Stable cyclopropene-containing analogs of the amino acid neurotransmitter glutamate

As a neurotransmitter, the amino acid glutamate has been the subject of efforts to generate structural analogs with unique properties. Here we report a practical, half-gram synthesis of two cyclopropene-containing glutamate analogs. These analogs are stable in solution, in the presence of the biological nucleophile glutathione, upon concentration, and during long-term storage, while maintaining their amenability to photo- or enzyme-caging and reactivity with bioorthogonal reaction partners like s-tetrazine or light-activated tetrazoles.     

Synthesis and monolayer characterization of phosphorylated amino acid analogs

The synthesis of a series of thiols containing phosphorylated and non-phosphorylated serine, threonine, and tyrosine amino acid residues is described. The synthesized molecules, based on 3-mercaptopropionic acid, were assembled onto gold and subsequently characterized using infrared reflection-absorption spectroscopy, ellipsometry, X-ray photoelectron spectroscopy, and contact angle goniometry. The ellipsometric analysis indicates that they form densely packed and well-oriented monolayers on gold, with thicknesses that are in good agreement with estimated values from space-filling models. The bulky and space-demanding phosphorylated threonine analog was, however, found to be an exception. The increase in layer thickness when adding a phosphate group to the threonine is only 35% of that observed for the two other analogs. A detailed infrared examination of the influence of cation coordination to the phosphorylated serine analog using calcium and magnesium reveals structural similarities to those of the inorganic phosphate compound calcium hydroxy apatite. We furthermore discuss the application of these monolayers as soft templates for biomineralization.     

Efficient ecofriendly synthesis of pyrazole acryloyl analogs by amino acid catalysis

An easy and effective green approach of Knoevenagel condensation and arylidene formation with the substrates involves pyrazole-3-carbaldehydes and active methylenes under catalytic action of glycine (the simplest amino acid) in dimethylsulfoxide. These reactions were successfully carried out at room temperature.     

Linear polynuclear tetrazole-containing compounds

Linear polynuclear tetrazole-containing compounds were synthesized. Alkylation of 5-[-(5-phenyl-2-tetrazolyl)alkyl]tetrazoles with ethyl bromoacetate and chloroacetamide gave the corresponding esters and amides. Treatment of the latter with tetrachlorosilane-sodium azide afforded compounds containing three tetrazole rings linked through polymethylene bridges. Acid ionization constants of the products possessing an NH-tetrazole ring (pK _a = 2.9–3.2) and the corresponding carboxylic acids (pK _a = 2.9–3.1) in aqueous methanol were determined by potentiometric titration.Translated from Zhurnal Organicheskoi Khimii, Vol. 40, No. 10, 2004, pp. 1580–1586.Original Russian Text Copyright © 2004 by Morozova, Komissarov, Esikov, Zubarev, Malin, Ostrovskii.     

Synthesis of biologically active analogs of luliberin with shortened amino acid sequences

Two new analogs of the releasing factor of the luteinizing hormone with shortened amino acid sequences have been synthesized by the methods of classical peptide chemistry. The influence of the preparations on the action of chorionic gonadotropin and on the course of processes of ovulation in experimental animals has been studied. The promising nature in this direction of the search for active analogs for luliberin has been shown.     

Branched tetrazole-containing polymers

It has been established that the polycondensation (polyalkylation) of 5-chloromethyltetrazole occurs in a basic medium to give rise to heterochain oligomeric products. When carried out in the presence of N-H unsubstituted poly(C-vinyltetrazoles), polycondensation yields high-molecular-mass graft copolymers containing side poly(methylenetetrazole) chains. Some properties of branched polymeric products that are characterized by a high density and a large relative content of nitrogen have been studied.     

Influence of the second amino acid residue on the antidepressive activity of melanostatin analogs

It has been shown for melanostatin analogs that the energy of the HOMO, calculated by the CNDO/2 method for side substitutents of the second amino acid residue, is correlated with the antidepressive activity. The excessive electron density that appears in the peptide chain is delocalized on the MO of the substituent to which the AO of the first carbon atom makes the greatest contribution (LUMO).Translated from Teoreticheskaya i Éksperimental'naya Khimiya, Vol. 29, No. 3, pp. 255–259, May–June, 1993.     

