Ditopic crown ether-guanidinium ion receptors for the molecular recognition of amino acids and small peptides

A series of ditopic synthetic receptors based on a crown ether-guanidinium ion recognition motif is reported. The compounds show binding affinity to selected amino acids, including important neurotransmitters. The effect of the distance of the ammonium and the carboxylate ion, the rigidity of the spacer, and the use of pre-organized pyrrole- and pyrene-guanidinium groups on binding affinity and selectivity are discussed.     

Heteroditopic receptor based on crown ether and cyclen units for the recognition of zwitterionic amino acids

The molecular recognition of five targeted amino acids differing in the nature of the side (R)- group and in the size of the aliphatic chain, glycine (Hgly), phenylalanine (Hphe), glutamic acid (Hglu^?), 4-aminobutyric acid (Hgaba), and 6-aminohexanoic acid (Heahx), has been studied with a new heteroditopic receptor based in two distinct macrocycles, a cyclen and a crown ether moiety. The bismacrocycle L was synthesized via the bis-aminal route allowing to obtain the designed compound in gram scale and in good yield. Protonation constants of L and its binding constants with amino acids were determined by potentiometry in H₂O/MeOH (1:1 v/v) solutions at 298.2 K and I=0.10 mol dm^?3 in NMe₄NO₃. Stronger binding ability of the H_nLⁿ⁺ receptor for α-amino acids, Hgly and Hphen, than for the other studied substrates were found. Structural data derived from NMR studies showed that the binding of α-amino acids result from the cooperative participation of hydrogen bonds between the carboxylate group of amino acids and the polyammonium sites of cyclen, and the ion-dipole interactions between the ammonium group of the amino acids and the oxygen atoms of the crown ether.     

Direct separation of amino acid enantiomers using a chiral crown ether stationary phase. Application to 2-amino-omega-phosphonoalkanoic acids

The resolution of a series of 2-amino-omega-phosphonoalkanoic acid enantiomers using a crown ether chiral stationary phase is described. The method is applicable to other primary amino acid and shows some advantages over chiral derivatization with fluorometric detection. Optical isomers of under 0.5% may be quantified.     

Nanomolar binding of peptides containing noncanonical amino acids by a synthetic receptor

This paper describes the molecular recognition of phenylalanine derivatives and their peptides by the synthetic receptor cucurbit[7]uril (Q7). The 4-tert-butyl and 4-aminomethyl derivatives of phenylalanine (tBuPhe and AMPhe) were identified from a screen to have 20-30-fold higher affinity than phenylalanine for Q7. Placement of these residues at the N-terminus of model tripeptides (X-Gly-Gly), resulted in no change in affinity for tBuPhe-Gly-Gly, but a remarkable 500-fold increase in affinity for AMPhe-Gly-Gly, which bound to Q7 with an equilibrium dissociation constant (K(d)) value of 0.95 nM in neutral phosphate buffer. Structure-activity studies revealed that three functional groups work in a positively cooperative manner to achieve this extraordinary stability (1) the N-terminal ammonium group, (2) the side chain ammonium group, and (3) the peptide backbone. Addition of the aminomethyl group to Phe substantially improved the selectivity for peptide versus amino acid and for an N-terminal vs nonterminal position. Importantly, Q7 binds to N-terminal AMPhe several orders of magnitude more tightly than any of the canonical amino acid residues. The high affinity, single-site selectivity, and small modification in this system make it attractive for the development of minimal affinity tags.     

Luminescent silver nanoparticles stabilised by a crown ether capped with an organometallic cluster

Monolayer-protected clusters of silver have been synthesised by the NaBH₄ reduction of a mixture of silver nitrate and the crown ether (6-mercaptohexyloxy)methyl-15-crown-5, or the triosmium cluster derivative Os₃(μ-H)(CO)₁₀[(6-mercaptohexyloxy)methyl-15-crown-5]. The nanoparticles showed good stability, are soluble in a wide range of organic solvents, and are luminescent.     

Nucleophilicities of amino acids and peptides

The kinetics of the reactions of amino acids with stabilized diarylcarbenium ions (Ar(2)CH(+)) have been studied photometrically in aqueous solution at variable pH. In the range of 10.5 < pH < 12, the amino acids react much faster than the competing nucleophiles hydroxide and water. Though the pK(aH) values of the amino acids vary by almost four units, the nucleophilic reactivities of all primary amino groups differ by less than a factor of 4. The secondary amino group of proline is 10(2) times more reactive, and the thiolate site in cysteine exceeds the reactivities of the primary amino groups by a factor of 10(4). Nucleophilicity parameters N as defined by the correlation log k(20 degrees C) = s(N + E) have been determined in order to include amino acids into the most comprehensive nucleophilicity scales presently available, which provide a direct comparison of n-, pi-, and sigma-nucleophiles.     

