Synthesis of peptoid based small molecular gelators by a multiple component reaction

Article abstract of DOI:10.1039/c3cc41043a

We report the synthesis and self-assembling properties of a new class of tripeptoids synthesized by a one-pot Ugi reaction from simple starting materials. Among the focused library of tripeptoids synthesized, several efficient low molecular weight gelators were obtained for aqueous DMSO and ethanol mixtures.

Full text of DOI:10.1039/c3cc41043a

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Synthesis of peptoid based small molecular gelators by
a multiple component reaction†
Cite this: DOI: 10.1039/c3cc41043a
Hari P. R. Mangunuru,a Hao Yangb and Guijun Wang*a
Received 6th February 2013,
Accepted 7th March 2013
DOI: 10.1039/c3cc41043a
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We report the synthesis and self-assembling properties of a new intrinsic problems such as rapid clearance or degradation by
class of tripeptoids synthesized by a one-pot Ugi reaction from proteases. Therefore, peptidomimetic organo/hydrogelators
simple starting materials. Among the focused library of tripeptoids that contain certain structural features of the peptides but
synthesized, several efficient low molecular weight gelators were can withstand proteolysis will have profound applications in
obtained for aqueous DMSO and ethanol mixtures.
obtaining stimuli responsive advanced materials.
Among peptidomimetics, peptoids have been shown to be
Low molecular weight gelators (LMWGs) are small molecules able to self-assemble and form fibrous networks37 and recently
that can self-assemble in organic solvents or water and form a few octa-peptoid–peptide hybrids have been shown to func-
typically fibrous supramolecular architectures that immobilize tion as hydrogelators.38 Facile synthesis of simple peptoids that
the solvents.1–5 The driving forces for supramolecular gelation are more resistant to degradation and able to form suitable self-
are non-covalent forces such as hydrogen bonding, hydrophobic assembled structures will be a valuable endeavor. In this study,
interactions, p–p stacking, and van der Waals interactions, etc. we have designed and synthesized a small library of tripeptoids
Because gelation by LMWGs occurs through non-covalent inter- using simple building blocks by Ugi reaction. The multiple
actions, the process is typically reversible. Small molecule self- component reactions (MCRs) are useful for generating a diverse
assembly has shown great promise as a ‘‘bottom up’’ approach for array of compounds and for analyzing their properties. To the
preparing novel functional materials.6–12 The three-dimensional best of our knowledge, so far Ugi reaction has not been used in
networks formed by LMWGs are useful new materials with designing new types of small molecular gelators, though there
applications in various fields, including enzyme immobilization have been studies using the reaction in the modification of
and organocatalysis,6–7 tissue engineering and drug delivery polymer gelators.39–40
systems.8–12 Because of these interesting applications, a great deal
As shown in Scheme 1, the Ugi reaction is a very efficient
of effort has been devoted to studying new types of low molecular reaction involving four components in a one pot reaction, in
weight gelators.13–28 The structures of small molecule gelators which an acid, an isocyanide, an aldehyde or ketone and an
encompass a wide range of different functionalities. Several amine condense into a tripeptoid, 1.41 The reactions are carried
classes of organic compounds have been found to be useful out under mild conditions and usually give high yields. The
building blocks for the design and synthesis of LMWGs, these tripeptoids obtained are analogous to tripeptides. This is an
include amino acids, sugars, cholesterols, amides, and ureas.13–28 ideal reaction for exploring the structure diversity and to dis-
Gelators obtained from bio-based starting materials such as cover novel scaffolds for drugs or new materials.
amino acids and carbohydrates will in general produce bio-
For this study, we selected the readily available amines and
compatible materials or degradation products. Peptide based carboxylic acids (2–10) as the building blocks for the Ugi
hydrogelators have been extensively studied and have shown reaction, as shown in Fig. 1. In order to simplify product
great promise in tissue engineering and drug delivery.29–36 purification, formaldehyde was chosen as the aldehyde compo-
However, peptides are endogenous compounds that are essen- nent, which can produce a glycine unit in the product. Among
tial for many biological processes, and they suffer from the various building blocks, the isocyanide component is the
a Department of Chemistry and Biochemistry, Old Dominion University, Norfolk,
VA 23529, USA. E-mail: g1wang@odu.edu; Fax: +1 7576834628; Tel: +1 7576833781
b School of Medicine at Washington University in St. Louis, Division of
Radiological Sciences, St. Louis, Missouri, USA. E-mail: yangh@mir.wustl.edu
