Synthesis of rhenium-centric reverse turn mimics

Article abstract of DOI:10.1002/chem.201201766

Molecular scaffolds have been shown to facilitate and stabilise secondary structural turn elements, with a central core-arranging functionality in a defined three-dimensional orientation. In a peptide-based molecular imaging probe, this approach is of particular value as it would essentially hide a metal radioisotope within the ligand framework, making the labelling element a critical component of the receptor-bound structure. Starting from a 1,2-diaminoethane loaded 2-chlorotrityl resin, a versatile set of triamine ligand systems were synthesised by using solid-phase Fmoc-based peptide chemistry. The resultant resin-bound peptides then underwent amide reduction by treatment with borane-THF at 65 °C. This provided complete conversion to the corresponding polyamine entities in high purity for the majority of the amino acids utilised. The triamines were then coordinated on solid support by using [NEt₄]₂[Re(CO)₃(Br)₃] followed by resin cleavage and HPLC purification, to give the desired rhenium coordinated species. We have shown that amino acid sequences can be assembled, reduced and coordinated on-resin, resulting in a versatile set of metal-ligand constructs. These studies could be expanded to generate libraries of turn-based peptidomimetics containing Re/Tc^I organometallic scaffolds, with the intention of developing an improved approach for finding new diagnostic and therapeutic radiopharmaceutical entities. Redefining chemical space: Molecular scaffolds have been shown to facilitate and stabilise 2° structural turn elements, with a central core arranging functionality in a defined 3-dimensional orientation. By utilising a Re(CO)₃⁺ centre (see figure), we have demonstrated that amino acid sequences can be assembled, reduced and coordinated on-resin, resulting in a diverse set of turn-based peptidomimetics. Copyright

Full text of DOI:10.1002/chem.201201766

FULL PAPER
DOI: 10.1002/chem.201201766
Synthesis of Rhenium-Centric Reverse Turn Mimics
Jennifer L. Hickey[a] and Leonard G. Luyt*[a, b, c]
Abstract: Molecular scaffolds have
solid-phase Fmoc-based peptide chem-
istry. The resultant resin-bound pepti-
des then underwent amide reduction
by treatment with borane-THF at
658C. This provided complete conver-
sion to the corresponding polyamine
entities in high purity for the majority
of the amino acids utilised. The tria-
mines were then coordinated on solid
support by using [NEt4]2[Re(CO)3(Br)3]
been shown to facilitate and stabilise
secondary structural turn elements,
with a central core-arranging function-
ality in a defined three-dimensional
orientation. In a peptide-based molecu-
lar imaging probe, this approach is of
particular value as it would essentially
“hide” a metal radioisotope within the
ligand framework, making the labelling
element a critical component of the re-
ceptor-bound structure. Starting from a
1,2-diaminoethane loaded 2-chlorotrityl
resin, a versatile set of triamine ligand
systems were synthesised by using
followed by resin cleavage and HPLC
purification, to give the desired rheni-
um coordinated species. We have
shown that amino acid sequences can
be assembled, reduced and coordinated
on-resin, resulting in a versatile set of
metal–ligand constructs. These studies
could be expanded to generate libraries
of turn-based peptidomimetics contain-
ing Re/TcI organometallic scaffolds,
with the intention of developing an im-
proved approach for finding new diag-
nostic and therapeutic radiopharma-
ceutical entities.
Keywords: molecular diversity
·
peptidomimetics radiopharma-
·
ceuticals · rhenium · solid-phase
synthesis
Introduction
method of conveying the three-dimensional information of
peptide pharmacophores into non-peptidic drug candidates.
Reverse turns are common motifs found in the inherent
organisation of numerous biomolecules, encompassing a
wide range of structures with a well-defined three-dimen-
sional arrangement.[3] Recognition of turn elements general-
ly only involves an interaction between the amino acid side
chains and the receptor. This insinuates that the peptide
backbone is not a required constituent, and could be re-
placed by a scaffold, displaying functionality in the correct
orientation for ligand–receptor interaction to take place.
One area of research in which scaffolds have been exten-
sively studied is in the development of G protein-coupled
receptor (GPCR) targeting analogues.[4,5] GPCRs play an
important role in a variety of diseases from cancer and dia-
betes, to inflammatory and respiratory disorders,[6] and are
therefore of great interest in drug development. They have
become the most heavily investigated drug targets in the
pharmaceutical industry. In fact, around 40% of all prescrip-
tion drugs currently on the market act by targeting GPCRs
either directly or indirectly.[7,8] Upon cross-target analysis it
has also been revealed that many GPCR ligands have
common structural binding motifs.[9,10] These so-called “priv-
ileged structures” have demonstrated that a single molecular
framework can be utilised to create libraries of compounds
targeting a diverse set of GPCRs through structural modifi-
cation of the functionality extending from a central core.