Hydrogen-deuterium exchange and selective labeling of deprotonated amino acids and peptides in the gas phase

Hydrogen-deuterium exchange reactions of deprotonated amino acids and small peptides were studied. Selective labeling can be carried out at the alpha-amino group of lysine (2 of 4 labile hydrogens undergo exchange with CF3CH2OD) and the guanidine side chain of arginine (3 of 6 labile hydrogens undergo exchange with CH3CH2OD and C6H5CH2OD). Differential labeling of peptides also was accomplished, and the extent of H/D exchange is dependent on the amino acids which are present as well as their order in the chain.     

The unusually high proton affinity of aza-18-crown-6 ether: implications for the molecular recognition of lysine in peptides by lariat crown ethers

Recent studies have shown that 18-crown-6 ether (18C6) will selectively form adducts in the gas phase with small, lysine containing peptides. The present study extends this work by investigating the ability of aza-18-crown-6 ether (A18C6) and L1 (a simple lariat crown ether derivative of A18C6) to form similar noncovalent adducts with the side chain of lysine in model peptides in the gas phase. The substitution of nitrogen for oxygen greatly increases the proton affinity of A18C6 relative to 18C6 and inhibits the formation of noncovalent adducts with small lysine containing peptides. The proton affinity of A18C6 is determined by the kinetic method to be 250 +/- 1 kcal/mol. This value is much higher than that for diethanolamine (228 kcal/mol) or for 18C6 (231 kcal/mol). This unusually high basicity is rationalized by semi-empirical calculations that suggest a highly symmetrical structure for protonated A18C6 in which the three most distant oxygens are able to fold back and hydrogen bond with the protonated nitrogen. In the case of L1, the lariat side chain is attached by an amide bond, lowering the proton affinity of LI relative to that of A18C6. This allows L1 to form noncovalent adducts with lysine despite the fact that steric repulsion within the cavity of the crown is increased to some extent. The relative ammonium ion affinities of these various crown ethers are shown to serve as qualitative predictors for the molecular recognition of lysine. The order of the relative ammonium ion affinities is 18C6>L1>A18C6 as determined by the kinetic method. These results suggest that the substitution of nitrogen for oxygen in the crown ether is not beneficial for the molecular recognition of lysine.     

Enantiomeric differentiation of amino acids by a chiral crown ether derived fromd-mannose studied by the liquid membrane technique

Chiral 18-crown-6 incorporating ad-mannopyranoside unit displays noticeable enantioselectivity in the recognition of amino acids and their sodium and potassium salts in transport experiments across a liquid membrane containing the carrier.d-phenylalanine andd-phenylglycine were transported faster than their correspondingl-enantiomers, whereas the enantioselectivity was reversed with tryptophan.     

Infrared spectra of amino acids and peptides

Summary The ionization constants of glycine, glycylglycine, DL--alanine, and -alanine have been determined from their IR spectra.Khimiya Priodnykh Soedinenii, Vol. 3, No. 2, pp. 197–201, 1967     

From amino acids to heteroaromatics--thiopeptide antibiotics, nature's heterocyclic peptides

Amino acids, the building blocks of proteins, also serve as precursors to a wide range of other naturally occurring substances including alkaloids, antibiotics, and, the subject of this Review, heterocyclic peptides. Simple alpha-amino acids are converted into complex arrays of heteroaromatic rings that display interesting and potent biological activity. The thiopeptide antibiotics, with their complex molecular architectures, are wonderful examples. In this Review we show how organic chemists have developed innovative methods for the synthesis of the heterocyclic ring systems, including routes inspired by the likely biosynthetic processes, and successfully assembled such building blocks into the final target molecule by application of orthogonal protecting groups and coupling methodologies.     

Organophosphorus analogs of amino acids and peptides

A method for obtaining phosphorus analogs of homoproline was developed, and the complexing properties of these compounds were studied. An effective method for obtaining optically active 1-aminoalkylphosphonic acids that is based on the stereoselective enzymatic hydrolysis of their N-acyl derivatives is proposed. New approaches to the synthesis of phosphonopeptides using privalyl chloride as the condensing agent, silylated amino phosphonic acids as the amino components of peptide synthesis, and the proteinase papain as the stereoselective catalyst for the formation of the peptide bond were developed.Institute of Bioorganic Chemistry and Petrochemistry, Academy of Sciences of the Ukrainian SSR, Kiev. Translated from Teoreticheskaya i Éksperimental'naya Khimiya, Vol. 27, No. 3, pp. 288–293, May–June, 1991. Original article submitted February 8, 1991.