Novel therapeutic agents for bone resorption. Part 1. Synthesis and protonation thermodynamics of poly(amido-amine)s containing bis-phosphonate residues

Two poly(amido-amine)s (oligoPAM and oligoNER) containing bis-phosphonate residues were obtained by a Michael-type polyaddition of pamidronate and neridronate to 1,4-bis(acryloyl)piperazine. The SEC (size-exclusion chromatography) and the MALDI-TOF (matrix assisted laser desorption ionization) analyses were consistent with the presence of oligomeric species (2-3 kDa) and with a narrow polydispersity index. The thermodynamic results (log Ks, -DeltaH(o) , and DeltaS(o) obtained at 25 degrees C in 0.15 M NaCl) of both the oligomers and the corresponding low molecular weight precursors were in line with a cluster structure formed during the protonation of the basic nitrogen in the pamidronate. The solubility of the oligoNER with a longer aliphatic chain was improved at high pHs, allowing the evaluation of their solution properties. Preliminary biological results show that both the oligomers do not negatively affect the in vitro viability, proliferation, and cellular activity of either normal animal or human osteoblasts.     

Novel glycosylated [Lys(7)]-dermorphin analogues: synthesis, biological activity and conformational investigations.

Syntheses of the [Lys(7)]- and [Hyp(6),Lys(7)]-dermorphin analogues in which either Tyr(5) or Hyp(6) are O-glucosylated are described. For comparison, the carbohydrate-free peptides have also been prepared. Structural investigations by FT-IR and CD measurements were carried out on the synthetic analogues and some preliminary pharmacological experiments were also performed.The biological potency of the glucosylated analogues was compared with that of the micro-opioid receptor agonist dermorphin in GPI preparations. Glucosylation of either Tyr(5) or Hyp(6) reduces the potency of both [Lys(7)]-dermorphin and [Hyp(6),Lys(7)]-dermorphin. The effect induced by the Tyr(5) glucosylation is quite strong and the potency of both peptides is reduced by about 150 times. A similar but less dramatic effect is induced by the glucosylation of the Hyp(6) residue, and the potency of the parent peptide is reduced by about 15 times. The presence of acetyl groups on the sugar hydroxyl functions further reduces the agonistic potency of the glucosylated analogues. The analgesic potency of [Hyp(6),Lys(7)]-, [Hyp(betaGlc)(6),Lys(7)]- and [Tyr(betaGlc)(5),Lys(7)]-dermorphin were also tested in vivo by the tail-flick test. The glucosylated hydroxyproline-containing analogue is 8-10 times less active than the parent peptide, but its analgesic effect lasts significantly longer.     

Transcranial Direct Current Stimulation (tDCS) Induces Analgesia in Rats with Neuropathic Pain and Alcohol Abstinence

Neurochemical Research - Neuromodulatory techniques have been studied to treat drug addiction or compulsive eating as well as different chronic pain conditions, such as neuropathic and inflammatory...     

Fractionation of sugar beet pulp by introducing ion-exchange groups

Sugar beet pulp (SBP) was chemically modified with the goal to utilize this method for the preparation of water-soluble polysaccharides. Yields of the trimethylammoniumhydroxypropylated (TMAHP) polysaccharide fractions prepared under vacuum in absence of NaOH or KOH, as well as their molar masses, were higher than those obtained when the samples were only extracted with hydroxide at ambient pressure. The hydroxypropylsulfonated (HPS) fractions extracted at ambient pressure with NaOH had higher yields and molar mass than the TMAHP fractions extracted under vacuum with KOH. Introduction of both ion-exchange groups in one step under vacuum with NaOH gave better yields than with KOH, but smaller than for the solely sulfonated sample. The molar masses of chemically modified fractions were smaller than those extracted only with alkali or water. According to the monosaccharide composition all the fractions are mixtures of arabinogalactans and rhamnogalacturonoans.     

Structural characterization of cyclic kallidin analogues in DMSO by nuclear magnetic resonance and molecular dynamics.