Proteins are the primary means of cellular communication
in most biological systems and with such a vast array of
amino acid sequence assemblies available, they have the po-
tential to provide an abundance of distinct signalling mes-
sages. The majority of this cellular communication occurs
through the interaction of protein messengers with cell sur-
face receptors, relying on a defined spatial orientation of
amino acid functionality. However, the development of pep-
tides as drug candidates has proven difficult due to poor bi-
oavailability, rapid enzymatic degradation and limited shelf
stability.[1] Although a number of clinically relevant peptides
have been identified as drug targets,[2] it is exceedingly likely
that future lead compounds will emerge from research di-
rected at identifying non-peptidic structures. Therefore,
there is a need in drug development to generate an efficient
[a] Dr. J. L. Hickey, Prof. Dr. L. G. Luyt
Department of Chemistry, University of Western Ontario
1151 Richmond Street, London, Ontario N6A 5B7 (Canada)
E-mail: lluyt@uwo.ca
[b] Prof. Dr. L. G. Luyt
Department of Medical Imaging, University of Western Ontario
1151 Richmond Street, London, Ontario N6A 5B7 (Canada)
[c] Prof. Dr. L. G. Luyt
Department of Oncology, London Regional Cancer Program
790 Commissioners Road East, London
Ontario N6A 4L6 (Canada)
Metal-based scaffolds as secondary structure mimics: A
metal-based molecular scaffold could also act as a privileged
structure, organising the presentation of ligands in a defined
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201201766.
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three-dimensional orientation at a targeted binding site.
Whereas carbon is limited to linear, trigonal planar and tet-
rahedral geometries, transition metals have higher structural
diversity enabling a further exploration of chemical space.
This concept of a metal-based scaffold has proven to be
effective at generating high affinity ligands. Katzenellenbo-
genꢁs group, revealed that a cyclopentadienyl rhenium(I) tri-
carbonyl scaffold, with phenol functionality radiating from
the central core, could yield compounds with nanomolar af-
finity for the human estrogen receptor.[11] Meggers has
shown that the rigid backbone conformation of ruthenium
metal complexes, functionalised with various ligand sets,
produces structures similar to that of a peptide reverse turn,
providing potent inhibitors for a number of protein kinas-
es.[12] The literature also supports the use of a ferrocenyl
moiety to induce the formation of a peptide turn,[13] in
which the ferrocene derivatives can be coupled to subse-
quent amino acids and peptides to give the corresponding b-
sheet-like bioconjugates.
core. With this design, prior to metal coordination, the free
ligand will display low binding affinity toward the related bi-
ological receptor. However, once the biomolecule is coordi-
nated to the Re/Tc tricarbonyl core, it will be locked in the
desired turn orientation, resulting in a high-affinity ligand;
this means that metal incorporation is required in order for
biological activity to be present.
This project aims to design a synthetic approach towards
generating a diverse set of non-peptidic metal-based turn
mimics. We have accomplished this through the preparation
of rhenium-based scaffolds functionalised with various tria-
mine coordination spheres. These metal constructs can have
application in a wide variety of biological ligands that con-
tain a reverse-turn, providing a new approach for research-
ers who are involved in the radiolabelling of peptide-like
molecules.
Results and Discussion
Using a metal-based scaffold we can move away from the
traditional peptide-based molecular imaging probe and
progress toward that of a privileged structure, in which the
radiometal acts as a skeleton displaying the ligand frame-
work in a desired orientation. These proposed metal-centric
peptide mimics, would result in the formation of an integrat-
ed radiopharmaceutical, one in which the labelling element
forms a critical component of the receptor–ligand structure
(Figure 1). This is contrary to the current, most widely utilis-
The synthetic approach utilised focuses on the preparation
of a triamine chelation core, comprised of three variable po-
sitions allowing for chemical and spatial diversity (Figure 2).
Figure 2. Three areas of spatial diversity (R1, R2 and R3) present in a rhe-
nium-based scaffold containing a tridentate {NNN} chelation sphere.
In this design, R1 and R2 can consist of any d, l or unnatural
amino acid residue, while R3 can be any acid or anhydride-
containing compound (such as hydrocinnamic acid, acetic
anhydride or 4-methylvaleric acid). Simply modifying the
functionality present in these locations will allow for the po-
tential to create a diverse collection of chemical entities. For
example, if 40 different compounds were utilised in each of
the three variable sites, a library consisting of approximately
64000 compounds would be generated.
Figure 1. A pendant versus integrated approach to designing radiophar-
maceuticals. The pendant design places the radiolabel at a location re-
moved from the biologically active site. In contrast, the integrated privi-
leged structure incorporates the radiolabel directly into the framework of
the receptor ligand.
The advantage of this synthetic approach is that the cen-
tral core is composed of a transition metal complex. Organic
compounds containing sp2 and sp3 carbon atoms have limit-
ed variability in their three-dimensional orientation. The use
of a metal complex enables further exploration of chemical
space due to the existence of a variety of available geome-
tries and coordination numbers.[16] These metal complexes
will have a unique structural distinction from regular organ-
ic constructs, which would then allow for an increase in the
number of chemical entities within a library that are able to
bind to known biological targets.
ed pendant approach in developing a receptor binding radi-
opharmaceutical, where the radioisotope is attached to the
peptide via a side chain lysine, or through functionalization
of the carboxy or amine terminus of the ligand.[14,15]
An integrated secondary structural mimic would allow for
a significant decrease in the molecular weight of the ligand,
improved in vivo behaviour, and the ability to perform
structure–activity studies by simply modifying the amino
acid side chain functionality extending from the central
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Synthesis of Rhenium-Centric Reverse Turn Mimics
FULL PAPER
The crystal structure of a simple, unsubstituted rhenium
triamine has previously been reported.[17] From these data it
can be estimated that the distance between N1 and N3 in the
structure of a rhenium diethylenetriamine complex is ap-
proximately 3.5 ꢂ (Figure 3). It has also been stated that the
Figure 3. Comparison of a simple rhenium triamine with the distance be-
tween N1 and N3 estimated at 3.5 ꢂ, and a b-turn structure with a meas-
ured distance of 4–6 ꢂ between a-carbon i and a-carbon i+3.
complex fits in a sphere of 7 ꢂ in diameter.[18] This small
size correlates well with the dimensions of a b-turn struc-
ture. The distance between the a-carbon of residue i and the
a-carbon of residue i+3 has been determined experimental-
ly to be between 4–6 ꢂ in various naturally occurring re-
verse turn structures.[19] Therefore, due to their small com-
pact structure these rhenium diethylenetriamine metal con-
structs are of an appropriate scale to have application in the
targeting of receptors that bind biologically active molecules
in a turn conformation.
