Chiral liquid-crystalline side chain polymers by enantioselective modification of prochiral parent polymers

The preparation is reported of two side chain polyacrylate samples 1a , b containing a sulfide group linked to the mesogenic core. By oxidation with a preferentially chiral oxaziridine, samples 1a , b were chemoselectively and enantioselectively converted to the corresponding sulfoxide containing polymers 2a , b with an estimated 20% asymmetric induction. The mesophasic behaviour of the parent and oxidized polymer samples is analyzed by thermal and optical techniques. The modification of the prochiral sulfide groups into chiral sulfoxide groups slightly depresses the propensity of the resulting polymers to give stable and persistent mesophases.     

Synthesis and biological activities of new side chain and backbone cyclic bradykinin analogues.

A series of conformationally constrained cyclic analogues of the peptide hormone bradykinin (BK, Arg-Pro-Pro-Gly-Phe-Ser-Pro-Phe-Arg) was synthesized to check different turned structures proposed for the bioactive conformation of BK agonists and antagonists. Cycles differing in the size and direction of the lactam bridge were performed at the C- and N-terminal sequences of the molecule. Glutamic acid and lysine were introduced into the native BK sequence at different positions for cyclization through their side chains. Backbone cyclic analogues were synthesized by incorporation of N-carboxy alkylated and N-amino alkylated amino acids into the peptide chain. Although the coupling of Fmoc-glycine to the N-alkylated phenylalanine derivatives was effected with DIC/HOAt in SPPS, the dipeptide building units with more bulky amino acids were pre-built in solution. For backbone cyclization at the C-terminus an alternative building unit with an acylated reduced peptide bond was preformed in solution. Both types of building units were handled in the SPPS in the same manner as amino acids. The agonistic and antagonistic activities of the cyclic BK analogues were determined in rat uterus (RUT) and guinea-pig ileum (GPI) assays. Additionally, the potentiation of the BK-induced effects was examined. Among the series of cyclic BK agonists only compound 3 with backbone cyclization between positions 2 and 5 shows a significant agonistic activity on RUT. To study the influence of intramolecular ring closure we used an antagonistic analogue with weak activity, [D-Phe7]-BK. Side chain as well as backbone cyclization in the N-terminus of [D-Phe7]-BK resulted in analogues with moderate antagonistic activity on RUT. Also, compound 18 in which a lactam bridge between positions 6 and 9 was achieved via an acylated reduced peptide bond has moderate antagonistic activity on RUT. These results support the hypothesis of turn structures in both parts of the molecule as a requirement for BK antagonism. Certain active and inactive agonists and antagonists are able to potentiate the bradykinin-induced contraction of guinea-pig ileum.     

Beta-sheet side chain polymers synthesized by atom-transfer radical polymerization

Silks are a widely studied class of naturally occurring structural proteins. Dragline spider silk, in particular, is considered to be nature's high-performance material due to its remarkable combination of strength and toughness. These mechanical properties stem from the protein secondary structure, a combination of well-defined beta-sheets in a less well-defined glycine-rich matrix. The translation of this structure into a synthetic polymer was the aim of this investigation. To achieve this, a peptide-based monomer containing the sequence alanine-glycine-alanine-glycine, a well-known beta-sheet-forming sequence found in silk, was synthesized. Using atom-transfer radical polymerization and a bifunctional initiator, a well-defined peptide-based polymer was prepared. This was then used as the macroinitiator for the polymerization of methyl methacrylate. The resulting well-defined triblock copolymer was analyzed using IR spectroscopy, which clearly showed beta-sheet secondary structure had been introduced.     

Synthesis and delivery activity of new cationic cholesteryl glucosides

Cholesterol amphiphiles containing positively charged groups (pyridinium, N-methylimidazolium, N-methylmorpholinium, and N-methylpiperidinium) linked via β-glucosyl spacer were prepared by alkylation of the corresponding bases with 6-О-mesyl-β-d-cholesteryl glucopyranoside. IC₅₀ values were in the range 20-35 μM for the series of compounds and liposomal formulations with DOPE (1:1) were significantly less toxic. The liposomal formulations provided the accumulation of FITC-labeled oligonucleotide in cells, and the efficiency of this process was comparable to that of Lipofectamine® 2000. Cationic liposomes were able to deliver siRNA into the cells, and the liposomal formulation 7d/DOPE provided the most pronounced down-regulation of EGFP expression both in the presence and in the absence of serum (up to 30%).     

