001, 101, 3219–3232.
(7) (a) Vasudev, P. G.; Chatterjee, S.; Shamala, N.; Balaram, P.
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€ €
Chem. Rev. 2011, 111, 657–687. (b) Fulop, F.; Martinek, T. A.; Toth,
G. K. Chem. Soc. Rev. 2006, 35, 323–334.
(8) Vilaivan, T.; Lowe, G. J. Am. Chem. Soc. 2002, 124, 9326–9327.
(9) (a) Vilaivan, T.; Srisuwannaket, C. Org. Lett. 2006, 8, 1897–1900.
(b) Vilaivan, C.; Srisuwannaket, C.; Ananthanawat, C.; Suparpprom, C.;
Kawakami, J.; Yamaguchi, Y.; Tanaka, Y.; Vilaivan, T. Artif. DNA:
PNA XNA 2011, 2, 50–59.
(10) Ananthanawat, C.; Vilaivan, T.; Hoven, V. P.; Su, X. Biosens.
Bioelectron. 2010, 25, 1064–1069.
(11) (a) Vilaivan, T.; Suparpprom, C.; Harnyuttanakorn, P.; Lowe, G.
Tetrahedron Lett. 2001, 42, 5533–5536. (b) Vilaivan, T.; Suparpprom, C.;
Duanglaor, P.; Harnyuttanakorn, P.; Lowe, G. Tetrahedron Lett. 2003,
44, 1663–1666. (c) Ngamwiriyawong, P.; Vilaivan, T. Nucleosides,
Nucleotides Nucleic Acids 2011, 30, 97–112.
(12) (a) Fernandes, C.; Pereira, E.; Faure, S.; Aitken, D. J. J. Org.
Chem. 2009, 74, 3217–3220. (b) Declerck, V.; Aitken, D. J. Amino Acids
2011, 41, 587–595.
(13) (a) Schinnerl, M.; Murray, J. K.; Langenhan, J. M.; Gellman,
ꢂ
S. H. Eur. J. Org. Chem. 2003, 721–726. (b) Xu, D.; Prasad, K.; Repic, O.;
Blacklock, T. J. Tetrahedron: Asymmetry 1997, 8, 1445–1451.
(14) Lowe, G.; Vilaivan, T. J. Chem. Soc., Perkin Trans. 1 1997, 555–560.
(15) Taechalertpaisarn, J.; Sriwarom, P.; Boonlua, C.; Yotapan, N.;
Vilaivan, C.; Vilaivan, T. Tetrahedron Lett. 2010, 51, 5822–5826.
(16) Aitken, D. J.; Gauzy, C.; Pereira, E. Tetrahedron Lett. 2004, 45,
2359–2361.
Org. Lett., Vol. 14, No. 6, 2012
1441

73.8 °C is comparable to that of acpcPNA with the same
sequence (72.5 °C). Circular dichroism (CD) experiments
also clearly confirmed that the acbcPNA-homoT, but not
achcPNA-homoT, could form a stable hybrid with dA9
(Figure S9, Supporting Information). The melting curve
of the hybrid between acbcPNA-homoT and dA9, as
monitored by CD spectroscopy, was in good agreement
with that obtained from UVꢀvis experiments (Figure 2).
Although homopyrimidine PNAs generally form
(70% GþC) to 18 °C (20% GþC) in acbcPNA RNA
3
hybrids. Third, the general preference for binding to DNA
over RNA in the original acpcPNA was still observed in
acbcPNA. Finally, the achcPNA with a mix sequence
(achcPNA-mix) did not show any binding to cDNA or
RNA in both antiparallel and parallel orientations.
The results from Tm experiments were also further con-
firmed by CD spectroscopy. The binding of acbcPNA-mix
to antiparallel DNA, antiparallel RNA and parallel RNA
resulted in a significant change in CD spectra compared to
the sum of each component (Figure S12, Supporting
Information). On the other hand, no such change was
observed upon binding of acbcPNA-mix to parallel DNA
aswell asin all DNA and RNA hybridswith achcPNA-mix
(Figure S13, Supporting Information).
