Synthesis of thiourea derivatives as CCR4 antagonists

A series of thiourea derivatives have been synthesized. Their structures were confirmed by MS and 1H NMR. Several compounds showed potent activities as antagonists of CCR4 receptor.     

FRET-based assay of the processing reaction kinetics of stimulus-responsive peptides: influence of amino acid sequence on reaction kinetics

In the field of chemical biology, methods for controlling peptidyl function by a stimulus are attracting increasing attention. Recently, we reported a stimulus-responsive peptide, which can be cleaved after exposure to a stimulus. In this study, we developed a FRET-based assay system to estimate the kinetics of the stimulus-induced processing (peptide bond cleavage) reaction. Based on the FRET system, it was clarified that introduction of a sterically less-hindered or polar residue at the position adjacent to the stimulus-responsive amino acid accelerates the processing reaction.     

Synthesis and photophysical properties of a new amino acid possessing a BODIPY moiety

The synthesis of a new amino acid possessing a BODIPY fluorophore, which is of use in peptide synthesis, is described. The influence of the amino acid as well as of benzoxazole moieties on the BODIPY spectral and photophysical properties is discussed. The photophysical properties of this fluorophore were modified only to a small extent compared to those of the parent compound.     

Structural characterization of two oxadiazolic systems used as spacers for potential angiotensin II receptor antagonists

The structures of two oxadiazole derivatives, methyl 2-[5-(4-methylphenyl)-1,3,4-oxadiazol-2-yl]benzoate (1) and methyl 2-[3-(4-methylphenyl)-1,2,4-oxadiazol-5-yl]benzoate2, used as spacers in the synthesis of new potential non-peptide angiotensin receptor antagonists have been determined by X-ray crystallography. In both compounds π-π interactions were observed between the oxadiazole rings and the phenyl rings of neighboring molecules. In the crystal packing of the oxadiazole 2 two C-H?O interactions are present.     

Synthesis of compounds with potential antitumor activity: IV. Modification of lupinine and menthol by the taxol amino acid moiety

The synthesis and the results of biological testing of novel N-benzoylphenylisoserine-modified L-lupinine and L-menthol are reported.     

Synthesis of 1,2-azaphospholanes containing an amino acid fragment

2-Oxo-1,2-azaphospholanes and 1,2-azaphospholanium salts containing an amino acid fragment were synthesized by intramolecular P-alkylation of N-3-chloropropyl-substituted tricoordinate phosphorus amides. Hydrolysis of 2-oxo-1,2-azaphospholanes at the P-N bond gives rise to γ-aminopropylphosphonic acid derivatives. Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 11, pp. 2557–2562, November, 2005.     

Configurational Assignment of ‘Cryptochiral’ 10‐Hydroxystearic Acid Through an Asymmetric Catalytic Synthesis

An asymmetric catalytic total synthesis of (S)‐10‐hydroxystearic acid ( 1 ) for comparison of its absolute configuration to that of samples obtained by fermentative hydration of oleic acid is reported. The synthesis involves two catalytic key‐steps, namely Ru‐catalyzed anti‐Markovnikov hydration of 9‐decynoic acid ( 7 ) to 10‐oxodecanoic acid ( 5 ), followed by titanium‐mediated asymmetric catalytic addition of dioctylzinc ( 25 ) to 5 in presence of the chiral ligand N,N’‐((1R,2R)‐cyclohexane‐1,2‐diyl)bis(1,1,1‐trifluoromethanesulfonamide) ( 6 ). The synthesis is short and efficient and avoids use of protecting groups. Ozonolysis of 10‐undecynoic acid ( 9 ) to 5 provides an alternative entry point into the synthetic route. The double dehydrobromination of (ω,ω‐1)‐dibromoalkanoic acids to ω‐alkynoic acids under a variety of conditions was investigated with 10,11‐dibromoundecanoic acid ( 11 ) as model substrate and using qNMR to quantify all reaction products. The synthetic approaches presented here have the potential to be generalized to the asymmetric catalytic synthesis of a variety of n‐hydroxy‐fatty acids.     

