Atomic Insight on Inhibition of Fibrillization of Dipeptides by Replacement of Phenylalanine with Tryptophan.

Tryptophan (Trp) conjugates destabilize amyloid fibrils responsible for amyloidoses. However, the mechanism of such destabilization is obscure. Herein the self-assembly of four synthesized Trp-containing dipeptides Boc-xxx-Trp-OMe (xxx: Val, Leu, Ile, and Phe) has been investigated and compared with the existing report on their Phe congeners. Two among them are the C-terminal tryptophan analogs of Boc-Val-Phe-OMe (VF, Aß18-19) and Boc-Phe-Phe-OMe (FF, Aß19-20), part of the central hydrophobic region of amyloid-ß (Aß1-42). While Boc-Val-Trp-OMe (VW), Boc-Leu-Trp-OMe (LW), Boc-Ile-Trp-OMe (IW), and Boc-Phe-Trp-OMe (FW) displayed a spherical morphology in FESEM and AFM images, the corresponding phenylalanine-containing dipeptides displayed various fibrous structures. Single-crystal X-ray diffraction (SC-XRD) indicated that peptides VW and IW exhibited structures containing parallel ß-sheet, cross-ß-structure, sheet-like layer structure, and helical arrangement in the solid state. Interestingly, peptide FW displayed inverse γ-turn conformation (similar to open-turn structure), antiparallel ß-sheet structure, columnar structure, supramolecular nanozipper structure, sheet-like layer arrangement, and helical architecture in the solid state. The open-turn conformation and nanozipper structure formation by FW may be the first example of a dipeptide that forms such structures. The minute but consistent differences in molecular packing at the atomic level between Trp and Phe congeners may be responsible for their remarkably different supramolecular structure generation. This molecular-level structural analysis may be helpful for the de novo design of peptide nanostructures and therapeutics. Similar studies by the Debasish Haldar group are reported, but they investigated the inhibition of fibrillization of dipeptides by tyrosine and interactions are expectedly different.

Unprecedented C-C Bond Formation via Ipso Nucleophilic Substitution of 2,4-Dinitrobenzene Sulfonic Acid with Active Methylene Compounds.

The sulfonic acid functionalization of sufficiently electron-deficient benzene sulfonic acids undergoes ipso nucleophilic substitution with various active methylene compounds, leading to new C-C bond formation. Good to excellent yields are obtained under mild conditions without transition-metal (Pd or Cu) catalyst, PTC, and ligand. No solid waste is generated. It is a highly effective strategy for incorporating various active methylene compounds into the o-nitro-substituted benzene ring. This method has been applied not only for synthesizing APIs but also in materials chemistry. It shows a novel route for creating heavily crowded all-carbon quaternary centers. Carbon-carbon bond formation by substituting a sulfonic acid group was unknown.

Protecting Group-Directed Diversity in the Morphology of Self-Assembled Ant-Aib Dipeptides: Garland-Like Architecture and Nanovesicle Formation.

The morphology and molecular organization of a set of different N-terminal protecting groups containing dipeptides were investigated. The dipeptides consisted of two rigid noncanonical amino acids, Ant and Aib (X-Ant-Aib-OMe; Ant: anthranilic acid and 2-aminobenzoic acid, Aib: 2-aminoisobutyric acid). The change of the N-terminal protecting groups (X = Boc (peptide 1), Nα-fluorenylmethoxycarbonyl (Fmoc) (peptide 2), o-NBS (peptide 3), and p-NBS (peptide 4); NBS = nitrobenzyl sulfonyl group) displayed a characteristic morphological variety. Field emission scanning electron microscopy (FE-SEM), transmission electron microscopy (TEM), and atomic force microscopy (AFM) experiments suggested that while t-butyloxycarbonyl (Boc) and p-NBS containing peptides exhibited distinct rod-like fiber structures, Fmoc and o-NBS containing peptides displayed remarkable vesicular structures. FE-SEM and thermogravimetric analysis (TGA) suggested that peptide nanostructures demonstrated excellent thermal stability in dry conditions. Interestingly, peptides 2 and 4 exhibited a type-III N2 gas adsorption isotherm. Fluorescence microscopy analysis revealed that nanovesicles formed by peptides 2 and 3 have drug encapsulation properties exemplified by curcumin, rhodamine B, and carboxyfluorescein. These results will help in designing peptide-based nanomaterials for diverse applications.

FeCl3-Mediated Side Chain Modification of Aspartic Acid- and Glutamic Acid-Containing Peptides on a Solid Support.

An efficient, convenient, and selective Lewis acid-based strategy for on-resin deprotection of the side chain tert-butyl-protected aspartic acid and glutamic acid of a peptide is achieved. The method is mild, cost-effective, and Fmoc chemistry compatible and allows on-resin incorporation of amides, esters, and thioesters in good yield. This method will find wide applicability in peptide and protein modification because it enriches the toolbox of orthogonal protection/deprotection techniques.