The conformational properties in DMSO of two head-to-tail cyclic analogues of kallidin ([Lys(0)]-bradykinin, KL) as well as those of the corresponding linear peptides were studied by NMR and molecular dynamics (MD) simulations. The modifications in the sequence were introduced at position 6, resulting in the four peptides, [Tyr(6)]-KL (YKL), [Trp(6)]-KL (WKL), cyclo-([Tyr(6)]-KL) (YCKL) and cyclo-([Trp(6)]-KL) (WCKL).The linear WKL analogue was significantly more potent than kallidin on rat duodenum preparations, whereas YKL was significantly less potent. Both cyclic peptides, YCKL and WCKL displayed similar activity, lower than that of the linear analogues and also of cyclo-KL.The two linear analogues display high conformational flexibility in DMSO. In the predominant conformer, for both peptides, all three X-Pro bonds adopt a trans configuration. Three out of four conformers present in YCKL and WCKL were completely assigned. The configurations at the X-Pro bonds are the same for the two analogues. All cyclic conformers show a cis configuration in at least one X-Pro bond and always opposite configuration for the two consecutive X-Pro bonds.The NOE-restrained MD calculations resulted in the detection of several elements of secondary structure in each of the conformers. Such elements are described and their possible relevance to biological activity is discussed.     

Novel N1-substituted 1,3-dihydro-2H-benzimidazol-2-ones as potent non-nucleoside reverse transcriptase inhibitors

Several N(1)-substituted 1,3-dihydro-2H-benzimidazol-2-ones were synthesized and evaluated as anti-HIV agents. Some of them proved to be highly effective in inhibiting HIV-1 replication at nanomolar concentration as potent non-nucleoside HIV-1 RT inhibitors (NNRTIs) with low cytotoxicity. SAR studies highlighted that the nature of the substituents at N(1) and on the benzene ring of benzimidazolone moiety significantly influenced the anti-HIV activity of this class of potent antiretroviral agents.     

Non-covalent associations of cyclomaltooligosaccharides (cyclodextrins) with carotenoids in water. A study on the alpha- and beta-cyclodextrin/psi,psi-carotene (lycopene) systems by light scattering,ionspray ionization and tandem mass spectrometry

Water-soluble complexes of the dietary carotenoid psi,psi-carotene (lycopene 1) with cyclomaltohexaose (alpha-cyclodextrin, alphaCD) and cyclomaltoheptaose (beta-cyclodextrin, betaCD) have been prepared and characterized via multiangle light scattering (MALS), ionspray/electrospray ionization (IS/ESI) mass spectrometry (MS) and tandem MS. MALS experiments point out that large aggregates of particles, on the nanometer-size scale, are present in water, with meaningful differences in the shape of the alphaCD/1 aggregates with respect to betaCD/1 analogues. The true 1:1 alphaCD/1 inclusion complex has been observed by IS/ESIMS and confirmed by tandem MS. The structure of CD/1 aggregations in water is proposed which are consistent with the combined MALS and MS experimental results.     

Associating hyaluronan derivatives: a novel horizon in viscosupplementation of osteoarthritic joints

The association of two high-molecular-weight hyaluronan (HA) derivatives, namely a beta-cyclodextrin (HA-beta-CD) and an N-acylurea (EDC-HA), dissolved in aqueous NaCl, was studied. The weight-average of the molecular weights (Mw) of HA-beta-CD and of EDC-HA was 185.3 and 86.8 kDa, respectively. However, the Mw value determined for the equimolar mixture of the two biopolymers equaled 556.0 kDa. Similarly, the radius of gyration (dimension) Rg = 80.6 nm of the above equimolar mixture was significantly greater than the values found for the single macromolecules, i.e., 40.2 nm for HA-beta-CD and 23.8 nm for EDC-HA. These data indicate that the two kinds of substituents, borne by the HA polymeric chains, form host-guest inclusion complexes resulting in polymacromolecular associates/aggregates.