A Quaternary Nitronyl Nitroxide α‐Amino Acid: Synthesis, Configurational and Conformational Assignments, and Physicochemical Properties

Abstract

To expand the presently extremely limited repertoire of known nitronyl nitroxide α‐amino acids, we report here the synthesis of a novel, conformationally constrained, quaternary, chiral residue, Aic(CN), and its subsequent conversion into a blue‐colored, imidazolinyl nitronyl nitroxide‐bearing α‐amino acid, Aic(NN). Deprotection and peptide coupling reactions were examined. The configurational assignment of Aic(NN) was achieved by X‐ray crystallographic analysis of an appropriate tripeptide. This latter investigation, accompanied by an IR absorption conformational analysis, strongly supports the view that the Aic(NN) residue is an efficient peptide turn former. Numerous spectroscopic and magnetic properties of its derivatives and the tripeptide are also described. Of particular relevance for future applications are its UV/Vis absorption, NMR, and EPR signatures.

Synthesis of Intrinsically Blue-Colored bis-Nitronyl Nitroxide Peptidomimetic Templates and Their Conformational Preferences as Revealed by a Combined Spectroscopic Analysis

“…The synthesis in solution of the bis -Aic­(NN)-containing penta- and hexapeptides was performed from their respective synthetic precursors, each with two Aic­(CN) units. While it is feasible to exploit the Aic­(NN) residue directly in peptide synthesis, the acid- and light-sensitive nature of the nitronyl nitroxide radicals makes the use of its Aic­(CN) precursor more straightforward for this purpose . The coupling reagent O -(7-azabenzo-1,2,3-triazol-1-yl)-1,1,3,3-tetramethyluronium (HATU) hexafluorophosphate was used to synthesize the Aic­(CN)-based peptides in a stepwise manner.…”

“…Despite the severe steric hindrance of the Aic­(CN) residue, the coupling reactions resulted in moderate to good yields (61% for the tetra-, 66% for the penta-, and 54% for the hexapeptides). Syntheses and characterizations of the di- and tripeptides were already reported . Details of the synthetic strategy employed to obtain the tetra-, penta-, and hexapeptides are outlined in Scheme .…”

“…(A) FT-IR absorption spectra of the Boc-Ala-( R )-Aic­(NN)-Ala-OMe tripeptide (- · -) (taken from ref ), the bis -( R )-Aic­(NN) pentapeptide (---), and the bis -( R )-Aic­(NN) hexapeptide (−) in CDCl 3 solution in the amide N–H stretching region. The vertical scale is deliberately not reported to give particular emphasis to the ratios between the areas under the two peaks of each curve.…”

Nitroxide radicals appended to phthalonitriles: synthesis, structural characterization and photophysical properties

“…Among nitroxides, nitronyl (NN) and imino nitroxide (IN) radicals are proven to be a versatile family of spin labels as NNs are transformed into INs by reactive radicals generated in biological processes or decay completely to diamagnetic species; both cases can be easily monitored thanks to distinctive pattern in their EPR spectra (Joseph et al, 1993;Rosen et al, 2003;Medvedeva et al, 2004;Samuni et al, 2010;Wang et al, 2011;Sousa et al, 2016). NN and IN based spin probes are ideally suited for investigating the dynamic aspects of molecular interactions because of their covalent incorporation into biologically critical architectures (Okamoto et al, 2005;Ise et al, 2006;Tanaka et al, 2007;Maekawa et al, 2007Maekawa et al, , 2010Atsumi et al, 2012;Wright et al, 2014;De Zotti et al, 2017) and noncovalent interactions (Nakabayashi et al, 2007;Peresypkina et al, 2010;Vostrikova et al, 2011;Kobayashi et al, 2014Kobayashi et al, , 2018Strizhakov et al, 2014). On the other hand, nitrile-containing compounds are known to form protein-ligand interactions by hydrogen bonding, hydrophobic interactions and covalent bonding with numerous protein residues (Wang et al, 2018).…”

Conformational studies on peptides having dipropylglycine (Dpg) or 1‐aminocycloheptanecarboxylic acid (Ac7c) within the sequence of l‐leucine (Leu) residues

“…α,α‐Disubstituted α‐amino acids (dAAs), which have an additional substituent instead of α‐hydrogen in the α‐amino acid, have been shown to stabilize peptide secondary structures by introducing them into peptide sequences composed of natural α‐amino acids . Concerted efforts have been made to develop novel dAAs and conduct conformational studies on dAA‐containing peptides . Strategies to fix peptide secondary structures, such as those involving helical structures, are promising for the design of functional peptides.…”