Syntheses of enantiopure Si-centrochiral silicon-based muscarinic antagonists using an enantioselective enzymatic esterification as the key step

The muscarinic antagonists (R)-cyclopentyl(hydroxymethyl)phenyl[2-(piperidin-1-yl)ethyl]silane[(R)-1] and(R)-1-{2-[cyclopentyl(hydroxymethyl)phenylsilyl]ethyl}-1-methylpiperidinium iodide [(R)-2] were synthesized using anenantioselective enzymatic transformation as the key step. Apapain-catalyzed (E.C. 3.4.22.2) esterification ofrac-cyclopentyl(hydroxymethyl)phenyl(vinyl)silane(rac-3) with 5-phenylpentanoic acid afforded(R)-cyclopentyl(phenyl)[(5-phenylpentanoyloxy)methyl]vinylsilane[(R)-4] which upon chemical hydrolysis gave enantiomericallyenriched (R)-3 (68% ee). Repetition of thisesterification/hydrolysis sequence, starting from enantiomericallyenriched (R)-3, finally gave the enantiopure silane (R)-3(98% ee) which served as the starting material for thesubsequent chemical synthesis of (R)-1 and (R)-2{(R)-3 (R)-cyclopentyl(phenyl)[(trimethylsilyloxy)methyl]vinylsilane[(R)-5] (R)-1 (R)-2}.     

Synthesis of new boswellic acid derivatives as potential antiproliferative agents

Abstract

In the current investigation, a series of heterocyclic derivatives of boswellic acids were prepared along with new monomers of 3-O-acetyl-11-keto-β-boswellic acid (AKBA, 1) 11-keto-β-boswellic acid (KBA, 2) and several new bis-AKBA and KBA homodimers and AKBA-KBA heterodimers. The effects of these compounds on the proliferation of different human cancer cell lines, viz., FaDu (pharynx carcinoma), A2780 (ovarian carcinoma), HT29 (colon adenocarcinoma), and A375 (malignant melanoma), have been evaluated. Thus, KBA homodimer 21 effectively inhibited the growth of FaDu, A2780, HT29, and A375 cells with EC₅₀ values below 9?μM. In addition, compounds 7, 8, 11, 12, 15, 16, and 17 also exhibited cytotoxic effects for A2780, HT29, and A375 cancer cells. In particular, the pyrazine analog 8 was highly cytotoxic for A375 cancer cells with an EC₅₀ value of 2.1?μM.     

Voltammetric determination of volatile free sulfide and alkylthiols as contaminants in parenteral amino acid solutions

A method for the simultaneous voltammetric determination of free sulfide and volatile alkythiols (methanethiol/ethanethiol) existing as contaminant in parenteral nutrition (PN) solutions was developed. The volatile sulfides (dihydrogensulfide and alkylthiols) formed in the formulations were distilled over 45 min at 47°C in a purpose-made Conway cell. The analytes were quantified by differential pulse cathodic stripping voltametry (DPCSV) at the hanging mercury-drop electrode and determined, simultaneously as dihydrogensulfide and alkylthiols using a 60 s preconcentration time at −300 mV (versus Ag/AgCl, Cl⁻ 3.0 mol l⁻¹). The voltammetric signals were directly linear proportional to the sulfides concentrations in the PN solutions in the range 3–20 μmol l⁻¹ and detection limits of about 2 μmol l⁻¹ were calculated. Recoveries of sulfides from PN solutions in the range 90–110% were calculated using the method and nine commercial PN formulations were analyzed. Methanethiol and ethanethiol were quantified from their composite signals, and the mutual influence of the analytes on the DPCSV measurements is discussed.     

Synthesis of the glycan moiety of ganglioside HPG-7 with an unusual trimer of sialic acid as the inner sugar residue

The glycan moiety of ganglioside HPG-7, isolated from the sea cucumber (Holothuria pervicax), was synthesized for the first time. The characteristic substructure, a trisialic acid sequence embedded in the glycan, was deliberately constructed by utilizing suitably differentiated sialyl units for various synthetic purposes. Finally, a pentasaccharide was successfully delivered as the hexyl glycoside.     

Synthesis of glycosylated 5-hydroxylysine, an important amino acid present in collagen-like proteins such as adiponectin

The synthesis of naturally occurring glycosylated (2S,5R)-hydroxylysine still remains a challenge. This perspective highlights the importance of this post-translationally modified amino acid residue in the observed bioactivity of collagen and related collagen-like proteins such as adiponectin, an important target for the treatment of type II diabetes. Strategies employed to date for the syntheses of (2S,5R)-hydroxylysine and the methods to effect glycosylation of this modified amino acid are also summarized herein.     

Comparative molecular field analysis of CCK-A antagonists using field-fit as an alignment technique. A convenient guide to design new CCK-A ligands

Summary Comparative molecular field analysis (CoMFA) has been used as a three-dimensional quantitative structure-activity relationship (QSAR) method to correlate the affinities of several antagonists towards CCK-A receptors with their steric and electrostatic fields. In this publication, we describe, for the first time, a field-fit operation as an alignment technique. These results could serve as a guide for the design of new non-peptide antagonists.     