In order to further validate the use of rhenium/techneti-
um-containing tridentate chelation systems as turn mimics,
we have postulated that the skeleton of a Re/Tc complex
consisting of a tridentate {NNN} ligand system, not only is
of the appropriate size but also has a spatial orientation sim-
ilar to that of a naturally occurring reverse turn peptide.[20]
X-ray crystallography data (.cif) of a {NNN} tricoordinate
Re(CO)3 complex[18] was fit with the conformation of a pub-
lished NMR structure for Met-enkephalin,[21] a peptide
known to exist in a b-turn conformation (Figure 4, shown in
cyan, by using the modelling software Sybyl 7.3, Tripos,
St. Louis).
The three nitrogen atoms of the rhenium chelator were
lined up with the amide backbone atoms of the turn region
of enkephalin. Although enkephalin has substantial flexibili-
ty, the folded forms of the peptide overlay well with the
{NNN} tridentate chelation system. When these two struc-
tures are superimposed, good atom overlap is produced,
with a calculated three-atom fit of 0.48 ꢂ root mean square
(RMS) shown in blue. This demonstrates that tridentate rhe-
nium/technetium(I) tricarbonyl complexes are able to exist
in the proper orientation to mimic peptide-based turns.
Figure 4. Modelling of NMR spectroscopy data for Met-enkephalin
(cyan)[21] and X-ray crystallography data of a tridentate {NNN} Re(CO)3
chelation system[18] gives a three-atom fit of 0.48 ꢂ RMS (blue).
involves the development of a chelation sphere that pro-
motes chemical diversity. This can be accomplished through
the use of amino acid building blocks. However, a peptide
backbone consisting entirely of amide functionality is unde-
sirable as it will not readily coordinate to the Re/TcI tricar-
bonyl core. One way to overcome this obstacle is to assem-
ble the desired peptide sequence and then reduce the back-
bone amides to create a polyamine species, preserving the
functionality present in the amino acid side chains. Acyclic
triamine moieties are known to form highly stable, hydro-
philic cationic complexes upon coordination to rhenium/
technetium.[18] When evaluated in vivo, these metal com-
pounds display rapid clearance from blood and organs. This
indicates that triamines are biologically relevant alternatives
C-terminal carboxylic acid; general approach: The first step
in generating a library of rhenium-containing turn mimics
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L. G. Luyt and J. L. Hickey
to more common ligands, such as histidine or iminodiacetic
acid, which form neutral metal complexes with ReI upon co-
ordination.
The research groups of Hall and Houghten have widely
reported on the synthesis of polyamines through a borane
induced amide reduction while on a solid-phase polymer
support.[22–26] The initial approach that we attempted in-
volved the synthesis of a tetrapeptide loaded onto a chloro-
trityl resin through the C-terminal carboxylic acid
(Scheme 1). Once the linear peptide sequence was assem-
bled the resin was treated with borane-tetrahydrofuran
(BH3-THF) to reduce the backbone amide functionality.
The resultant polyamine was then treated with [NEt4]2-
[Re(CO)3Br3] while still attached to the solid support, fol-
lowed by trifluoroacetic acid (TFA) cleavage. This synthetic
route was designed to produce the unnatural amino acid 1,
containing a free C-terminal carboxylic acid and a protected
N terminus. This would allow for easy incorporation into
larger peptide structures where it could act as a turn induc-
ing element. However, after numerous attempts and modifi-
cations this method was abandoned as upon analysis of the
filtrate it was determined that the peptide was being cleaved
from the solid support during the on-resin reduction step.
There is support in the literature for a carboxylic triphenyl-
methyl ester being stable to borane reduction conditions, as
according to Greene, a trityl protected acid is expected to
be inert to diborane at 08C.[27] However, under our condi-
tions of heating at 658C, it was observed that the ester at-
tachment was cleaved, resulting in no observable amount of
the desired product being salvaged.
Scheme 2. General synthetic route towards the generation of rhenium-
centric reverse turn peptidomimetics, with the amino acid side chain pro-
tecting groups removed in the final rhenium coordinated products 3c–7c
by TFA treatment.
The resultant resin-bound peptides 3a–8a then underwent
a 72 h amide reduction through reaction with a 0.1m BH3-
THF solution at 658C. After treatment with borane, com-
plete conversion to the polyamine entities was achieved in
high purity for the majority of the amino acids utilised.
However, the generated secondary amines were found to
form very robust BH3-amine adducts, the cleavage of which
requires an extensive work-up. A mild oxidative method
was first attempted that involved the addition of iodine to
the resin in a THF buffered solvent mixture containing
acetic acid and diisopropylethylamine.[22] Iodine is used to
cleave the borane–amine complexation and the buffered sol-
ution traps the formed hydroiodic acid. This prevents the
solution from becoming too acidic, which would result in
the peptide being prematurely released from the solid sup-
port. Although this approach produced the desired triamine
product, a low purity was consistently observed by HPLC
analysis.