Synthesis and antimalarial properties of new chloro-9H-xanthones with an aminoalkyl side chain

The synthesis and antimalarial properties of twelve new chlorinated 9H-xanthones, carrying a [2-(diethylamino)ethyl]amino group in position 1, are reported. All compounds were found to be active towards the chloroquine-susceptible and chloroquine-resistant strains 3D7 and Dd2, resp., of the protozoa parasite Plasmodium falciparum. Especially one compound, 6-chloro-1-{[2-(diethylamino)ethyl]amino}-9H-xanthen-9-one (1k), was found to exhibit significant in vitro activity (IC50 = 3.9 microM) towards the resistant Dd2 strain.     

Synthesis and antimalarial activity of new chloroquine analogues carrying a multifunctional linear side chain

We report the synthesis and in vitro antimalarial activity of several new 4-amino- and 4-alkoxy-7-chloroquinolines carrying a linear dibasic side chain. Many of these chloroquine analogues have submicromolar antimalarial activity versus HB3 (chloroquine sensitive) and Dd2 (chloroquine resistant strain of Plasmodium falciparum) and low resistance indices were obtained in most cases. Importantly, compounds 11–15 and 24 proved to be more potent against Dd2 than chloroquine. Branching of the side chain structure proved detrimental to the activity against the CQR strain.     

Synthesis of new phorbol derivatives having ethereal side chain and evaluation of their anti-HIV activity

Several new phorbol derivatives having ethereal substituents at the 12-position were synthesized and subjected to biological evaluation to find new candidates of an anti-HIV agent. Among them, 12-O-(methoxymethyl)phorbol 13-decanoate showed potent inhibitory activity against infection of HIV-1 in MT-4 cells (EC50: 1.3 ng/mL) and relatively low cytotoxicity (CC50: 8.3 microg/mL). This compound was also found to have sufficient stability in mouse plasma compared with the corresponding 12-acetate derivative, which was an equipotent HIV-1 inhibitor, but with an activity that decreased considerably after plasma treatment.     

Synthesis of dehydroalanine fragments as thiostrepton side chain mimetics

Syntheses of dehydroalanine derivatives via a solid-support route, starting from selenocystein, and via conventional solution phase chemistry are described along with initial biological testing. The target compounds were designed as mimetics of the dehydroalanine side chain of the macrocyclic antibiotic thiostrepton that acts on the bacterial ribosome.     

Synthesis and anticancer activity of side chain analogs of the crambescidin alkaloids

Twenty three side chain analogs of the crambescidin alkaloids were prepared from the corresponding pentacyclic zwitterionic core acid. In the crambescidin 800 and 657 series, potency increased with increasing chain length. In addition, substantial variations in tumor selectivity with structure were seen. Crambescidin analogs having short, nonpolar side chains were identified for the first time as promising anticancer agents.     

Synthesis and cytotoxicity of oligomycin A derivatives modified in the side chain

A novel way of chemical modification of the macrolide antibiotic oligomycin A (1) at the side chain was developed. Mesylation of 1 with methane sulfonyl chloride in the presence of 4-dimethylaminopyridine produced 33-O-mesyl oligomycin in 56% yield. Reactions of this intermediate with sodium azide produced the key derivative 33-azido-33-deoxy-oligomycin A in 60% yield. 1,3-Dipolar cycloaddition reaction with propiolic acid, methyl ester of propiolic acid, and phenyl acetylene resulted in 33-deoxy-33-(1,2,3-triazol-1-yl)oligomycin A derivatives substituted at N4 of the triazole cycle. The mesylated oligomycin A and 33-deoxy-33-azidooligomycin A did not inhibit F₀F₁ ATFase ATPase; however, 33-azido-33-deoxy-oligomycin A and the derivatives containing 4-phenyltriazole, 4-methoxycarbonyl-triazole and 3-dimethylaminoethyl amide of carboxyltriazole substituents demonstrated a high cytotoxicity against K562 leukemia and HCT116 human colon carcinoma cell lines whereas non-malignant skin fibroblasts were less sensitive to these compounds. Novel series of oligomycin A derivatives allow for the search of intracellular molecules beyond F₀F₁ ATP synthase relevant to the cytotoxic properties of this perspective chemical class.     

