Asymmetric synthesis of β,γ-unsaturated α-amino acids via efficient kinetic resolution with cinchona alkaloids

The β,γ-unsaturated amino acids are versatile chiral building blocks and biologically interesting compounds. The asymmetric synthesis of β,γ-unsaturated amino acids presents a challenging task as these compounds are labile toward racemization as well as the undesirable double bond isomerization. An efficient, general and mild kinetic resolution with readily accessible and fully recyclable cinchona alkaloid catalysts has been developed to provide a reliably useful approach toward optically active β,γ-unsaturated amino acids.     

Sugar amino acid based peptide epoxyketones as potential proteasome inhibitors

This paper describes the synthesis and biological evaluation of nine epoxomicin-derived sugar amino acid containing peptide epoxyketones. The title compounds are assembled from six sugar amino acid dipeptide isosteres and are synthesized using solution-phase peptide synthesis protocols. Although neither of the compounds displays inhibitory activity towards any of the proteasome active sites, our approach holds promise towards the development of structurally new proteasome inhibitors. It is likely that the central sugar amino acid dipeptide isoster needs to be designed such that it closely resemble dipeptides at position P2 and P3 in proteasome substrates inhibitors, such as the Thr-Ile dipeptide present in the lead compound, epoxomicin.     

Membrane permeability parameters for some amino acids and beta-lactam antibiotics: application of the boundary layer approach

The boundary layer approach to analyzing the results of the perfused intestinal segment method of measuring membrane permeabilities is applied to the amino acids; leucine, valine, phenylalanine, lysine and aspartic acid and the beta-lactam antibiotics, cephalexin and penicillin V. The analysis indicates that in determining the membrane parameters, Pw vs. Cw data are preferable to using Jss = PwCw vs. Cw data. It is further shown that the carrier permeability, Pc* = Jmax*/Km, may be the most significant parameter to consider since luminal amino acid or drug concentration may generally be below the Km value. A comparison of P*c values for the beta-lactams with results for passively absorbed compounds indicates that the cephalosporins would be expected to be well absorbed orally based on the perfusion results. This suggests that this approach may be useful in estimating oral drug absorption for compounds that are absorbed passively as well as by a carrier-mediated mechanism.     

Pyranocoumarin, a novel anti-TB pharmacophore: synthesis and biological evaluation against Mycobacterium tuberculosis

Pyranocoumarin compounds were identified to embody a novel and unique pharmacophore for anti-TB activity. A systematic approach was taken to investigate the structural characteristics. Focused libraries of compounds were synthesized and evaluated for their anti-TB activity in primary screening assays. Compounds shown to be active were further determined for MIC and MBC values. Three of the four bactericidal compounds (16, 17c, and 18f) were amino derivatives, with MIC values of 16 microg/mL and respective MBC values of 32, 32, and 64 microg/mL.     

Automated solid-phase synthesis of linear nitrogen-linked compounds

A synthetic library motif has been developed to create linear, nitrogen-linked compounds as screening libraries to target structured RNA for drug discovery. Scaffolds were created in situ from suitably protected bifunctional compounds linked together either by acyl or amine links. Acyl links were created from amino acids, which also introduce one degree of functionality. Amine links from the amino acid nitrogen were created from an N-protected amino alcohol via Fukuyama Mitsunobu alkylation. Each amine site can then be used for introducing functionality or extending the scaffold. This synthetic scheme can be used to create a wide variety of modified-backbone PNA in situ, as shown by the synthesis of a PNA-type monomer. The synthesis steps have been enabled on a 96-well parallel-array synthesizer for high-throughput synthesis. The present study represents a versatile synthetic approach to a wide variety of potential RNA-binding molecules.     

A biomimetic domino reaction for the concise synthesis of capreomycidine and epicapreomycidine

The non-proteinogenic amino acids capreomycidine and epicapreomycidine are constituents of antibiotically active natural products, but the synthesis of these unusual cyclic guanidine derivatives is challenging. The biosynthesis of capreomycidine has therefore been employed as a guideline to develop a concise biomimetic synthesis of both epimeric amino acids. The resulting domino-guanidinylation-aza-Michael-addition reaction provides the most convenient access to these amino acids in racemic form. Attempts to dissect the domino reaction into two separate transformations for a stereocontrolled version of this synthetic approach have also been made. The synthesized didehydro-arginine derivatives with urethane-protected guanidine moieties did not undergo the aza-Michael-addition anymore. These results may have wider implications for the 1,4-addition of guanidines to α,β-unsaturated carbonyl compounds, particularly to didehydro amino acids.     