† Electronic supplementary information (ESI) available: The experimental proce-
dure and characterization data of compounds 14–26. See DOI: 10.1039/c3cc41043a
Scheme 1 Ugi one-pot four component reaction.
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Fig. 1 Structure of the starting materials chosen for the MCR reaction.
Fig. 3 Optical micrographs of the gels formed by compounds 18 (a), 26 (b) and
21 (c–f); a–d solvent DMSO : H2O (1 : 2), e and f solvent EtOH : H2O (1 : 2).
gelation. The ethyl glycine series are in general more efficient
gelators than the cyclohexyl series. Among the different amines
used, p-methoxylbenzylamine performed the best, and the
Fig. 2 The structures of peptoids synthesized by a one pot reaction.
least commercially available starting material. We selected protected glucosamine also gave products that are effective
cyclohexyl isocyanide 12, which is based on our finding from gelators; the unsubstituted benzyl group did not perform well.
previous studies that compounds containing a cyclohexyl group Among the different acids used, aryl acids are in general more
are generally effective gelators.25 Ethyl 2-isocyanoacetate 13 was efficient than aliphatic acids, and substituted aryl groups
selected due to the resulting glycine ester products. Protected performed much better than the unsubstituted analogs.
glucosamine 5 was also chosen as the amino building block;
Fig. 3 shows the optical micrographs of several gels. Com-
this can introduce a sugar function into the peptoids. Also in pound 18 formed a gel in DMSO aqueous mixture at 2 wt%,
our previous studies, various glucosamine derivatives have which is not a very efficient gelator, and the gel exhibited rod- or
shown excellent gelation properties and a broad range of sheet-like morphology (Fig. 3a). Compound 26 formed a gel in
substituents can be tolerated.24–25
DMSO–H2O (1: 2) at 0.66 wt%, which is a more efficient gelator,
From these building blocks we synthesized a small library of and the gels formed narrower fibrous networks (Fig. 3b). Com-
peptoids as shown in Fig. 2. The gelation properties of these pound 21 is the most efficient gelator identified in this study,
compounds were then tested in several solvents and the results interestingly the self-assembled structures in both DMSO–H2O
are shown in Table 1.
and EtOH–H2O appeared as very long and uniform fibrous
Only two aliphatic acid derivatives 14 and 15 are synthesized assemblies. The DMSO–H2O gel on the edge appeared to form
here. The rest of the compounds contain two aromatic groups in a cluster of aligned fibers bundled together during the drying
their structures, and these will introduce the aryl–aryl inter- process while in the middle of the sample showed more sepa-
action, which is an important factor in hydrogelator designs.
rated fibers (Fig. 3c and d). The EtOH–H2O gel showed more
From Table 1 we can see that a majority of these compounds uniform fibrous structures with an average diameter of 0.5 mm
were able to form gels in at least one of the tested solvents, and over 300 mm in length (Fig. 3e and f). The morphology study
several compounds turned out to be efficient gelators for indicated that there is a certain correlation between the gelation
ethanol aqueous solutions and DMSO aqueous solutions. The efficiency and the fibrous assemblies.
gels are thermoreversible. The best performing compound
In summary, we have designed and synthesized a series of
is 21, which forms gels at 0.2 wt% in a DMSO–water (1 : 2) low molecular weight peptoids by a one-pot Ugi reaction and
mixture. A general trend for these compounds is that branching obtained several effective organo/hydrogelators. These compounds
or substitutions on the aryl group are generally necessary for represent a new class of organo/hydrogelators and can have
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Table 1 Gelation test results for the library compounds
Compound
Hexane
Water
EtOH
EtOH : H2O (1 : 1)
EtOH : H2O (1 : 2)
DMSO : H2O (1 : 1)
DMSO : H2O (1 : 2)
14
15
16
17
18
19
20
21
22
23
24
25
26
I
P
I
I
I
S
P
I
S
I
P
P
I
P
S
I
S
P
P
S
P
S
P
S
P
P
P
S
P
G 20.0
P
P
P
P
P
G 2.8
P
P
G 20.0
G 20.0
G 10.0
G 20.0
P
G 20.0
P
G 5.0
G 10.0
P
G 6.6
G 2.0
P
G 20.0
P
P
P
P
P
S
S
S
I
G 20.0
G 20.0
P
G 10.0
G 5.0
P
G10.0
G 20.0
G 20.0
G 5.0
G 2.5
S
G 20.0
P
S
G 20.0
G 20.0
I
P
P
P
P
I
P
G 20.0
G 20.0
G 20.0
G 10.0
P
G 6.6
G, gel at room temperature, the numbers are the corresponding minimum gelation concentrations (MGCs) in mg mLÀ1; I, insoluble;
P, precipitating; S, soluble at B20 mg mLÀ1; the ratios for mixed solvents are volume : volume ratios.
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Using MCRs to discover low molecular weight gelators is a valid
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the resulting peptoid gels would be more resistant to peptidases
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This work was supported by a grant from NSF CHE 1153129.
We also thank Dr Patrick Hatcher and Susan Hatcher at
COSMIC of ODU for their help with Mass spectrometry and
NMR access.
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