An alternative work-up procedure, involving the addition
of piperidine at 658C, was utilised for ensuing attempts.[26]
The potential for racemisation to occur during both reduc-
tion and basic work-up steps has been examined previously
and it was reported that this methodology does not affect
the stereochemistry present at the a-carbon of the amino
acid residues.[26] Upon treatment with piperidine at 658C for
12 h, the desired diethylenetriamine species 3b–8b were ob-
C-terminal diaminoethane; general approach: A new ap-
proach was then developed, in which a diamino moiety was
loaded onto the trityl resin as the C-terminal attach-
ment.[22,23] The technique of having an amine appended to
the trityl resin proved more successful than that of a C-ter-
minal carboxylic acid. Starting with 1,2-diaminoethane pre-
loaded onto a 2-chlorotrityl resin 2, the respective amino
acid residues were constructed onto the solid support by
using standard 9-fluorenylmethoxycarbonyl (Fmoc)-based
solid-phase peptide chemistry (Scheme 2). In this design the
N-terminal amino acid was substituted with a more structur-
ally simple modified acid or anhydride moiety, thus limiting
the potential complexity caused by having an N-terminal
amine protecting group. The first two amino acids were as-
sembled onto the resin, followed by a third coupling reac-
tion or acetylation giving variable functionality in R1, R2
and R3.
Scheme 1. Initial attempt at synthesising a rhenium-containing unnatural amino acid by on-resin amide reduction methodology.
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Synthesis of Rhenium-Centric Reverse Turn Mimics
FULL PAPER
Table 1. Summary of amino acid compatibility. Amino acid building
blocks utilised in positions 1, 2 and 3, which remain intact upon BH3-
THF treatment.
tained in high purity. The triamines were then coordinated
on solid support with [NEt4]2[Re(CO)3(Br)3] to give the re-
sultant resin-bound metal complexes. In a final step, the
metal complexes were treated with TFA to afford cleavage
from the resin and removal of all side chain protecting
groups. Due to the presence of a primary amine at the C ter-
minus of the peptide, the rhenium coordination must take
place on-resin as opposed to via solution-phase methodolo-
gies. This amine would act as a fourth chelation site, com-
peting with the tridentate coordination sphere created by
the amide reduction, resulting in a complicated mixture of
products. Treatment of the polyamine with rhenium results
in the formation of isomers of the desired product due to
the presence of secondary amines.[28] The crude material was
purified by preparative HPLC, giving the desired rhenium
coordinated species 3c–7c, which were further analysed by
ESI-MS as well as by NMR spectroscopy. Reaction progress
and purity of each synthetic step was monitored by taking a
small portion of the resin, treating it with TFA to afford
cleavage from the solid support, followed by LC-MS analy-
sis.
Position 1
Position 2
Position 3
Phe
Ala
Ser
Thr
Leu
Lys
Tyr
Val
the peptide chain as it undergoes cyclisation, forming the
corresponding pyroglutamate lactam.[29,30] This is a very
common post-translational enzymatic modification found in
many proteins and natural peptides. However, this cyclisa-
tion will also occur spontaneously under both acidic and
basic conditions.
In this instance, even though glutamine was not posi-
tioned near the N terminus of peptide 5, once cleaved from
the resin, the residue is in very close proximity to the C-ter-
minal amine functionality. Since resin cleavage occurs under
acid conditions, the amide bond connecting glutamine to the
diamine linker could react with the side chain of the gluta-
mine residue forming a six-membered ring. Alternatively,
the C-terminal primary amine may react with the amide
side chain of the glutamine residue, resulting in the forma-
tion of a nine-membered ring. Even though both of these
options seem unfavourable, the HPLC-MS data of the linear
Rhenium complexes: In an attempt to test the limits of this
synthetic approach, amino acid residues containing an array
of side chain functionality and protecting groups were incor-
porated into the various rhenium complexes. Borane is a
mild reducing agent that should reduce the amide function-
ality present in the peptide backbone, leaving the side chain
protected functionality in its current state. It has been previ-
ously reported that tBu-protected carboxylic acid containing
amino acids, such as aspartic acid and glutamic acid, will un-
dergo reduction to the corre-
sponding tBu-protected ethers
under borane reduction condi-
tions.[22,26] However, these resi-
dues were still employed be-
cause we wanted to ensure that
rhenium coordination was unaf-
fected. Boc-protected histidine
has been reported to not be
able to withstand the borane re-
duction protocol[22] and there-
fore has been left out of this in-
vestigation.
Table 2. HPLC purity and exact mass found for the linear peptide, reduced sequence and rhenium complex
after TFA micro-cleavage.
Compound R1
R2
R3
HPLC MW calcd[a] MW found
purity
[%]
3a
3b
3b
3c
4a
4b
4c
5a
5b
5c
6a
6b
6c
7a
7b
7c
8a
8b
CH2C6H5
CH3
CH3
CH3
CH3
CH2C6H4OtBu
CH2C6H4OtBu
CH2C6H4OH
CH3
CH3
CH3
CH3
95
321.2
279.3
279.3
549.2
443.2
401.3
671.2
330.2
274.3
544.2
407.3
365.3
635.3
437.2
367.3
637.2
417.3
374.3
321.3 [M+H]+
279.3 [M+H]+
279.3 [M+H]+
549.2 [M]+
CH2C6H5
CH2C6H5
CH2C6H5
CH2OtBu
CH2OtBu
CH2OH
65[b]
96
92[c]
A
443.3 [M+H]+
401.4 [M+H]+
671.3 [M]+
AHCTUNGTRENNUNG
A
(CH2)2CONH
(CH2)3NH(Trt)
(CH2)3NH2
(Trt) CH
A
CH3
CH3
CH3
96[d]
96[e]
99[c]
330.3 [M+H]+
274.3 [M+H]+
544.2 [M]+
Using this synthetic ap-
proach, complete reduction to
the desired triamine species
was achieved for the majority
of the amino acids utilised
(Table 1); HPLC purity and
ESI-MS data for seven different
systems are shown in Table 2.
