Molecular engineering of tyrosine and tyrosine derived peptides to produce organogel

https://doi.org/10.1016/j.colcom.2020.100270Get rights and content

Highlights

  • •

    Molecular engineering concept was applied to convert nongelator tyrosine derivatives into gelators.

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    Incorporation of a nitro group was sufficient enough to convert tyrosine into a gelator.

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    The effect of a nitro was found to be so effective that it can gellify a rigid tripeptide also.

  • •

    pH responsive organogels were developed.

Abstract

This present work deals with the synthesis of a series of organogel derived from substituted tyrosine derivatives via applying the concept of molecular engineering. Phenylalanine and tyrosine are structurally very similar amino acids. But only phenylalanine forms gels in both water and organic solvents. That is why the challenge was taken to transform tyrosine into a gelator and the concept of molecular engineering was applied. It was observed that a single nitro group is sufficient enough to transform it into a gelator. Not only a Boc-protected amino acid but also dipeptide and tripeptide were also found to produce organogel. Theoretical studies were also performed to understand the interactions involved during the gelation process. The gels derived from 1, 2, and 4 were found to be responsive towards a strong base like hydroxide which also helped us to get information regarding the gel model.

Introduction

The self-assembly of peptide-based materials with rationally designed structural framework has received great attention in recent years [[1], [2], [3], [4]]. A gel is a very common example of self-assembly shown by peptide-based materials [[5], [6], [7], [8], [9], [10], [11]]. Gels can be derived from large polypeptide as well as low molecular weight oligopeptide or amino acid-based materials. Among these peptide-based materials, small-molecule peptide hydrogels i.e. supramolecular gels are extremely attractive as potential biomaterials [51] in various applications including tissue engineering [[12], [13], [14], [15]], drug delivery [[16], [17], [18], [19]], enzyme assay [20,21], protein separation [22], biosensors [[23], [24], [25]] and wound healing [26]. Generally in supramolecular gelation, gelator molecules are self-assembled into nanoscale fibrils in a particular solvent. Then these nanoscale fibrils further self-assemble to produce fibers. These fibers then create a three-dimensional network where solvent molecules are trapped in this network to produce supramolecular gels [27]. There are various non-covalent interactions such as hydrogen bonding, π-π stacking, hydrophobic interactions, and electrostatic interactions which are the driving force behind this supramolecular gel formation [28]. The growing interest in designing low molecular weight supramolecular gel lies in its responsiveness towards various stimuli like pH, temperature, ionic strength, etc. Various stimuli-responsive supramolecular gels have been reported by various researchers across the world [[42], [43], [44], [45], [46], [47]]. This is an active field and still, scientists are involved in designing various stimuli-responsive gels.

Though there has been significant progress in designing various kinds of new gelators, still scientific community is not sure enough to predict whether a compound will surely form a gel or not. The scenario is more complicated in the case of low molecular weight gelators. Because in the case of polymeric systems or macromolecules, there are several possible interactions to facilitate the gelation process. But for small molecules, there are very few interactions available. It is generally found that only a slight modification of an existing small molecule-based gelator causes the disappearance of the gel-forming tendency. Here we can consider the case of amino acid phenylalanine. Phenylalanine is the only amino acid to form both organogel and hydrogel in its amino acid form [60,61]. In phenylalanine, the benzene ring plays a crucial role in making intermolecular π-π stacking. Intermolecular hydrogen bonding in association with this π-π stacking interaction helps in the gel formation in the case of phenylalanine. In this context tyrosine structurally resembles phenylalanine very much. The only difference between these two amino acids is the presence of a phenolic OH group in tyrosine at 4 position of benzene. But in the case of tyrosine, the additional phenolic OH group is more interested in forming intermolecular hydrogen bond through this OH functional group rather than forming π-π stacking. As a result, tyrosine does not form gel in its amino acid form. So if we can produce gels derived from tyrosine and tyrosine derivatives via some modification, then various useful biomaterials can be derived based on those gels. To fulfill this, the concept of molecular engineering needs to be introduced. And nowadays molecular engineering is gaining immense attention in various fields [29]. It is an emerging field that deals with methods associated with the design and synthesis of new molecules with desirable physical and chemical properties [30]. Molecular engineering can lead to better self-assembled materials with enhanced molecular properties. Molecular engineering is very much interdisciplinary which covers the area of chemistry, chemical engineering, physics, materials science, bioengineering, etc. [[31], [32], [33], [34], [35]] Utilizing the concept of molecular engineering, various polymers [52] have been designed and synthesized which have utilities in various cutting edge applications like photocatalytic water splitting [53]. Various next-generation molecular tectons [54], composite membranes [55], supra-amphiphiles [56], porphyrin [58], etc. are also resulting via utilizing the concept of molecular engineering. Nowadays energy harvesting from nonconventional sources is the prime focus for the scientific community and in this scenario, efficient perovskite solar cells [57] have been synthesized via molecular engineering. Molecular engineering also covers the area of biomedical application. For example, squarene dyes for imaging and photothermal therapy in metastatic breast cancer [59] were developed using molecular engineering. In this context, it is very crucial to utilize the concept of molecular engineering in the area of gels as it can further open the direction to derive various smart gels from nonconventional materials [36]. Molecular engineering concept has been successfully applied in case of tyrosine and tyrosine derivatives. The target was to inhibit the effect of hydrogen bonding based on the phenolic-OH group. For that, a simple modification in the form of attachment of a nitro group adjacent to the phenolic OH group was done because a nitro group is well known to form intramolecular hydrogen bonding with the phenolic OH group. The change was found to be highly effective to convert nongelator tyrosine into a gelator. We have tested the effect of the nitro group in the case of rigid dipeptide and tripeptide also. Surprisingly the effect of the nitro group was found to be positive in terms of gelation for these compounds also. Nowadays the demand for designing various stimuli-responsive materials are increasing for various practical applications [[48], [49], [50]]. Here also all of our synthesized gels show pH-responsive supramolecular gel to sol transformation which can be useful for sensing basic vapors. Various other aspects of these gelation processes have been investigated along with their stimuli-responsive properties.

