Synthesis and Self-assembly of Peptide Mimetics

Roy Chowdhury, Srayoshi (2023) Synthesis and Self-assembly of Peptide Mimetics. PhD thesis, Indian Institute of Science Education and Research Kolkata.

Text (PhD thesis of Srayoshi Roy Chowdhury (15IP012)) 15IP012.pdf - Submitted Version Restricted to Repository staff only Download (17MB)

Abstract

This thesis entitled as “Synthesis and self-assembly of peptide mimetics” is all about the design, synthesis, characterization, conformational analysis, self-assembly and application of peptide based molecules using proteinogenic and / or non-coded amino acids. The main focus of this thesis is to develop synthetic peptides or Peptide mimetics composed of both genetically coded and non-coded amino acids for studying and understanding the molecular self-assembly processes of these peptides in supramolecular helices, sheets and to study their further aggregation behavior in forming gels or nanomaterials like tube, vesicle, fibre, porous structure and their versatile applications in several fields. Here, we have designed and synthesized a γ-turn mimetic using fenamic acid and α-aminoisobutyric acid (Aib), and also study the conformation and optoelectronic properties which can be changed by appropriate external stimuli. From single-crystal X-ray diffraction analysis, the compound has a kink-like conformation that is stabilized by a six-membered intramolecular N–H⋯O=C hydrogen bond. The γ-turn mimetic 1 molecules self-assemble via intermolecular N–H⋯O hydrogen bonds to form chains extending in the c-direction. The γ-turn mimetic 1 further assembled to form a complex sheet-like structure through multiple π–π stacking interactions along the crystallographic a and c directions. The γ-turn mimetic compound selectively recognizes Cu(II) over Cu(I) and others like Ni(II), Pb(II), Mg(II), Zn(II), Mn(II), Co(II), Fe(III), and As(III), with a distinct colour change. In situ oxidation of Cu(I) with an oxidizing agent such as H2O2 exhibits the same effect as that of Cu(II). Interestingly, the brown colour of the complex turned colourless by elimination of Cu(II) via reduction to Cu(I) using ascorbic acid. Based on this reversible selective Cu(II) sensing event, we have developed a combinatorial multiple logic gate. The thesis also represents the effect of fenamic acid−α-aminoisobutyric acid as a corner motif in α,β,γ-hybrid peptides. From X-ray single-crystal diffraction studies, it is observed that Phe-containing peptide 1 has an “S”-shaped conformation that is stabilized by two consecutive intramolecular N−H···N hydrogen bonds. However, the tyrosine analogue peptide 2 has an “S”-shaped conformation, which is stabilized by consecutive intramolecular six-member N−H···N and seven-member N−H···O hydrogen bonds. The asymmetric unit of peptide 3 containing m-aminobenzoic acid has two molecules which are stabilized by multiple intermolecular hydrogen-bonding interactions. There are also π−π stacking interactions between the aromatic rings of fenamic acid. The peptides 1 and 2 have polydisperse microsphere morphology, but peptide 3 has an entangled fiber like morphology. Peptides 1−3 do not form organogels. However, in the presence of water, the peptide 3 forms a phase-selective instant gel in xylene. The gel exhibits high stability and thermal reversibility. The phase-selective gel of peptide 3 is highly responsive to H₂SO₄. The thesis includes the formation of supramolecular polymer by non-covalent interactions between complementary building blocks entraps solvents and develops supramolecular polymer gel. A supramolecular polymer gel was prepared by the heating-cooling cycle of β-cyclodextrin (β-CD) and naphthalenediimide (NDI) solution in N,N-dimethylformamide (DMF). The host-guest inclusion complex of β-CD and NDI 1 containing dodecyl amine forms the supramolecular polymer and gel in DMF. However, β-CD and NDI 2, having glutamic acid, fail to form the supramolecular polymer and gel under the same condition. X-ray crystallography shows that the alkyl chains of NDI 1 are complementary to the hydrophobic cavity of the two β-CD units. From rheology, the storage modulus was approximately 1.5 orders of magnitude larger than the loss modulus, which indicates the physical crosslink and elastic nature of the thermo-responsive gel. FE-SEM images of the supramolecular polymer gel exhibit flake-like morphology and a dense flake network. The flakes developed from the assembly of smaller rods. Photophysical studies show that the host-guest complex formation and gelation have significantly enhanced emission intensity with a new hump at 550 nm. Upon excitation by a 366 nm UV-light, NDI 1 and β-CD gel in DMF shows white light emission. The gel has the potential for the fabrication of organic electronic devices. The thesis also describes that the molecular conformations, the three dimensional structure of geometrically rigid compound is highly important for study the recognition and assembly process and has wide application in medicine and material science. A novel series of discotic compounds containing benzoic acid, m-dibenzoic acid, benzene 1,3,5-tricarboxylic acid were designed with increasing hydrophobicity. The orientation of the amide bonds with respect to central aromatic core yielded variation of structure and self-assembly propensities of the compounds. The aggregation behavior of the compounds has studied by various spectroscopic techniques. The morphology of the resulting aggregates was studied by polar optical microscopy and field emission electron microscopy. From X-ray single-crystal diffraction analysis, it is observed that N,N'-dicyclohexylurea containing compound 3 has a “bowl”-shaped conformation and self-assembled to form supramolecular honeycomb-like framework that is stabilized by multiple intermolecular hydrogen bonds. However, the compound 2 has a kink-like conformation and self-assembled to form sheet-like structure stabilized by multiple intermolecular hydrogen bonds. These studies exhibited that the orientation of the hydrophobicity has a strong influence on the intermolecular interactions, resulting in huge differences in aggregation propensities, and morphology of the discotic peptides. The thesis also discusses a sustainable approach for C−C cross-coupling reaction at room temperature in water and to avoid tedious Pd separation, reduce the carbon footprint, and save energy. Another important aspect is the catalyst recycling and easy product separation. α,γ-Hybrid peptides were designed to selectively use as a ligand for C−C cross-coupling catalysts as well as to form organogels. The peptides form antiparallel sheet-like structures in the solid state. The peptide containing m-aminobenzoic acid, glycine, and dimethylamine forms a whitish gel in toluene, and co-gelation with Pd(OAc)₂ results in light brown gel, which acts as a biphasic catalyst for Suzuki−Miyaura cross-coupling at room temperature in water by mild shaking. The organic−inorganic hybrid gel was characterized by rheology, field-emission scanning electron microscopy, transmission electron microscopy, and energy-dispersive X-ray analyses. On completion of the cross-coupling reaction, the basic aqueous layer (containing products) above the gel can be simply decanted and the intact organic−inorganic hybrid gel can be recycled by topping-up fresh reactants multiple times. The reaction permitted a range of different substitution patterns for aryl and heterocyclic halides with acid or phenol functional groups. Both electron-donating- and electron-withdrawing-substituted substrates exhibited good results for this transformation. The findings inspire toward a holistic green technology for Suzuki−Miyaura coupling reaction and an innovative avenue for catalyst recycling and product isolation.

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