However, we did encounter
some synthetic challenges along
the way. Glutamine is often a
problematic amino acid when
N
CH
CH
ACHTUNGTRENNUNG
ACHTUNGTRENNUNG
CH
CH
U
CH2CH
N
N
407.3 [M+H]+
365.4 [M+H]+
635.3 [M]+
R
ACHTUNGTRENNUNG
CH(OH)CH3
CH2CO(OtBu)
(CH2)2OtBu
(CH2)2OH
A
ACHTUNGTRENNUNG
G
T
G
N
437.1 [M+H]+
367.3 [M+H]+
637.2 [M]+
R
N
R
ACHTUNGTRENNUNG
T
T
ACHTUNGTRENNUNG
CH2C8H5NBoc
CH2C8H5NBoc
T
CH3
CH3
98
–
417.3 [M+H]+
–
AHCTUNGTRENNUNG
[a] All protecting groups were removed during TFA micro-cleavage. [b] Mild work-up conditions were at-
tempted with this peptide sequence (I2 buffered solution as reported by Hall),[22] resulting in a decreased
purity. [c] Determined after HPLC purification. [d] Combined value from desired product and cyclised gluta-
located near the N terminus of mine residue. [e] Purity determined by HPLC-MS mass TIC chromatogram due to the absence of UV active
functionality.
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L. G. Luyt and J. L. Hickey
peptide sequence 5a show two different products, one with
the desired mass and a second peak with a mass loss equiva-
lent to that of ammonia.
goal is creating a library of metal constructs, the formation
of diastereomers may in fact be beneficial in that it increases
the likelihood of attaining the desired conformation for bio-
logical affinity, even though only one of the isomers may be
active. Since there are three secondary amines in the coordi-
nation sphere, there is the potential to produce eight differ-
ent rhenium-containing products. However, only a maxi-
mum of four isomers were ever seen upon cleavage from
the solid support for 3c–7c, and the major isomer was iso-
lated for characterisation by preparative HPLC in high
purity.
The purity reported in Table 1 for compound 5a is a com-
bined integration of what we believe to be a cyclised lactam
and the desired linear peptide sequence, as cyclisation is ap-
parently inevitable during these highly acidic conditions. It
is, however, important to note that this modification only
occurs during the micro-cleavage analysis step and that the
linear peptide sequence, which remains on the solid support,
is still of the correct orientation. Therefore, this outcome
does not affect the subsequent reduction and metal coordi-
nation reaction steps. A second structural alteration, which
1
After HPLC purification, 3c–7c were analysed by H and
1H-1H gCOSY NMR spectroscopy. Upon coordination to
rhenium, the methylene groups in the diethylenetriamine
backbone become diastereotopic in nature, due to the
locked conformation enforced by the metal. Also upon coor-
dination, the NH protons no longer exchange with the sol-
vent, and therefore show correlations to the aliphatic region
of the spectrum, enabling full characterisation of the com-
plexes. These purified rhenium triamine species were also
analysed by HPLC-MS, with the effectiveness of this techni-
que in generating rhenium-centric peptide mimic structures
illustrated in Figure 5 and Figure 6.
occurred to the GlnACTHNUTRGNEUNG(Trt) residue, was complete conversion
of the amide functionality to the corresponding primary
amine during the borane reduction step. This reduced amide
side chain results in the formation of an ornithine amino
acid, which could still be desirable in a library synthesis.
Since this modified product 5b was obtained in high purity,
the reaction to form the rhenium coordinated species was
still attempted. Also, as previously reported, we observed a
reduction of the glutamic acid and aspartic acid side chains
in 7 to the corresponding primary alcohol functionality.
The Boc-protected tryptophan residue in 8 proved to be
most problematic during the reaction, as it appeared to de-
compose or polymerise upon BH3-THF treatment. Hought-
en also reported that aggregates or polymerised products
were observed when using tryptophan residues;[26] however,
The analytical HPLC, as well as ESI mass spectral data
for compound 4 through each of the three reaction steps are
illustrated in Figure 5. This peptide was synthesised to con-
tain two tert-butyl protecting groups, adding further com-
plexity due to the presence of an additional functionality.
The top panel of this Figure shows the crude HPLC UV
chromatogram of the linear peptide sequence 4a, and dis-
plays a peak corresponding to the desired species in 90%
purity. The identity of the compound was verified by ESI
mass spectrometry with the desired [M+H]+ exact mass
presented in the inset on the right-hand side. Panel B dis-
plays the crude HPLC trace of the peptide following on-
resin BH3-THF reduction and subsequent piperidine work-
up conditions, giving compound 4b in 89% purity. The cor-
responding mass spectrum confirms the identity of the tria-
mine species, as the retention time of these two compounds
does not vary that greatly by HPLC. The bottom panel
shows an analytical trace of the rhenium complex 4c after
preparative HPLC purification, with the corresponding mass
spectrum verifying the presence of rhenium through obser-
vation of the characteristic isotopic signature.
Confirmation of purity and reaction progression through-
out the three synthetic steps is also shown for compound 6
(Figure 6). With this example, however, there is a visible dif-
ference in the crude HPLC retention time for the linear
peptide sequence 6a and that of the reduced peptide 6b.