Efficient synthesis of thymidine boranophosphoramidates conjugated with amino acids

An efficient synthesis of a thymidine boranophosphoramidate prodrug was accomplished using a phosphoramidite approach in high yield. This new class of compounds is designed to have improved antiviral and anticancer advantages conferred by combining the boranophosphate and normal nucleoside amino acid phosphoramidate. Compounds were characterized by MS and 31P NMR.     

Reproductive response of generalist and specialist aphid morphs with the same genotype to plant secondary compounds and amino acids

Many studies have paid particular attention to the role of either secondary plant compounds or amino acids as determinants of host-plant range in phytophagous insects. Here we examine the relative importance of both of these classes of compound in host acceptance by generalist and specialist morphs of the black bean aphid, Aphis fabae, that are morphologically similar and genetically identical. Eleven secondary plant compounds and six amino acids with known biological activity in aphids are presented to insects within an artificial membrane system as single compounds, mixtures of same-class compounds and combined mixtures of the two classes of compound. It is found that 1) when specific single secondary compounds and amino acids are presented to generalist and specialist morphs of A. fabae, differential responses are exclusively consistent with plant-use strategy for amino acids but not for secondary compounds, 2) neither secondary compound nor amino acid mixtures give reproductive responses entirely consistent with plant range, but the response to secondary compounds is broadly consistent with plant range whereas the response to amino acids is not, 3) when secondary compounds and amino acid mixtures are combined, the response to secondary compounds generally dominates that to amino acids. Some scenarios of plant-range determination by secondary plant compounds and amino acids, suggested by results, are discussed.     

An Original Strategy for Gln Containing Peptide Synthesis Using SPPS and Glu(OH)-1-OAll

Using multiple peptide synthesis in parallel, a series of 24 compounds analogues of tripeptide sequence Z-Leu-Phe-Gln-H, modified by imidazole moiety were synthesized. An effective and simple scheme for including imidazole heterocycle to C- and/or N-terminus of Gln residue was created by means of allyl group as α-COOH protecting group for Fmoc-Glu. The approach using Fmoc-Glu-1-OAll as a first amino acid linked to the resin could be useful for the synthesis of a large number of amino acids and/or heterocyclic moieties including compounds. Based on the preliminary biological trials we could conclude that the presence of imidazole heterocycle affect positively the antiviral activity against Coxsackieviruses B1 and Poliovirus type 1.     

Antimicrobial benzodiazepine‐based short cationic peptidomimetics

Antimicrobial peptides (AMPs) appear to be good candidates for the development of new antibiotic drugs. We describe here the synthesis of peptidomimetic compounds that are based on a benzodiazepine scaffold flanked with positively charged and hydrophobic amino acids. These compounds mimic the essential properties of cationic AMPs. The new design possesses the benzodiazepine scaffold that is comprised of two glycine amino acids and which confers flexibility and aromatic hydrophobic ‘back’, and two arms used for further synthesis on solid phase for incorporation of charged and hydrophobic amino acids. This approach allowed us a better understanding of the influence of these features on the antimicrobial activity and selectivity. A novel compound was discovered which has MICs of 12.5 µg/ml against Staphylococcus aureus and 25 µg/ml against Escherichia coli, similar to the well‐known antimicrobial peptide MSI‐78. In contrast to MSI‐78, the above mentioned compound has lower lytic effect against mammalian red blood cells. These peptidomimetic compounds will pave the way for future design of potent synthetic mimics of AMPs for therapeutic and biomedical applications. Copyright © 2015 European Peptide Society and John Wiley & Sons, Ltd.     

New approach for amino acid profiling in human plasma by selective fluorescence derivatization

A new approach for the separation of 6-aminoquinolyl-carbamyl (AQC)-derivatized amino acids has been proposed. The chromatography used ion-pairing mechanism to increase the method selectivity. Mobile phase was based on triethylamine buffer containing N,N-dimethyloctylamine as a modifier. A number of factors, buffer composition and pH, counterion concentration, temperature and acetonitrile gradient profile, were optimized to achieve final chromatographic conditions. With the presented analytical method, the separation and identification of 34 AQC-amino acids and amino compounds present in human plasma is possible. The results of validation proved the applicability of the method for quantification of 27 amino acids in biological samples. The ultrafiltration proposed as deproteinization procedure gave repeatable and reliable results for the amino acids under investigation. This method introduced in routine testing can be a suitable tool for amino acid profiling in plasma including all aspects of clinical application.     