(PNA)2 DNA triplexes by WatsonꢀCrick/Hoogsteen
3
base pairing,17 UV and CD titrations of acbcPNA-homoT
and dA9 (Figure S10, Supporting Information) clearly
showed that only the 1:1 duplex was formed. The lack of
triplex formation is analogous to acpcPNA, which may
be ascribed to the steric repulsion of the bulky acpcPNA/
acbcPNA backbone that destabilizes such triplexes.9
Table 2. Thermal Stabilities of Mismatched DNA Hybrids of
acbcPNA-mix
entry
DNA (50f30)
Tm (°C)a
Δ Tm (°C)b
1
2
dAGTGATCTAC
dAGTAATCTAC
dAGTTATCTAC
dAGTCATCTAC
dAGTGGTCTAC
dAGTGTTCTAC
dAGTGCTCTAC
dAGTGAGCTAC
dAGTGAACTAC
dAGTGACCTAC
dAGTGATGTAC
dAGTGATATAC
dAGTGATTTAC
66.1 (53.3)
40.4 (26.4)
40.6 (27.8)
42.8 (31.0)
36.4 (23.9)
46.6 (29.4)
39.8 (23.8)
46.0 (26.5)
47.0 (28.4)
45.1 (28.8)
41.2 (26.4)
38.3 (24.2)
44.6 (28.5)
ꢀ
ꢀ25.7 (ꢀ26.9)
ꢀ25.5 (ꢀ25.5)
ꢀ23.3 (ꢀ22.3)
ꢀ29.4 (ꢀ29.5)
ꢀ19.5 (ꢀ23.9)
ꢀ26.3 (ꢀ29.5)
ꢀ20.1 (ꢀ26.8)
ꢀ19.1 (ꢀ24.9)
ꢀ21.0 (ꢀ24.5)
ꢀ24.9 (ꢀ26.9)
ꢀ27.8 (ꢀ29.1)
ꢀ21.5 (ꢀ24.8)
3
4
5
6
7
8
9
10
11
12
13
a Tm values of the corresponding acpcPNA hybrids under identical
conditions9 are shown in parentheses. Conditions: 10 mM sodium phosphate
buffer pH 7.0, 100 mM NaCl, and [PNA] = [DNA] = 1 μM. b Tm (comple-
mentary) ꢀ Tm (mismatched). Tm values are accurate to within (0.5 °C.
Figure 2. CD spectra of hybrid of acbcPNA-homoT and dA9 at
different temperatures (a) and change of CD signal at 248 nm as a
function of temperature (b). Conditions: 10 mM sodium phos-
phate buffer pH 7.0, 100 mM NaCl, and [PNA] = [DNA] = 1 μM.
Specificity is perhaps one of the most important aspects
of any nucleic acid recognition systems. The Tm of
hybrids between the PNA acbcPNA-mix and various
DNA targets carrying a mismatched base at the positions
4ꢀ7 (Table 2) showed that the specificity (determined
from the difference of Tm values between mismatched and
cDNA hybrids) was comparable to acpcPNA. A Tm
decrease of >20 °C was observed in all but two cases
(pT dT and pA dA mismatch, which showed ΔTm
The binding studies of a mixed sequence PNA with
DNA and RNA in both antiparallel and parallel orienta-
tions were performed on three different acbcPNA se-
quences with various GþC contents (acbcPNA-mixAT,
acbcPNA-mix, acbcPNA-mixGC) and one achcPNA se-
quence (achcPNA-mix) (Table 1 and Figure S11, Sup-
porting Information). The results were compared with the
corresponding Tm values from acpcPNA with identical
sequences.9 Several important observations were made.