Section snippets

Materials

All L-amino acids, DCC (N,N′-dicyclohexylcarbodiimide), and HOBt (1-hydroxybenzotriazole) were purchased from Sigma-Aldrich. NaOH, Boc-anhydride, methanol, and 1,4-Dioxane were purchased from Merck chemicals. Ethyl acetate and hexane were purchased from Rankem. TLC silica gel 60 F254 was supplied by Merck. 60–120 silica gel was purchased from SRL Chemicals.

NMR experiments

All NMR spectra were recorded on a JEOL 400 MHz spectrometer at 278 K. At first, the desired amount of sample was weighed in an eppendorf.

Design of gelators

In the introduction, we have already mentioned that though tyrosine structurally resembles phenylalanine very much, it does not form a gel. So, we tried to investigate tyrosine from the ground basis. First of all, we tried to investigate tyrosine by protecting either N-terminal or C-terminal. So Boc-protected tyrosine and methyl ester of tyrosine were tested for gelation. These two compounds represent the non-engineered system. The gelation experiment was tested with a maximum of 50 mg/mL for

Conclusion

So in this present work, we tried to investigate gel on the molecular level. Designing a gelator is always a difficult task. The design process is also highly confusing. Though phenylalanine and tyrosine are structurally very similar, only phenylalanine forms gels. From that point of view, the challenge was taken to transform tyrosine into a gelator. So the concept of molecular engineering was applied. It was observed that a single nitro group is sufficient enough to transform a nongelator into

Declaration of Competing Interest

The authors declare no conflicts of interest.

Acknowledgements

MM thanks CSIR India for the fellowship and IISER Kolkata for the research infrastructure.

CRediT author statemen

Mrittika Mohar: Performed synthesis of gelators, Characterization, Data collection, writing, editing and formatting of final manuscript.

Tanmay Das: Performed the microscopic studies and base responsive study, co-wrote the paper.

Arijit Bag: Performed the theoretical studies, co-wrote the paper.

References (61)

  • X.H. Yan et al.

    Self-assembly and application of diphenylalanine-based nanostructures

    Chem. Soc. Rev.

    (2010)
  • Z.L. Luo et al.

    Designer nanomaterials using chiral self-assembling peptide systems and their emerging benefit for society

    Chem. Soc. Rev.

    (2012)
  • M. Zelzer et al.

    Enzyme responsive materials: design strategies and future developments

    Biomater. Sci.

    (2013)
  • B. Adhikari et al.

    Short peptide based hydrogels: incorporation of graphene into the hydrogel

    Soft Matter

    (2011)
  • E.K. Johnson et al.

    Peptide based low molecular weight gelators

    J. Mater. Chem.

    (2011)
  • A. Baral et al.

    Time-dependent gel to gel transformation of a peptide based supramolecular gelator

    Soft Matter

    (2015)
  • B. Adhikari et al.

    Short-peptide-based hydrogel: a template for the in situ synthesis of fluorescent silver nanoclusters by using sunlight

    Chem. Eur. J.

    (2010)
  • C. Yana et al.

    Rheological properties of peptide-based hydrogels for biomedical and other applications

    Chem. Soc. Rev.

    (2010)
  • R.J. Mart et al.

    Peptide-based stimuli-responsive biomaterials

    Soft Matter

    (2006)
  • A. Baral et al.

    Assembly of an injectable noncytotoxic peptide-based Hydrogelator for sustained release of drugs

    Langmuir

    (2014)
  • K.M. Galler et al.

    Self-assembling multidomain peptide hydrogels: designed susceptibility to enzymatic cleavage allows enhanced cell migration and spreading

    J. Am. Chem. Soc.

    (2010)
  • A. Mahler et al.

    Rigid, self-assembled hydrogel composed of a modified aromatic dipeptide

    Adv. Mater.

    (2006)
  • T.C. Holmes et al.

    Extensive neurite outgrowth and active synapse formation on self-assembling peptide scaffolds

    Proc. Natl. Acad. Sci.

    (2000)
  • L.A. Haines et al.

    Light-activated hydrogel formation via the triggered folding and self-assembly of a designed peptide

    J. Am. Chem. Soc.

    (2005)
  • J. Li et al.

    d-Amino Acids Boost the Selectivity and Confer Supramolecular Hydrogels of a Nonsteroidal Anti-Inflammatory Drug (NSAID)

    J. Am. Chem. Soc.

    (2013)
  • H. Komatsu et al.

    Supramolecular hydrogel exhibiting four basic logic gate functions to fine-tune substance release

    J. Am. Chem. Soc.

    (2009)
  • X. Li et al.

    Multifunctional, biocompatible supramolecular Hydrogelators consist only of nucleobase, amino acid, and glycoside

    J. Am. Chem. Soc.

    (2011)
  • S. Kiyonaka et al.

    Semi-wet peptide/protein array using supramolecular hydrogel

    Nat. Mater.

    (2004)
  • Z. Yang et al.

    Intracellular enzymatic formation of nanofibers results in Hydrogelation and regulated cell death

    Adv. Mater.

    (2007)
  • Y. Gao et al.

    Using supramolecular hydrogels to discover the interactions between proteins and molecular nanofibers of small molecules Chem

    Commun.

    (2012)

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