Synthesis of a boronated amino acid as a potential neutron therapy agent: 1-amino-3-[(dihydroxyboryl)ethyl]cyclobutanecarboxylic acid

A novel boronated aminocyclobutanecarboxylic acid was synthesized in 10 steps for potential use in neutron capture therapy. The molecule was modeled after the unnatural amino acid 1-aminocyclobutanecarboxylic acid, which has shown high uptake in brain tumors.     

Diastereoselective synthesis of the 5-hydroxy-pyrrolidinone amino acid of the microsclerodermins and model studies for an end-game strategy for microsclerodermin B

The first diastereoselective synthesis of the 5-hydroxy-pyrrolidinone amino acid common to eight members of the microsclerodermin family is presented. Our strategy involves formal hydration of an unsaturated precursor via the use of a two-step hydroxybromination-debromination protocol; this procedure provides exclusively the requisite 4,5-cis-pyrrolidinone. Furthermore model studies are presented that indicated the potential viability of this hydration strategy in the context of a synthesis of microsclerodermin B.     

Synthesis of a novel series of tetracyclic opioid antagonists incorporating an 8-aminobicyclo[3.2.1]oct-6-ene sub-unit

The bridged bicyclo[3.2.1]oct-ene and -ane amines 9-13 have been prepared via [3+2]cycloaddition of allylic alcohols 6 to alkynes 7, and assessed as ligands at opioid receptors. Amine 10b is a potent antagonist at μ receptors.     

Synthesis and characterization of nonconventional surfactants of aromatic amino acid-glycerol ethers: effect of the amino acid moiety on the orientation and surface properties of these soap-type amphiphiles

The synthesis, characterization, and surface properties of soap-type amphiphiles comprising alkyl chains of 10-16 carbon atoms linked through an ether group to a glycerol-amino acid hydrophilic head group is described. The surface properties of members of this series derived from histidine and tyrosine were compared with those of phenylalanine and tryptophan derivatives described previously and with those of conventional soaps. In all cases, the amino acid derivatives showed superior surface properties, and an interesting differentiation was discovered regarding the orientation of tryptophan derivatives.     

Synthesis and biological evaluation of novel farnesylthiosalicylic acid/salicylic acid hybrids as potential anti-tumor agents

A series of FTS/salicylic acid hybrids was designed and synthesized and their in vitro antitumor activities were evaluated.It was found that the anti-proliferation activities of hybrids were better than that of FTS.Compound 10 a displayed the strongest antitumor activities with IC_(50) values of 5.72-9.76 μmol/L and selectively inhibited tumor cell proliferation.In addition,10 a induced tumor cell apoptosis in a dosedependent manner by up-regulating the expression of Bax and caspase-3 and down-regulating Bcl-2.Our findings suggest that these novel hybrids may hold a great promise as therapeutic agents for the intervention of human cancers.     

Solid-Phase Synthesis of an Insect Pyrokinin Analog Incorporating an Imidazoline Ring as Isosteric Replacement of a trans Peptide Bond

A facile solid-phase synthetic method for incorporating the imidazoline ring motif, a surrogate for a trans peptide bond, into bioactive peptides is reported. The example described is the synthesis of an imidazoline peptidomimetic analog of an insect pyrokinin neuropeptide via a cyclization reaction of an iminium salt generated from the preceding amino acid and 2,4-diaminopropanoic acid (Dap).     

Extensive conformational searches of 13 representative dipeptides and an efficient method for dipeptide structure determinations based on amino acid conformers

Conformations of peptides are the basis for their property studies and the predictions of peptide structures are highly important in life science but very complex in practice. Here, thorough searches on the potential energy surfaces of 13 representative dipeptides by considering all possible combinations of the bond rotational degrees of freedom are performed using the density functional theory based methods. Careful analyses of the conformers of the 13 dipeptides and the corresponding amino acids reveal the connections between the structures of dipeptide and amino acids. A method for finding all important dipeptide conformers by optimizing a small number of trial structures generated by suitable superposition of the parent amino acid conformations is thus proposed. Applying the method to another eight dipeptides carefully examined by others shows that the new approach is both highly efficient and reliable by providing the most complete ensembles of dipeptide conformers and much improved agreements between the theoretical and experimental IR spectra. The method opens the door for the determination of the stable structures of all dipeptides with a manageable amount of effort. Preliminary result on the applicability of the method to the tripeptide structure determination is also presented. The results are the first step towards proving Anfinsen's hypothesis by revealing the relationships between the structures of the simplest peptide and its constituting amino acids. It implies that the structures of peptides are not only determined by their amino acid sequences, but also closely linked with the amino acid conformations. © 2009 Wiley Periodicals, Inc. J Comput Chem 2009