Synthesis of novel heterobranched beta-cyclodextrins having beta-D-N-acetylglucosaminyl-maltotriose on the side chain

From a mixture of N-acetylglucosaminyl-beta-cyclodextrin (GlcNAc-betaCD) and lactose, beta-D-galactosyl-GlcNAc-betaCD (Gal-GlcNAc-betaCD) was synthesized by the transfer action of beta-galactosidase. GlcNAc-maltotriose (Glc3) and Gal-GlcNAc-Glc3 were produced with hydrolysis of GlcNAc-betaCD by cyclodextrin glycosyltransferase, and Gal-GlcNAc-betaCD by bacterial saccharifying alpha-amylase respectively. Finally, GlcNAc-Glc3-betaCD and Gal-GlcNAc-Glc3-betaCD were synthesized in 5.2% and 3.5% yield when Klebsiella pneumoniae pullulanase was incubated with the mixture of GlcNAc-Glc(3) and betaCD, or Gal-GlcNAc-Glc3 and betaCD respectively. The structures of GlcNAc-Glc3-betaCD and Gal-GlcNAc-Glc3-betaCD were analyzed by FAB-MS and NMR spectroscopy and identified as 6-O-alpha-(6(3)-O-beta-D-N-acetylglucosaminyl-maltotriosyl)-betaCD, and 6-O-alpha-(4-O-beta-D-galactopyranosyl-6(3)-O-beta-D-N-acetylglucosaminyl-maltotriosyl)-betaCD respectively.     

Synthesis and antibacterial activity of the C-7 side chain of 3-aminoquinazolinediones

A novel series of bacterial topoisomerase (3-aminoquinazolinediones) inhibitors are described. The side-chain SAR against Gram-positive and Gram-negative organisms as well as DNA gyrase activity is reported.     

Synthesis and reactivity with beta-lactamases of a monobactam bearing a retro-amide side chain

The monobactam sodium 3-benzylcarbamoyl-2-oxo-1-azetidinesulfonate, bearing a retro (vs classical beta-lactam)-amide side chain, has been synthesized and the kinetics of its reaction with typical beta-lactamases studied. The new compound is generally a poorer substrate than the analogous compound with a normal side chain but its formation of a transiently stable complex with a class C beta-lactamase sustains the retro-amide side-chain concept.     

Synthesis and spectroscopic characterisation of new ESIPT fluorescent protein probes.

Three new benzazole isothiocyanate fluorescent dyes, 2-(4'-isothiocyanate-2'-hydroxyphenyl)benzoxazole, 2-(4'-isothiocyanate-2'-hydroxyphenyl)benzothiazole and 2-(4'-isothiocyanate-2'-hydroxyphenyl)benzimidazole were synthesised, purified until optical purity grade and characterised by spectroscopic techniques. UV/VIS and steady-state fluorescence were also applied to characterise the photophysical behaviour of the dyes. These dyes exhibit an intense fluorescence emission with a large Stokes shift, inherent to the class of benzazoles which relax by the excited state intramolecular proton transfer (ESIPT) mechanism. The dyes were studied for labeling bovine serum albumin (BSA), resulting conjugates BSA-dye with a remarkable photostability under UV/VIS radiation in relation to classical protein labels. The resulting conjugates presented fluorescence in the blue-green region. Direct fluorescence detection of protein-labeled with those dyes after polyacrylamide gel electrophoresis indicates their potential use as fluorescent probes for proteins.     