This clear separation in retention time confirms that the on-
resin reduction does in fact go to completion as there is no
visible starting material remaining after reacting for 72 h at
658C. This validates the borane-THF on-resin reduction ap-
proach as a viable technique to generate libraries of metal
constructs. In a library system, reaction progress is not
always easily monitored; therefore, this on-resin reduction
and subsequent coordination approach, which we have de-
Hall witnessed that the TrpACTHNURGTNE(UNG Boc) residue remained intact
throughout the synthesis of their polyamines.[23] Due to
these contrasting results, both the piperidine, as well as the
mild oxidative iodine work-ups were attempted with com-
pound 8b. Still, no discernable amount of the desired tria-
mine was obtained; therefore, rhenium coordination was not
attempted with this system. Also, since the HPLC-MS chro-
matograms displayed multiple peaks, none of which match-
ed the molecular weight of the desired product, it was diffi-
cult to determine if the LysACTHNUTRGENUGN(Boc) had endured the borane
reductions conditions. However, since the structure of lysine
and ornithine are very similar, with lysine only containing
one additional methylene group in the side chain, for future
attempts it is believed that lysine would be able to withstand
the reaction conditions as well. Apart from these limitations
associated with tryptophan and amino acid residues contain-
ing acid/amide side chain functionality, there remains ample
diversity available with this protocol through the use of
other d, l and unnatural amino acids.
On-resin complexation and analysis: The resultant triamine
species 3b–7b were coordinated on-resin by using the rhe-
nium(I) reagent [NEt4]2[Re(CO)3(Br)3], which was synthes-
ised according to a procedure published by Alberto.[31] The
complexation reaction was stirred for 4 h at 658C, upon
which time the peptide was analysed by HPLC-MS. One dis-
advantage of using a secondary amine-based coordination
sphere is that diastereomers can form upon metal complexa-
tion.[28] However, in this particular instance where the end
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Synthesis of Rhenium-Centric Reverse Turn Mimics
FULL PAPER
Figure 6. Analytical HPLC and ESI-MS traces for the peptide derivative
6. A) The linear peptide 6a. B) The peptide 6b, following treatment with
borane-THF and piperidine work-up. C) The rhenium coordinated tria-
mine 6c after HPLC purification.
Figure 5. Analytical HPLC and ESI-MS (inset) traces for the peptide de-
rivative 4. A) The linear peptide 4a. B) The reduced triamine 4b, follow-
ing treatment with borane-THF and piperidine work-up. C) The rhenium
coordinated triamine 4c after HPLC purification.
veloped, will provide the desired rhenium diethylenetria-
mine species in high purity. Such a reliable approach would
be especially advantageous in a one-bead one-compound
methodology in which identity of peptide sequences and ver-
ification of purity is rarely performed prior to biological
screening.[32]
ing a metal scaffold, and aide in the discovery of new drug-
like diagnostic and therapeutic radiopharmaceutical entities.
Experimental Section
General procedures and materials: All chemicals were purchased from
commercial sources and used without further purification unless other-
wise noted. Analytical HPLC was performed by using a Waters Atlant-
is T3 C18 column 4.6ꢃ150 mm, 5 mm or a Waters Sunfire C18 column
4.6ꢃ150 mm, 5 mm. Preparative HPLC was performed by using a Waters
Atlantis T3 Prep C18 OBD column 19ꢃ150 mm, 5 mm or a Waters Sun-
fire Prep C18 OBD column 19ꢃ150 mm, 5 mm. A gradient system was
used consisting of: CH3CN+0.1% TFA (solvent A) or MeOH (sol-
vent B)+0.1% TFA and H2O+0.1% TFA (solvent C) and the absorb-
ance was detected by using a Waters 2998 photodiode array detector.
Electrospray ionisation mass spectra were obtained by using a Micromass
Quatro Micro LCT mass spectrometer. NMR spectroscopy data were ob-
tained on the Varian Inova 600 MHz in [D4]MeOH with the chemical
shifts referenced to solvent signals ([D4]MeOH, 1H 3.31 ppm) relative to
TMS. For compounds containing rhenium, both 185Re and 187Re were ob-
served in the ESI-MS and HRMS chromatogram in the correct isotopic
ratio; however, only the more abundant 187Re molecular weight is report-
ed in this section.
Conclusion
In conclusion, it has been demonstrated that amino acid se-
quences can be assembled, reduced and coordinated on-
resin, resulting in a versatile set of rhenium-ligand con-
structs for use as reverse-turn mimics. Due to the existence
of a variety of available geometries and coordination num-
bers, these metal complexes will have a unique structural
distinction from regular organic molecules, potentially al-
lowing for an increase in the number of chemical entities
displaying affinity towards various biological targets.
Through the use of simple d, l and unnatural amino acid
residues, this synthetic approach will allow for the genera-
tion of a diverse set of turn-based peptidomimetics contain-
Chem. Eur. J. 2012, 00, 0 – 0
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L. G. Luyt and J. L. Hickey
General peptide synthesis: Fully protected resin-bound peptides were
synthesised by standard Fmoc solid-phase peptide chemistry by using
manual peptide synthesis methods. 2-Chlorotrityl resin preloaded with
1,2-diaminoethane (1.0 mmol, loading 0.9 mmolgÀ1) was utilised as the
solid support. All N-Fmoc amino acids were employed. Fmoc removal
was achieved by treatment with piperidine (20%) in DMF for 5 and
20 min with consecutive DMF and CH2Cl2 washes after each addition.
