Foldamers from Aromatic Amino Acid: Structure and Function

Joseph, Ibukun Olamilekan (2023) Foldamers from Aromatic Amino Acid: Structure and Function. PhD thesis, Indian Institute of Science Education and Research Kolkata.

Text (PhD thesis of Ibukun Olamilekan Joseph (19RS076)) 19RS076.pdf - Submitted Version Restricted to Repository staff only Download (17MB)

Abstract

This thesis entitled as “Foldamers from Aromatic Amino Acid: Structure and Function” 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 are (i) to develop synthetic peptides or peptide mimetics composed of both genetically coded and non-coded amino acids (ii) to studying and understanding the molecular self-assembly processes of these peptides in supramolecular helices, sheets (iii) to study their further aggregation behavior in forming gels or nanomaterials like tube, vesicle, fibre, porous structure (iv) and explore the material properties of the foldamers containing non-coded amino acids. Here, we have designed and synthesized a supramolecular microtube by self-assembly of a co-drug and antifungal activities against Saccharomyces cerevisiae. Benzotriazole esters have been reported to work as inactivators for severe acute respiratory syndrome (SARS) 3CL protease. A well-known calcium channel blocker m-Nifedipine and benzotriazole esters were combined to synthesized co-drug m-Nifedipine-3-benzotriazol-1-yl-ester. The single-crystal Xray diffraction study shows that there are two molecules with opposite chirality in the asymmetric unit. Intramolecular π-π stacking interactions stabilize the tripod shape compound 1 molecules. In higher-order assembly, compound 1 molecules are assembled by intermolecular hydrogen bonding, maintaining a proper registry to form a supramolecular nanotube-like structure. Moreover, compound 1 inhibits the growth of the Saccharomyces cerevisiae. The minimal inhibitory concentration (MIC) against the Saccharomyces cerevisiae was 10 μg/mL. The docking studies indicate that compound 1 has a strong affinity (binding energy -8.67 kcal/mol) for the enzyme lanosterol 14α-demethylase of the Saccharomyces cerevisiae. The compound 1 binds to Leu58 and Ser50 of lanosterol 14α-demethylase through intermolecular hydrogen bonding interactions. The thesis includes a simple protocol for the synthesis of ferrocene substituted benzoic acid and an efficient synthetic approach towards ferrocene appended peptide mimetic with a high reaction rate, yields and purity. From X-ray single crystal analysis, the ferrocene appended peptide mimetic adopts an extended conformation and self-aggregate to form dimer structure by intermolecular hydrogen bonds. The dimer formation is also supported by mass spectrometry. In higher order packing, the dimeric subunits further self-assembled to form a complex sheet-like structure stabilized by multiple π-π stacking interactions between phenyl and cyclopentandienyl ring of ferrocene. Moreover, the ferrocene appended peptide mimetic forms stimuli-responsive metallogel in DMF-water. The rheology experiments support the formation of strong gel. The metallogel burst on addition of other salt such as Cu(OAc)₂.4H₂O, Pb(OAc)₂, Zn(OAc)₂.2H₂O, Cd(OAc)₂.4H2O, Mn(OAc)₂.4H₂O. The thesis also represents the first example of an iodine supported glycosidase activity with an enzyme mimic at room temperature. Glycoside hydrolases are ubiquitous in nature as intracellular or extracellular enzymes that are largely involved in nutrient acquisition. In E. coli bacteria, glycoside hydrolases are the enzyme beta-galactosidase (LacZ), which is involved in regulation of expression of the lac operon. An enzyme mimetic tetrapeptide was designed and synthesized containing L-phenylalanine, ⍺-aminoisobutyric acid (Aib), L-leucine and m-Nifedipine. From X-ray crystallography, the peptide adopts a -hairpin conformation. The β-hairpin structure is stabilized by two 10-members and one 18-member NH…O=C hydrogen bonds. Moreover, the peptide was found to be highly efficient to hydrolases ethers and glycosides in presence of iodine. From X-ray crystallography, the backbone conformation of the enzyme mimetic is almost unchanged after the glycosidases reaction. The thesis also describes the effect of spacers on the structure and self-assembly of the compounds. We have designed and synthesized a series of FF peptide mimetic with conformationally rigid and flexible spacers to study the effect of spacers on the structure and self-assembly of the compounds. From X-ray single crystal analysis, the m-diamino benzene appended FF peptide mimetic adopts a duplex structure stabilized by multiple intermolecular hydrogen bond. There is also a water molecule bridging between two strands of the duplex. Moreover, the duplex is stabilized by three face-to-face, face-to-edge and edge-to-edge π–π interactions. The duplex formation is also supported by mass spectrometry. In higher order packing, the dimmeric subunits further self-assembled to form a complex she t-like structure stabilized by multiple intermolecular hydrogen bonding and π-π stacking interactions. Moreover, the 1,4 butadine and m-xylylenediamine appended FF peptide mimetics forms stimuli-responsive organogel in wide range of organic solvents including methanol. The rheology experiments of FF peptide mimetics gel as a function of angular frequency and oscillatory strain also supported the formation of strong physical crosslink gel. The SE-FEM images of the xerogel obtained from different organic solvents show that depending on the nature of the solvents, the network morphology of FF peptide mimetics varies from solvent to solvent. The thesis also discusses nanogenerator from self-assembly of m-Nifedipine appended perylene derivative. From emission spectroscopy, as concentration increases, the emission intensity of the perylene derivative increases with the peak shifting from 575 nm to 578 nm. From FE-SEM, the perylene derivative nanospheres morphology. The average diameter of the nanospheres is 200 nm. The nanospheres further aggregated to form flakes like structures. Using diverse experimental techniques, we demonstrate that the compound exhibit excellent piezoelectric properties. The output open-circuit voltage (Voc) for the device reached 2.5 V under an applied force of 25 N, comparable to those produced with nanogenerators made up of organic polymers or inorganic materials.

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