Molecularly imprinted polymers: synthesis and characterisation

This short review aims to present, in clear English, a summary of the principal synthetic considerations pertaining to good practice in the polymerisation aspects of molecular imprinting, and is primarily aimed at researchers familiar with molecular imprinting methods but with little or no prior experience in polymer synthesis. It is our hope that this will facilitate researchers to plan their own syntheses of molecular imprints in a more logical and structured fashion, and to begin to appreciate the limitations of the present synthetic approaches in this molecularly complex area, as well as the scope for rationally designing improved imprinted materials in the future.     

Effects of side chain configuration and backbone spacing on the gene delivery properties of lysine-derived cationic polymers

A series of lysine-based oligomers (18 residues) that differ in side chain configuration or side chain spacing along the backbone was tested for DNA transfection activity. Although materials constructed from lysine are not the most effective polymeric transfection agents, we have chosen L-lysine-based molecules as a starting point because this system allows us to examine the functional effects of incremental changes in polycation structure. The oligomer constructed from beta(3)-homolysine (beta(3)-hLys) and that from alpha-D-lysine were superior to an alpha-L-lysine 18-mer in gene delivery assays. This improved activity is attributed to the fact that the alpha-L-peptide is a protease substrate while the other 18-mers are not. This conclusion is supported by the effects of chloroquine on transfection activity, based on the protease inhibition activity of chloroquine. To our knowledge, these results represent the first direct comparison of a D-lysine oligomer with an L-lysine oligomer in the context of gene delivery. Poly(beta(3)-hLys) was synthesized from the ring opening polymerization of the corresponding lactam. The DNA transfection ability of this polymer was compared with that of commercially available poly(L-lysine) (PLL). In each case the polymer was more active than the corresponding oligomer.     

Synthesis and electrochemical characterisation of new tantalum (V) alkythio phthalocyanines

The synthesis and electrochemical characterisation of octa-pentylthio (4a) and octa-octylthio (4b) - phthalocyaninato tantalum (III) hydroxide are hereby reported. These TaPc complexes absorb in the near infrared region (∼800 nm in dichloromethane). They show good solubility in most common solvents especially non-viscous solvents such as dichloromethane and chloroform. NMR, mass and infrared spectroscopy and elemental analysis confirmed the structures and purity of the synthesised complexes. The cyclic voltammograms (CVs) showed reversible reduction couples and irreversible oxidation peaks. The latter exhibited adsorption behavior. The reduction processes were observed at −0.74 and −1.13 V (versus Ag|AgCl) for 4a, and −0.67, −1.02 and −1.48 V (versus Ag|AgCl) for 4b. Spectroelectrochemistry confirmed one metal reduction, with the rest of the redox processes being centered on the phthalocyanine ring.     

A new approach to the rapid determination of protein side chain conformations

Two efficient algorithms have been developed which allow amino acid side chain conformations to be optimized rapidly for a given peptide backbone conformation. Both these approaches are based on the assumption that each side chain can be represented by a small number of rotameric states. These states have been obtained by a dynamic cluster analysis of a large data base of known crystallographic structures. Successful applications of these algorithms to the prediction of known protein conformations are presented.     

Synthesis of cholesteryl doxorubicin and its anti-cancer activity

Doxorubicin (dox) has been used as anti-cancer agent, but there are disadvantages such as rapid excretion, short retention time and cardiotoxicity. For giving lipophilic properties to dox, it was modified with cholesterol derivatives that were validated as a component of liposomal gene delivery. This article describes the synthesis of dox derivatives (lipo-dox A-D), their cytotoxicity and cellular uptake. In A549, HeLa, MCF7 and MDA MB 231 cell lines, lipo-dox A and lipo-dox B substituted at alcohol group showed similar anti-cancer effect as dox, but lipo-dox C and lipo-dox D substituted at amino group did not. As a result, the amino group of dox seems an important site for its cancer cell inhibition. Lipophilic property of lipo-dox A and lipo-dox B induced more accumulation in cells compared to parent drug. Therefore, the newly synthesized lipo-dox A and lipo-dox B would be a good candidate for anti-cancer agent.     

Synthesis and characterisation of polyglucuronan

Several samples of polyglucuronan have been prepared by oxidation of cellulose with nitrogen oxides. Optimisation of the reaction conditions in terms of degree of oxidation and molecular weight of the products was carefully performed.