Upregulation of p53 through induction of MDM2 degradation: Amino acid prodrugs of anthraquinone analogs

Previously, we reported a class of MDM2-MDM4 dimerization inhibitors that upregulate p53 and showed potent anticancer activity in animal models. However, water solubility hinders their further development. Herein we describe our effort to develop a prodrug approach that overcomes the solubility problem. The prodrug of BW-AQ-238, a potent anthraquinone analog, was made by esterification of the hydroxyl group with various natural amino acids. Cytotoxicity of these compounds toward Hela and EU-1 cells, their aqueous solubility, and the release kinetics of these prodrugs in buffer and in the presence of hydrolytic enzymes were studied. The results demonstrate that the amino acid prodrug approach significantly improved the water solubility while maintaining the potency of the parent drug.     

A robust and convergent synthesis of dipeptide-DOTAM conjugates as chelators for lanthanide ions: new PARACEST MRI agents

A generally applicable synthetic approach to dipeptide-DOTAM conjugates has been developed which is based on the peralkylation of 1,4,7,10-tetraazacyclododecane (cyclen) with protected N-iodoacetyl dipeptides. Standardized procedures were used for the alkylation, metalation, and purification of the resultant lanthanide complexes. Using this approach, we have been able to rapidly and reliably prepare and screen five different ligands each with up to six lanthanide ions. This preliminary investigation has identified several paramagnetic compounds with strong chemical exchange saturation transfer (PARACEST) properties in water at physiological temperature and pH. Extension of the synthetic approach to a wide variety of amino acids is possible.     

GluK1 antagonists from 6-(carboxy)phenyl decahydroisoquinoline derivatives. SAR and evaluation of a prodrug strategy for oral efficacy in pain models

The synthesis and structure–activity relationship of decahydroisoquinoline derivatives with various benzoic acid substitutions as GluK1 antagonists are described. Potent and selective antagonists were selected for a tailored prodrug approach in order to facilitate the evaluation of the new compounds in pain models after oral administration. Several diester prodrugs allowed for acceptable amino acid exposure and moderate efficacy in vivo.     

Covalent modification as a strategy to block protein-protein interactions with small-molecule drugs

It is generally difficult to block protein-protein interactions with small-molecule drugs. A novel pharmaceutical development strategy to block protein interactions is emerging: targeted covalent modification to sterically block interactions. By this approach, compounds first interact non-covalently with a specific target protein. This interaction juxtaposes a weakly reactive group of the drug with a target amino acid sidechain, which then react by virtue of their high local concentration.     

Active site chemical mutagenesis of Ecballium elaterium trypsin inhibitor II: new microproteins inhibiting elastase and chymotrypsin

Seven microproteins analogous to Ecballium elaterium Trypsin Inhibitor II. were synthesized. The study of their inhibiting power showed a change in selectivity from trypsin to elastase for 5 of the compounds and to alpha-chymotrypsin for another one. A striking characteristic that appeared during this synthetic approach was the ability of the 28 amino acid peptides to refold and close correctly the 3 disulfide bridges, giving in each case an active compound.     

Tripeptidic BACE1 inhibitors devised by in-silico conformational structure-based design

Previously reported pentapeptidic BACE1 inhibitors, designed using a substrate-based approach, were used as lead compounds for the further design of non-peptidic BACE1 inhibitors. Although these peptidic and non-peptidic inhibitors, with a hydroxymethylcarbonyl isostere as a substrate transition-state mimic, exhibited potent BACE1 inhibitory activities, their molecular-sizes appeared a little too big (molecular weight of >600daltons) for developing practical anti-Alzheimer's disease drugs. To develop lower weight BACE1 inhibitors, a series of tripeptidic BACE1 inhibitors were devised using a design approach based on the conformation of a virtual inhibitor bound to the BACE1 active site, also called 'in-silico conformational structure-based design'. Although these tripeptidic BACE1 inhibitors contained some natural amino acid residues, they are expected to be useful as lead compounds for developing the next generation BACE1 inhibitors, due to their low molecular size and unique structural features compared with previously reported inhibitors.     

Effect of substituents on the configurational stability of the stereogenic nitrogen in metal(II) complexes of α‐amino acid Schiff bases

Herein, we report a general method for quantitative measurement of the configurational stability of the stereogenic nitrogen coordinated to M (II) in the corresponding square planar complexes. This stereochemical approach is quite sensitive to steric and electronic effects of the substituents and shown to work well for Ni(II), Pd(II), and Cu(II) complexes. Structural simplicity of the compounds used, coupled with high sensitivity and reliability of experimental procedures, bodes well for application of this approach in evaluation of chemical stability and stereochemical properties of newly designed chiral ligands for general asymmetric synthesis of tailor‐made amino acids.