For all Fmoc amino acid coupling, the resin was treated twice with Fmoc
amino acids (3 equiv), HBTU (3 equiv) and DIPEA (6 equiv) in DMF
(20 mL) for 30 min to 2 h. Once the dipeptide was synthesised, following
Fmoc removal, the resin was treated twice with a solution of either:
1) acetic anhydride (10%) in DMF for 15 min to afford N-terminal acety-
lation, or 2) a third coupling reaction consisting of 3-phenylpropanoic
acid (3 equiv), HBTU (3 equiv) and DIPEA (6 equiv) in DMF for 30 min
to 2 h. Once the linear sequence was assembled a micro-cleavage was
performed where a very small portion of the peptide was deprotected
and removed from the trityl resin by treatment with a 50:50 mixture of
TFA/CH2Cl2 for 3 h to determine the reaction progression and purity
through HPLC-MS analysis.
[ReACHTUNGERTG(NUNN 4b)(CO)3] CHTUNRTGENNUG ACTHNGUTREN(NUGN 4c): Purification was carried out by prepara-
+A[CF3CO2]À
tive HPLC (linear gradient of 40 to 80% solvent B in C) and the purity
of the isolated pale yellow powder was determined to be 90% by analyti-
cal HPLC (linear gradient 40 to 80% solvent B in C, tR =7.87 min).
Yield: 50 mg (8%); 1H NMR (600 MHz, CD3OD): d=7.32–7.23 (m, 4H,
CH, ar), 7.20 (m, 1H, CH, ar), 6.99 (m, 2H, CH, ar), 6.71 (m, 2H, CH,
ar), 6.35 (m, 1H, NH), 5.21 (m, 1H, NH), 5.12 (m, 1H, NH), 3.67–3.53
(m, 3H), 3.50 (m, 1H, CH), 3.41 (m, 1H, CH), 3.33 (m, 1H, CH), 3.27–
3
3.13 (m, 4H), 3.04 (dd, JHÀH =3.9, 13.9 Hz, 1H, CH), 2.90 (m, 2H), 2.82–
2.63 (m, 4H), 2.51 (dd, 3JHÀH =9.2, 13.9 Hz, 1H, CH), 2.25 (m, 1H, CH),
2.00 ppm (m, 1H, CH); HRMS (ESI): m/z calcd for C26H36N4O5187Re:
671.2243; found: 671.2260 [M]+.
[ReACHTUGNERTN(NNGU 5b)(CO)3] CHTUNRTGENNUG ACTHNGUTREN(NUGN 5c): Purification was carried out by prepara-
+A[CF3CO2]À
tive HPLC (linear gradient of 20 to 60% solvent B in C) and the purity
of the isolated white powder was determined to be 99% by analytical
HPLC (linear gradient 20 to 60% solvent B in C, tR =7.14 min). Yield:
75 mg (13%); 1H NMR (600 MHz, CD3OD): d=6.42 (m, 1H, NH), 5.00
(m, 1H, NH), 4.77 (m, 1H, NH), 3.66 (m, 2H), 3.44 (m, 2H), 3.32 (m,
1H, CH), 3.25 (m, 1H, CH), 3.18 (m, 1H, CH), 3.07–2.92 (m, 5H), 2.82
3
(ddd, JHÀH =3.9, 13.9, 13.9 Hz, 1H, CH), 2.52 (m, 1H, CH), 2.21 (m, 1H,
General amide reduction procedure: The resin containing the linear pep-
tide sequence was placed in an oven-dried round-bottom flask under
argon. A solution of borane-THF was added (0.1m, 10 equiv per amide)
to the flask and the reaction mixture was stirred at 658C for 72 h. Over
the course of the reaction, the resin changed from a pale yellow grainy
texture to a fluffy white consistency. At this time, the entire reaction mix-
ture was poured back into a glass peptide vessel to remove the borane-
THF solution. The resin was then thoroughly washed with THF (ꢃ3) and
MeOH (ꢃ3).
CH), 1.88 (m, 1H, CH), 1.76 (dq, 3JHÀH =7.5, 7.5 Hz, 2H, CH2), 1.65 (m,
1H, CH), 1.38 (t, 3H, CH3), 1.09 (d, 3H, CH3), 1.00 ppm (d, 3H, CH3);
HRMS (ESI): m/z calcd for C17H35N5O3187Re: 544.2298; found: 544.2212
[M]+.
[ReACHTUGNERTN(NNGU 6b)(CO)3] CHTUNRTGENNUG ACTHNGUTREN(NUGN 6c): Purification was carried out by prepara-
+A[CF3CO2]À
tive HPLC (linear gradient of 50 to 90% solvent B in C) and the purity
of the isolated white powder was determined to be 98% by analytical
HPLC (linear gradient 50 to 90% solvent B in C, tR =6.80 min). Yield:
65 mg (10%); 1H NMR (600 MHz, CD3OD): d=7.30–7.18 (m, 5H, CH,
ar), 6.39 (m, 1H, NH), 5.18 (m, 1H, NH), 5.00 (m, 1H, NH), 3.88 (dq,
3JHÀH =6.2, 6.2 Hz, 1H, CH), 3.55 (m, 2H), 3.43 (m, 2H), 3.29 (m, 2H),
3.05 (ddd, 3JHÀH =5.4, 12.0, 12.0 Hz, 1H, CH), 2.92–2.65 (m, 7H), 2.28
(m, 1H, CH), 1.98 (m, 1H, CH), 1.46 (m, 2H), 1.28 (m, 4H, CH and
CH3), 0.89 (d, 3JHÀH =6.2 Hz, 3H, CH3), 0.85 ppm (d, 3JHÀH =6.2 Hz, 3H,
CH3); HRMS (ESI): m/z calcd for C24H40N4O4187Re: 635.2607; found:
635.2640 [M]+.
