Synthesis of truncated analogues of preptin-(1–16), and investigation of their ability to stimulate osteoblast proliferation

Preptin, a 34-amino acid residue peptide hormone is co-secreted with insulin from the β-pancreatic cells and is active in fuel metabolism. We have previously established that a shorter fragment of preptin, namely preptin-(1–16), stimulates bone growth by proliferation and increasing the survival rate of osteoblasts. This was demonstrated in both in vitro and in vivo models. These findings suggest that preptin-(1–16) could play an important role in the anabolic therapy of osteoporosis. However, due to the large size of the peptide it is not an ideal therapeutic agent. The aim of this study was to identify the shortest preptin analogue that retains or even increases the bone anabolic activity as compared to the parent preptin-(1–16) peptide. Truncations were made in a methodical manner from both the N-terminus and the C-terminus of the peptide, and the effect of these deletions on the resulting biological activity was assessed. In order to improve the enzymatic stability of the shortest yet active analogue identified, ruthenium-catalysed ring closing metathesis was used to generate a macrocyclic peptide using allylglycine residues as handles for ring formation. We have successfully identified a short 8-amino acid preptin (1–8) fragment that retains an anabolic effect on the proliferation of primary rat osteoblasts and enhances bone nodule formation. Preptin (1–8) is a useful lead compound for the development of orally active therapeutics for the treatment of osteoporosis.     

The effective molarity (EM) - A computational approach

The effective molarity (EM) for 12 intramolecular S_N2 processes involving the formation of substituted aziridines and substituted epoxides were computed using ab initio and DFT calculation methods. Strong correlation was found between the calculated effective molarity and the experimentally determined values. This result could open a door for obtaining EM values for intramolecular processes that are difficult to be experimentally provided. Furthermore, the calculation results reveal that the driving forces for ring-closing reactions in the two different systems are proximity orientation of the nucleophile to the electrophile and the ground strain energies of the products and the reactants.     

Synthetic access to spacer-linked 3,6-diamino-2,3,6-trideoxy-alpha-D-glucopyranosides--potential aminoglycoside mimics for the inhibition of the HIV-1 TAR-RNA/Tat-peptide complex

The synthesis of spacer-linked neoaminoglycoside 5 is described. Key steps of the synthesis are the introduction of nitrogen functionalities at C-3 and C-6 and the olefin cross metathesis of allyl glycoside 16. Although it is known that Grubbs catalysts tolerate nitrogen functionalities, difficulties were encountered in the cross metathesis reaction. Factors that govern this dimerization are the steric and electronic demands of the catalyst and the substrate. Preliminary biological evaluation of homodimer 5, by studying the inhibition of HIV-1 TAR-RNA/Tat-peptide complex using a method based on fluorescence titration, revealed an inhibitory effect of 5.     

Volatiles in Distillates of Fresh Radish of Japanese and Kenyan Origin

The steam-volatile constituents of fresh radish of Japanese and Kenyan origin have been studied by GC-MS technique. The over-all pattern of compounds in the two materials was similar. Ten mustard oils, of which pentyl, hexyl, and 4-methylpentyl isothiocyanate have not previously been reported as products of natural derivation, two related nitriles, dimethyl disulfide, methyl methanethiolsulfinate and 1-methylthio-3-pentanone, a novel sulfide-ketone, together constitute the major volatile sulfur products in the two radish materials. A few non-sulfur volatiles have also been identified. The diversity in chemical structure of the sulfur constituents becomes less surprising when regarded in terms of their biogenetic origin.     

Diurnal Changes in Uric Acid Metabolism of Rats Fed a Casein Diet

Direct gas chromatographic determination of tobacco smoke was developed. Tobacco smoke condensate was collected on a glass fiber filter and the components were converted into their trimethylsilyl derivatives and then subjected to glass capillary column gas chromatography. By this method, all tobacco smoke components, including unstable phenolic substances and water-soluble polyhydroxy compounds, were simultaneously determined. Compositional differences between lamina and midrib smoke of flue-cured tobacco leaves were also clarified by the method. The results indicate that there are quantitative differences in nicotine, phenols, levoglucosan, quinic acid γ-lactone and the other major components between lamina and midrib smoke.     

Synthesis of purine homo-N-nucleosides modified with coumarins as free radicals scavengers*

Cross metathesis (CM) of 9-butenylpurines with 4-butenyloxycoumarin in the presence of Grubbs 2nd generation catalyst under MW irradiation resulted to conjugated compounds containing homo-N-nucleosides and coumarins. Analogous derivatives received by the CM reaction of 9-butenyl-6-piperidinylpurine with 6- or 7-butenyloxycoumarins, allyloxycoumarins or coumarinyl acrylate. These compounds were tested in vitro for their antioxidant activity and they present significant scavenging activity. The presence of a pentenyloxy moiety, the attachment position on coumarin ring as well as a purine homo-N-nucleoside group are considered as important structural features.     

Synthesis and Antitumor Activity of Fluorocyclopentenyl-Pyrimidines

Synthesis of fluorocyclopentenyl pyrimidine nucleosides 6–9 was enantiopurely accomplished employing oxidative rearrangement, RCM reaction and electrophilic fluorination starting from d-ribose. Cytosine analog 8 was found to exhibit significant anticancer activity in various human tumor cell lines.     

New Dinucleoside Analogues via Cross-Coupling Metathesis

Synthesis of 3′-3′, 5′-5′, and 3′-5′ dimeric thymidine, linked by an olefinic chain between glycosidic moieties is described. Cross metathesis reaction of 3′ or 5′ O-allyl analogues of thymidine led to the expected 3′-3′ and 5′-5′ dimeric compounds, respectively. In order to obtain the 3′-5′ dimer, 5′-O-allyl and 3′-O-allyl monomers were first linked by their free 3′ OH and 5′ OH groups through a glutaryl spacer; ring closing metathesis was then operated upon this temporary dimer, followed by glutaryl removal.     

Tandem Ru‐alkylidene‐catalysed cross metathesis/hydrogenation: synthesis of lipophilic amino acids

Highly efficient synthesis of lipidic amino acids can be achieved via Ru‐alkylidene‐catalysed cross metathesis of long chain alkenes with commercially available allylglycine. The resultant unsaturated analogues can be then optionally hydrogenated under mild reaction conditions by using the spent metathesis catalyst. Copyright © 2013 European Peptide Society and John Wiley & Sons, Ltd.     

Synthesis of 3-vinyl-2,5-dihydrofuran ring system via enyne metathesis

An efficient route, starting from but-3-en-1,2-diol, is described to synthesize racemic diastereoisomeric (5-ethoxy-4-vinyl-2,5-dihydrofuran-2-yl) methanol derivatives. Acyclic enyne intermediates having the alkyne moiety directly connected to the asymmetric carbon atom of an acetal were obtained in two steps. These reactive substrates were then subjected to ruthenium-catalyzed enyne metathesis to produce the target compounds in racemic form. The relative configurations were determined by NOE proton NMR experiments. Similar strategy starting from (2S)-but-3-en-1,2-diol was proposed to provide pure enantiomers.