Synthesis and properties of tetrazole-containing double polymers

Based on poly(5-vinyltetrazole) and a copolymer of 2-methyl-5-vinyltetrazole with 2-(vinyloxyethoxy)methyloxirane, tetrazole-containing network double polymers capable of gelation both in organic media and in water have been obtained. It has been shown that the covalent bonding of linear polymer macromolecules is the result of alkylation of unsubstituted N-H tetrazole cycles of poly(5-vinyltetrazole) with oxirane cycles incorporated into the copolymer structure.     

Calculation of the free energy of solvation for neutral analogs of amino acid side chains

The ability of the GROMOS96 force field to reproduce partition constants between water and two less polar solvents (cyclohexane and chloroform) for analogs of 18 of the 20 naturally occurring amino acids has been investigated. The estimations of the solvation free energies in water, in cyclohexane solution, and chloroform solution are based on thermodynamic integration free energy calculations using molecular dynamics simulations. The calculations show that while the force field reproduces the experimental solvation free energies of nonpolar analogs with reasonable accuracy the solvation free energies of polar analogs in water are systematically overestimated (too positive). The dependence of the calculated free energies on the atomic partial charges was also studied.     

Solvation free energies of amino acid side chain analogs for common molecular mechanics water models

Quantitative free energy computation involves both using a model that is sufficiently faithful to the experimental system under study (accuracy) and establishing statistically meaningful measures of the uncertainties resulting from finite sampling (precision). In order to examine the accuracy of a range of common water models used for protein simulation for their solute/solvent properties, we calculate the free energy of hydration of 15 amino acid side chain analogs derived from the OPLS-AA parameter set with the TIP3P, TIP4P, SPC, SPC/E, TIP3P-MOD, and TIP4P-Ew water models. We achieve a high degree of statistical precision in our simulations, obtaining uncertainties for the free energy of hydration of 0.02-0.06 kcal/mol, equivalent to that obtained in experimental hydration free energy measurements of the same molecules. We find that TIP3P-MOD, a model designed to give improved free energy of hydration for methane, gives uniformly the closest match to experiment; we also find that the ability to accurately model pure water properties does not necessarily predict ability to predict solute/solvent behavior. We also evaluate the free energies of a number of novel modifications of TIP3P designed as a proof of concept that it is possible to obtain much better solute/solvent free energetic behavior without substantially negatively affecting pure water properties. We decrease the average error to zero while reducing the root mean square error below that of any of the published water models, with measured liquid water properties remaining almost constant with respect to our perturbations. This demonstrates there is still both room for improvement within current fixed-charge biomolecular force fields and significant parameter flexibility to make these improvements. Recent research in computational efficiency of free energy methods allows us to perform simulations on a local cluster that previously required large scale distributed computing, performing four times as much computational work in approximately a tenth of the computer time as a similar study a year ago.     

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.     

Modeling the protein-nucleic acid base interactions through hydrogen-bonded complexes of N-heterocyclic analogs of Indene with amino acid side-chain mimics

A series of hydrogen-bonded complexes between N-heterocyclic analogs of Indene and amino acid side-chain mimics have been analyzed employing second-order Møller-Plesset perturbation (MP2) theory and density functional theory with dispersion function (DFT-D) calculations with the aim of gaining greater insight in to the nature of intermolecular interactions in these systems. In this study, the hydrogen bonding ability of N-heterocyclic analogs of Indene towards amino acid side-chain mimics follows the sequence Azaindazole (AIND) > Indazole (IND) > Azaindole (AIN) > Indole (IN) whereas the hydrogen bonding ability of amino acid side-chain mimics towards N-heterocyclic analogs of Indene follows the sequence AcOH > MeNH₂ > MeOH > MeSH. Bader’s theory of atoms in molecules (AIM) and natural bond orbitals (NBO) analyses are employed to elucidate the interaction characteristics in the complexes under study. The purpose of conducting these studies is to measure the relative strength of hydrogen bonding interactions such as N-H···O=C, N-H···O, N-H···S, N-H···N, and O-H···N in these complexes and their role in providing stability to the complexes. The AIM theory shows good correlation of the electron density and its Laplacian at the bond critical points (BCP) with the computed stabilization energy for all the complexes under study.