First, the acbcPNA binds to DNA and RNA preferen-
tially in an antiparallel direction, although it can also
3
3
of ꢀ19.5 and ꢀ19.1 °C, respectively). This level of mismatch
discrimination is better than the corresponding DNA and
the original aegPNA (typical ΔTm ꢀ10 to ꢀ14 °C).2
Another unique property of acpcPNA is the inability to
form self-pairing hybrids between two complementary
acpcPNA sequences.9 This could lead to a number of
useful applications in targeting DNA duplexes by a double
duplex invasion mechanism that has been traditionally
achieved with pseudocomplementary aegPNA bearing
modified bases (2,4-diaminopurine/2-thiouracil).18
form quite stable parallel acbcPNA RNA hybrids. Sec-
3
ond, both acbcPNA DNA and acbcPNA RNA hybrids
3
3
show higher thermal stabilities than the corresponding
acpcPNA hybrids. The extent of Tm increase depends on
GþC content, ranging from 9 °C (20% GþC) to 15 °C
(70% GþC) in acbcPNA DNA hybrids and from 15 °C
3
(17) Kim, S. K.; Nielsen, P. E.; Egholm, M.; Buchardt, O.; Berg,
ꢀ
(18) Lohse, J.; Dahl, O.; Nielsen, P. E. Proc. Natl. Acad. Sci. U.S.A.
1999, 96, 11804–11808.
R. H.; Norden, B. J. Am. Chem. Soc. 1993, 115, 6477–6481.
1442
Org. Lett., Vol. 14, No. 6, 2012

According to UV and CD melting studies, the PNA
acpcPNA-sCom with a 10-mer self-complementary se-
quence showed no cooperative melting. On the other
hand, acbcPNA-sCom showed a broad UV melting curve
with apparent Tm of ca. 45 °C. At 20 °C, the same PNA
showed a positive CD signal at 260 nm and a strong
negative CD signal at 280 nm, which is distinctly differ-
ent from the CD spectra of nonself-complementary
acbcPNA (compare Figures S12 and S16, Supporting
Information). These signals disappeared upon heating
and reappeared upon cooling. The results suggest that
acbcPNA-sCom can form a self-complementary hybrid.
We also synthesized the (20R,40S) epimer of both acbcPNA
and acpcPNA to compare the self-pairing behavior with the
“normal” acpcPNA and acbcPNA. As shown in Table 3
and Figures S15 and S16, Supporting Information, the
epi-acbcPNA-sCom self-pairing hybrid was considerably
more stable than the corresponding epi-acpcPNA-sCom
self-pairing hybrid. All self-complementary pyrrolidinyl
PNAs can form stable hybrids with DNA with Tm values
in the range of 67 °C (acpcPNA) to 73ꢀ78 °C (acbcPNA).
might be explained by a more favorable preorganiza-
tion of acbcPNA as follows: Models of dapcPNA
and acpcPNA showed the values of torsional angle
NHꢀC2ꢀC1ꢀCO (θ) (Figure S17, Supporting
Information) of the D-APC and (S,S)-ACPC spacers
of 99.2 ( 6.4° and 99.2 ( 3.1° (averaged from 10 D-APC
and 13 ACPC residues, respectively). A relatively large
difference between these values compared to the corre-
sponding θ figure from an X-ray structure of (R,R)-ACPC
oligomer (ꢀ85.9 ( 12.2°; averaged from 6 residues)21
suggests that there must be a substantial conformational
reorganization of the ACPC moiety to allow optimal
binding to DNA. While the five-membered ring of ACPC
is flexible enough to allow this, there is an entropic penalty
associated with the conformational reorganization process.
On the other hand, the torsional angle θ obtained from an
X-ray structure of (R,R)-ACBC oligomer (ꢀ95.5 ( 3.7°;
averaged from 8 residues)22 is closer to the optimal θ values
shown above. Hence, the acbcPNA is better preorganized for
binding to DNA when compared to acpcPNA. The torsional
angle θ of ACHC obtained from an X-ray structure
of (S,S)-ACHC hexamer was in the range of only
51.5ꢀ61.4°.23 The large deviation from the optimal θ,
together with the rigidity of the cyclohexane ring system
which does not allow efficient conformational reorgani-
zation, should explain the inability of achcPNA to pair
with DNA. The origin of the greater stabilization of
acbcPNA RNA compared to acpcPNA RNA hybrids
In all cases, the PNA DNA hybrids are more stable than
3
the PNA PNA hybrids at the same total strands concentra-
tion. The difference between Tm of PNA DNA and
3
3
PNA PNA hybrids is smallest in epi-acbcPNA (ΔTm
14 °C) and greatest in acpcPNA (ΔTm > 46 °C).
