Effects of flavonoids on glycosaminoglycan synthesis: implications for substrate reduction therapy in Sanfilippo disease and other mucopolysaccharidoses

Sanfilippo disease (mucopolysaccharidosis type III, MPS III) is a severe metabolic disorder caused by accumulation of heparan sulfate (HS), one of glycosaminoglycans (GAGs), due to a genetic defect resulting in a deficiency of GAG hydrolysis. This disorder is characterized as the most severe neurological form of MPS, revealing rapid deterioration of brain functions. Among therapeutic approaches for MPS III, one of the most promising appears to be the substrate reduction therapy (SRT). Genistein (5, 7-dihydroxy-3- (4-hydroxyphenyl)-4H-1-benzopyran-4-one) is an isoflavone that has been used in SRT for MPS III. In this report, we tested effects of other flavonoids (apigenin, daidzein, kaempferol and naringenin) on GAG synthesis. Their cytotoxicity and anti-proliferation features were also tested. We found that daidzein and kaempferol inhibited GAG synthesis significantly. Moreover, these compounds were able to reduce lysosomal storage in MPS IIIA fibroblasts. Interestingly, although genistein is believed to inhibit GAG synthesis by blocking the tyrosine kinase activity of the epidermal growth factor receptor, we found that effects of other flavonoids were not due to this mechanism. In fact, combinations of various flavonoids resulted in significantly more effective inhibition of GAG synthesis than the use of any of these compounds alone. These results, together with results published recently by others, suggest that combination of flavonoids can be considered as a method for improvement of efficiency of SRT for MPS III

Self-adjuvanting polymer-peptide conjugates as therapeutic vaccine candidates against cervical cancer

Dendrimers are structurally well-defined, synthetic polymers with sizes and physicochemical properties often resembling those of biomacromolecules (e.g. proteins). As a result they are promising candidates for peptide-based vaccine delivery platforms. Herein, we established a synthetic pathway to conjugate a human papillomavirus (HPV) E7 protein-derived peptide antigen to a star-polymer to create a macromolecular vaccine candidate to treat HPV-related cancers. These conjugates were able to reduce tumor growth and eradicate E7-expressing TC-1 tumors in mice after a single immunization, without the help of any external adjuvant

Amidoalkylation of Phosphorus Trichloride with Acetamide and Alkyl Oxocycloalkanecarboxylates

Abstracting & Indexing Online Submissions Related Websites General Information Permissions Information Reprints iOpen Amidoalkylation of Phosphorus Trichloride with Acetamide and Alkyl Oxocycloalkanecarboxylates Authors: Zyta Ziora a;Pawelstrok Kafarski a Affiliation: a Department of Bioorganic Chemistry, Faculty of Chemistry, Technical University of Wroclstrokaw, Wroclstrokaw, Poland DOI: 10.1080/10426500902737356 Publication Frequency: 12 issues per year Published in: journal Phosphorus, Sulfur, and Silicon and the Related Elements, Volume 184, Issue 4 April 2009 , pages 1047 - 1053 Subjects: Inorganic Chemistry; Materials Chemistry; Organic Chemistry; Formats available: HTML (English) : PDF (English) You have: ACCESS ACCESS Previously published as: Phosphorous and Sulfur and the Related Elements (0308-664X) until 1989 Article Requests: Order Reprints : Request Permissions View Article: View Article (PDF) View Article (PDF) View Article (HTML) View Article (HTML) Abstract The course of the reaction between phosphorus trichloride, acetamide, and ethyl oxoalkanecarboxylates was studied in terms of the production of side-products. When alkyl 2-oxocycloalkanecarboxylates were used as substrates, together with the expected products—2-amino-2-phosphonocycloalkanecarboxylic acids—three side-products, namely 1-aminocycloalkanephosphonic acids (decarboxylation products of the latter compounds), 1-aminoethane-1,1-diphosphonic acids, and 1-hydroxyethane-1,1-diphosphonic acids were identified. Ethyl 1-oxocycloalkanecarboxylate afforded 4-amino-4-phosphonocyclohexane carboxylic acid in good yield. Copyright Taylor & Francis Group, LL

Effect of unsaturated bonds in the sn-2 acyl chain of phosphatidylcholine on the membrane-damaging action of Clostridium perfringens alpha-toxin toward liposomes

Clostridium perfringens alpha-toxin degrades phosphatidylcholine (PC) in the bilayer of liposomes and destroys the membrane. The effect of the type and position of unsaturation in the fatty acyl chain of PC (18:0/18:1 PC) synthesized on the toxin-induced leakage of carboxyfluorescein (CF) from PC liposomes was examined. Differential scanning calorimetry showed that the phase transition temperature (T.) was minimal when the triple bond was positioned at C (9) in the sn-2 acyl chain. The toxin-induced CF leakage decreased with the migration of the bond from C (9) to either end of the acyl chain in PC. The PC containing the cis-double bond had a similar T-m to that with the triple bond, but a lower value than the PC containing the trans-double bond. Furthermore, the toxin-induced leakage from liposomes composed of PC containing the cis-double bond resembled that with PC having the triple bond and was greater than that from liposomes with PC having the trans-double bond. The binding of a H148G mutant to PC liposomes showed a reciprocal relationship in terms of the T-m value of PC containing the triple bond. These results indicate that the toxin-induced membrane damage is closely related to membrane fluidity in liposomes. (c) 2007 Elsevier B.V. All rights reserved

Peptidomimetic synthesis: drug discovery for Alzheimer's disease

The biomolecular system mainly consists of nucleic acids, proteins, peptides, and sugar chains, and they play a critical role in cell growth, differentiation induction, apoptosis, and immunity. Among these components, peptides are the most commonly studied due to their relatively low molecular weight and high biocompatibility as well as in vitro and in vivo lability and often applied as drugs, agricultural chemicals, food, and tools in diagnostic and biological research. Peptidomimetics have been reported to function as protein-protein interaction inhibitors and thus could serve in many biomolecular systems. This chapter describes the synthesis of peptidomimetics used for discovery of drugs that target β-secretase inhibitors and amyloid-β aggregation inhibitors in Alzheimer's disease. For this purpose, natural amino acids and other synthetic acids or amines were used in a solid-phase peptide synthesis (SPPS)