Oxidative work-up procedure A (compounds 3 and 7): A buffered THF
solution (7:2:1, THF/AcOH/DIPEA) was added to a peptide vessel con-
taining the reduced diamine species attached to the trityl support in a
volume of 10 mL per every gram of resin utilised. This was followed by
the addition of iodine (5 equiv per amine) as a concentrated THF solu-
tion. The vessel was placed on an orbital for 4 h, after which the resin
was rinsed extensively with THF (ꢃ3), 1:3 NEt3/DMF (ꢃ3), MeOH (ꢃ3)
and CH2Cl2 (ꢃ3). At this point, a micro-cleavage was performed to check
the purity of the reduced peptides by HPLC-MS.
[ReACHTUGNERTN(NNGU 7b)(CO)3] CHTUNRTGENNUG ACTHNGUTREN(NUGN 7c): Purification was carried out by prepara-
+A[CF3CO2]À
tive HPLC (linear gradient of 30 to 60% solvent B in C) and the purity
of the isolated white powder was determined to be 99% by analytical
HPLC (linear gradient 10 to 80% solvent A in C, tR =10.6 min). Yield:
49 mg (8%); 1H NMR (600 MHz, CD3OD): d=7.31–7.19 (m, 5H, CH,
ar), 6.39 (m, 1H, NH), 5.24 (m, 1H, NH), 5.05 (m, 1H, NH), 3.72 (m,
2H), 3.64 (m, 1H, CH), 3.58 (m, 2H), 3.51 (m, 1H, CH), 3.44 (m, 2H),
3.35 (m, 1H, CH), 3.26 (m, 1H, CH), 3.14 (m, 2H), 3.00 (m, 1H, CH),
2.82 (m, 1H, CH), 2.72 (m, 4H), 2.24 (m, 1H, CH), 2.01 (m, 1H, CH),
1.91 (m, 3H), 1.56 (m, 1H, CH), 1.51 ppm (m, 2H); HRMS (ESI): m/z
calcd for C23H38N4O5187Re: 635.2400; found: 635.2372 [M]+.
Oxidative work-up procedure B (compounds 4, 5, 6 and 7): After rinsing,
the resin was then placed into a round-bottom flask, followed by the ad-
dition of piperidine (30 mL). The reaction mixture was subsequently
heated to 658C and stirred for 12 h. The heterogeneous solution was then
poured back into a peptide vessel, where it was drained and the resin
was rinsed with THF (ꢃ3), MeOH (ꢃ3), CH2Cl2 (ꢃ3) and DMF (ꢃ3).
Again, a micro-cleavage was performed by treatment with 50:50, TFA/
CH2Cl2 for 3 h to determine reaction progression and purity by HPLC-
MS analysis.
General rhenium coordination on-resin procedure: The resin containing
the reduced peptide was placed in a round-bottom flask with methanol
(6 mL) and DMF (6 mL), followed by the addition of NEt3 (209 mL,
1.5 equiv). The [NEt4]2[Re(CO)3(Br)3] (1.1 equiv) was dissolved in
a
50:50 solvent ratio of MeOH/DMF (8 mL) and then added to the reac-
tion mixture. The heterogeneous solution was stirred at 658C for 4 h, at
which time the contents of the flask were poured into a peptide vessel
where the resin was rinsed extensively with MeOH (ꢃ3) and DMF (ꢃ3).
A micro-cleavage was performed where a small portion of peptide was
deprotected and cleaved from the resin by treatment with 50:50, TFA/
CH2Cl2 for 3 h to determine reaction progression and purity by HPLC-
MS analysis.
Acknowledgements
Financial assistance was gratefully received from the Natural Sciences
and Engineering Research Council (NSERC) of Canada and the Ministry
of Research and Innovation of Ontario, through an Early Researcher
Award.
[ReACHTUNGTRENNUNG(3b)(CO)3] CHTUNGTRENNUNG ACHTNGUTREN(NUGN 3c): Purification was carried out by prepara-
+A[CF3CO2]À
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of the isolated yellow oil was determined to be 92% by analytical HPLC
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(3%);1H NMR (600 MHz, CD3OD): d=7.34–7.25 (m, 5H, CH, ar), 6.45
(m, 1H, NH), 5.13 (m, 1H, NH), 4.90 (m, 1H, NH), 3.56 (m, 1H, CH),
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Synthesis of Rhenium-Centric Reverse Turn Mimics
FULL PAPER
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Received: May 18, 2012
Published online: && &&, 0000
Chem. Eur. J. 2012, 00, 0 – 0
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
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L. G. Luyt and J. L. Hickey
Redefining chemical space: Molecular
scaffolds have been shown to facilitate
and stabilise 28 structural turn ele-
ments, with a central core arranging
functionality in a defined 3-dimen-
sional orientation. By utilising a
Peptidomimetics
J. L. Hickey, L. G. Luyt* . . . &&&& — &&&&
Synthesis of Rhenium-Centric Reverse
Turn Mimics
+
Re(CO)3 centre (see figure), we have
demonstrated that amino acid sequen-
ces can be assembled, reduced and
coordinated on-resin, resulting in a
diverse set of turn-based peptidomi-
metics.
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ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 0000, 00, 0 – 0
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These are not the final page numbers!