=
3
3
3
cannot be explained without further structural informa-
tion, but the ability to bind strongly to RNA in addition
to DNA clearly suggests potential of applications of
acbcPNA involving RNA targets.
Table 3. Thermal Stabilities of Self-Complementary and DNA
Hybrids of acbcPNA and acpcPNAa
entry
PNA
config
Tm self
Tm apDNA
1
2
3
4
acbcPNA-sCom
acpcPNA-sCom
20R,40R
20R,40R
20R,40S
20R,40S
45.7
<20
77.7
66.8
73.3
66.8
In conclusion, we have successfully synthesized homo-
logues of acpcPNA with four-membered ring (acbcPNA)
and six-membered ring (achcPNA) spacers. The replace-
ment of ACPC with ACBC resulted in a new pyrrolidinyl
PNA with general binding properties similar to acpcPNA
but with an increase of Tm with cDNA and RNA hybrids
by 0.9ꢀ1.8 °C per modification without compromising
the specificity. In contrast, the replacement of ACPC with
ACHC resulted in total loss of binding to both DNA and
RNA. The results are explained by a more favorable
conformational preorganization of the ACBC residue
compared to ACPC and ACHC.
epi-acbcPNA-sCom
epi-acpcPNA-sCom
59.3
32.7
a Conditions: 10 mM sodium phosphate bufferpH7.0, 100mMNaCl,
and [PNA] = 2 μM (self-hybridization) or [PNA] = [DNA] = 1 μM
(PNA DNA hybridization). Tm values are accurate to within (0.5 °C.
3
Since the absence of NH in proline residues does not
allow the formation of regular 11- and 14/15-helices
usually observed in R/β peptides,19 the preorganization
into helical conformations of these R/β pyrrolidinyl PNA
should be governed by the limited conformational space
available to the cyclic β-amino acid spacer rather than
hydrogen bonding. Based on our previous molecular
dynamics simulations,20 the origin of stabilization of
acbcPNA DNA relative to acpcPNA DNA hybrids
Acknowledgment. Financialsupportstothisworkcome
from the Thailand Research Fund (RTA5280002) (to T.V.)
and the Ratchadaphiseksomphot Endowment Fund from
Chulalongkorn University (postdoctoral fellowship to
W.M.).
3
3
(19) Choi, S. H.; Guzei, I. A.; Spencer, L. C.; Gellman, S. H. J. Am.
Chem. Soc. 2008, 130, 6544–6550.
(20) Siriwong, K.; Chuichay, P.; Saen-oon, S.; Suparpprom, C.;
Vilaivan, T.; Hannongbua, S. Biochem. Biophys. Res. Commun. 2008,
372, 765–771.
(21) Appella, D. H.; Christianson, L. A.; Klein, D. A.; Richards, M. R.;
Powell, D. R.; Gellman, S. H. J. Am. Chem. Soc. 1999, 121, 7574–7581.
Supporting Information Available. Synthesis of Fmoc-
(1S,2S)-ACBC-OH and NMR spectra, analytical HPLC
and MALDI-TOF mass spectral data of PNA, and addi-
tional UV and CD spectra. This material is available free
of charge via the Internet at http://pubs.acs.org.
ꢀ
(22) Fernandes, C.; Faure, S.; Pereira, E.; Thery, V.; Declerck, V.;
Guillot, R.; Aitken, D. J. Org. Lett. 2010, 12, 3606–3609.
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Gellman, S. H. J. Am. Chem. Soc. 1999, 121, 6206–6212.
The authors declare no competing financial interest.
Org. Lett., Vol. 14, No. 6, 2012
1443