     

Investigation of the sunscreen octocrylene's interaction with amino acid analogs in the presence of UV radiation

Octocrylene is an organic UV filter, commonly used in sunscreens and cosmetics, which can give rise to both contact and photocontact allergy. Our aim was to investigate octocrylene's interaction with amino acid analogs in the presence of UV radiation to better understand the reason for octocrylene's photoallergenic capacity. The amino acid analogs were photolysed in presence and absence of octocrylene for 1 h in cyclohexane. The rate of degradation was considerably slower for all amino acid analogs when octocrylene was present in the mixture. Benzylamine, the lysine analog, did react with octocrylene during the photolysis and the corresponding amide was formed in an acylation reaction. By varying the benzylamine concentration and keeping the octocrylene concentration fixed the reaction rate was shown to be independent of the amine concentration. The same type of acylation reaction took place when octocrylene alone was photolysed in ethanol in which the ethyl ester was formed from octocrylene and ethanol. Our results suggest that octocrylene's ability to cause photocontact allergy could be due to its photoinduced reactivity toward primary amines and alcohols.     

Mode of action of the gramicidin S analogs lacking hydrophilic amino acid residues on biomembranes.

The gramicidin S analog lacking basic ornithine residues, cyclo(-Val-Ala-Leu-delta Phe-Pro-)2 (where delta Phe represents alpha, beta-dehydrophenylalanine), increased the K+ permeability of human erythrocytes and Staphylococcus aureus similarly to the parent gramicidin S. This analog altered the normal discoid shape of human erythrocytes to an invaginated form. The direction of the shape change was opposite to the case of gramicidin S causing crenated cells. We suppose that the analog accumulated predominantly into the inner half monolayer of membrane and destabilized the membrane structure, resulting in a break in the membrane.     

Synthesis and properties of tetrazole-containing oligomers

Linear, star-shaped, and hyperbranched oligomeric compounds containing tetrazole cycles in the main chains are synthesized via the polycondensation (polyalkylation) of N-H unsubstituted bis(tetrazoles), tris(tetrazoles), and tetrakis(tetrazoles) with compounds containing mobile halogen atoms. Some properties of the oligomers are studied. Some of the oligomers are characterized by high density and a large content of nitrogen.     

Synthesis of phosphinic analogs of sulfur-containing amino acids

Phosphinic analogs of the key compounds of the metabolism of methionine were synthesized. The compounds obtained were selectively oxidized either at the phosphinic group or at the sulfur-containing fragment. Translated fromIzvestiya Akademii Nauk. Seriya Khimicheskaya, No. 7, pp. 1360–1363, July, 1999.     

Meldrum's acid and its analogs

2-Substituted or 2,2-disubstituted 4,6-dioxo-1,3-dioxanes, which are analogs of Meldrum's acid and were obtained by reaction of malonic acid with acetic anhydride and the appropriate carbonyl compound in the presence of sulfuric acid, exist in solution preferably in a single form according to the PMR and ¹³C NMR spectral data. Fluctuation of the CH₂ group is not observed. The mass spectra are characteristic and are distinguished by splitting out of the carbonyl compound from the molecular ion or successive splitting out of CO₂ and ketene molecules. The Meldrum acid analogs do not affect plant growth but have a depressive effect on the central nervous system of animals and low toxicity.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 11, pp. 1482–1486, November, 1975.     

Properties of lipoic acid analogs

Two chain-shortened analogs of lipoic (1,2-dithiolane-3-pentanoic) acid, viz. bisnor-lipoic (1,2-dithiolane-3-propanoic) and tetranorlipoic (1,2-dithiolane-3-carboxylic) acids, have been chemically synthesized. The ir, uv, pmr, and mass spectroscopic properties and paper, thin-layer, and column chromatographic mobilities of lipoic acid and its analogs were investigated and are given.     

Polynuclear heterocyclic compounds

The cyclization of halogenophenyldiindanedionylmethanes to the corresponding halogenophenyldibenzoylenepyrans and dibenzoylenedihydropyridines is investigated. The latter are readily oxidized to dibenzoylenepyridines.For Part XX see [15].