Synthesis of 2-arylamino substituted 5,6-dihydropyrido[2,3-d]pyrimidine-7(8H)-ones from arylguanidines

A practical protocol was developed for the synthesis of 2-arylamino substituted 4-amino-5,6-dihydropyrido[2,3-d]pyrimidin-7(8H)-ones from ??,??-unsaturated esters, malononitrile, and an aryl substituted guanidine via the corresponding 3-aryl-3,4,5,6- tetrahydropyrido[2,3-d]pyrimidin-7(8H)-ones. Such compounds are formed upon treatment of 2-methoxy-6-oxo-1,4,5,6-tetrahydropyridine-3-carbonitriles with an aryl substituted guanidine in 1,4-dioxane and are converted to the desired 4-aminopyridopyrimidines with NaOMe/MeOH through a Dimroth rearrangement. The overall yields of this three-step protocol are, generally speaking, higher than the multicomponent reaction, previously developed by our group, between an ??,??-unsaturated ester, malononitrile, and an aryl substituted guanidine.     

Algebraic Characterizations for Universal Fragments of Logic

In this paper we address our efforts to extend the well-known connection in equational logic between equational theories and fully invariant congruences to other–possibly infinitary–logics. In the special case of algebras, this problem has been formerly treated by H. J. Hoehnke [10] and R. W. Quackenbush [14]. Here we show that the connection extends at least up to the universal fragment of logic. Namely, we establish that the concept of (infinitary) universal theory matches the abstract notion of fully invariant system. We also prove that, inside this wide group of theories, the ones which are strict universal Horn correspond to fully invariant closure systems, whereas those which are universal atomic can be characterized as principal fully invariant systems.     

Evidence of the existence of micelles in the fibrillogenesis of beta-amyloid peptide

Alzheimer's disease (AD) is characterized by the deposition of fibrillar deposits formed by the amyloid beta (Abeta) peptide. The most widely accepted model of fibrillogenesis of Abeta affirms that fibrillogenesis occurs in two distinct stages, nucleation and elongation. A modification of the model includes the formation of micelles. We have demonstrated with accurate experimental determinations the existence of aggregates with micellar properties (namely, the critical micellar concentration, CMC, and aggregation number). Values of the CMC were obtained by analysis of surface tension (17.5 microM) and changes in the fluorescence of pyrene (17.6 microM), respectively. The average aggregation number determined by fluorescence quenching was 25, and it was independent of peptide concentration. The presence of micelles implies that above the CMC all excess peptide is incorporated into micelles, and consequently, the monomer concentration is kept almost constant. Thus, micelles act as a peptide reservoir. Micelles are located on-pathway, since they serves as nucleation centers. Experimental data support the model, since above 17.7 microM the time of half-aggregation is independent of peptide concentration, and the overall reaction of the conversion of monomer peptide into fibril can be treated as an apparent first-order reaction.     

Stimulatory and inhibitory effects of alkyl bromide surfactants on beta-amyloid fibrillogenesis

Beta-amyloid peptide (Abeta), in fibrillar form, is the primary constituent of senile plaques, a defining feature of Alzheimer's disease. In solution assays, fibril formation exhibits a lag time, interpreted as a nucleation/condensation-dependent process. The kinetics of fibrillogenesis is controlled by two key parameters: nucleation and elongation rate constants. We characterized the time course of Abeta fibril formation by measuring the scattering caused by peptide aggregates. We report here the interaction of Abeta with three alkylammonium bromides (dodecyl, tetradecyl, and hexadecyl) at supra- and submicellar concentrations and their influence on the kinetic constants. We observed a dual behavior: surfactants promoted or retarded fibril formation in a concentration-dependent manner. Below a determined surfactant concentration (close to the corresponding critical micellar concentration in medium without peptide), surfactants favor aggregation, presumably by means of electrostatic interactions that destabilize the native conformation. Beyond such concentration, the stabilizing effects of the monomer predominate. As a general rule, surfactants delay but do not completely inhibit aggregation.     

1H-Pyrazolo[3,4-b]pyridines: Synthesis and Biomedical Applications

Pyrazolo[3,4-b]pyridines are a group of heterocyclic compounds presenting two possible tautomeric forms: the 1H- and 2H-isomers. More than 300,000 1H-pyrazolo[3,4-b]pyridines have been described which are included in more than 5500 references (2400 patents) up to date. This review will cover the analysis of the diversity of the substituents present at positions N1, C3, C4, C5, and C6, the synthetic methods used for their synthesis, starting from both a preformed pyrazole or pyridine, and the biomedical applications of such compounds.     

Effect of the graft ratio on the properties of polythiophene‐g‐poly(ethylene glycol)

Graft copolymers formed by anchoring poly(ethylene glycol) (PEG) chains to conjugated polythiophene have been prepared by copolymerizing two compounds: unsubstituted α‐terthiophene (Th₃) and a thiophene‐derived macromonomer having an α‐terthiophene conjugated sequence and one Th₃ bearing a PEG chain with molecular weight of 2000 as substitute at the 3‐position of the central heterocycle (Th₃‐PEG₂₀₀₀). The grafting ratio of the resulting copolymers (PTh₃^*‐g‐PEG), which were obtained using 75:25 and 50:50 Th₃‐PEG₂₀₀₀:Th₃ weight ratios, is significantly smaller than that of copolymers derived from polymerization of macromonomers consisting of a α‐pentathiophene sequence in which the central ring bears a PEG chain of M_w = 2000 (PTh₅‐g‐PEG). The electroactivity and electrochemical stability of PTh₃^*‐g‐PEG is not only higher than that of PTh₅‐g‐PEG but also higher than that of PTh₃, the latter presenting a very compact structure that makes difficult the access and escape of dopant ions into the polymeric matrix during the redox processes. Furthermore, the optical π‐π^* lowest transition energy of PTh₃^*‐g‐PEG is lower than that of both PTh₅‐g‐PEG and PTh₃. These properties, combined with suitable wettability and roughness, result in an excellent behavior as bioactive platform of PTh₃^*‐g‐PEG copolymers, which are more biocompatible, in terms of cellular adhesion and proliferation, and electro‐compatible than PTh₅‐g‐PEG. © 2014 Wiley Periodicals, Inc. J. Polym. Sci., Part B: Polym. Phys. 2015 , 53, 239–252     

Histidine‐Rich Oligopeptides To Lessen Copper‐Mediated Amyloid‐β Toxicity

Brain copper imbalance plays an important role in amyloid‐β aggregation, tau hyperphosphorylation, and neurotoxicity observed in Alzheimer's disease (AD). Therefore, the administration of biocompatible metal‐binding agents may offer a potential therapeutic solution to target mislocalized copper ions and restore metallostasis. Histidine‐containing peptides and proteins are excellent metal binders and are found in many natural systems. The design of short peptides showing optimal binding properties represents a promising approach to capture and redistribute mislocalized metal ions, mainly due to their biocompatibility, ease of synthesis, and the possibility of fine‐tuning their metal‐binding affinities in order to suppress unwanted competitive binding with copper‐containing proteins. In the present study, three peptides, namely HWH , HK^CH , and HAH , have been designed with the objective of reducing copper toxicity in AD. These tripeptides form highly stable albumin‐like complexes, showing higher affinity for Cu^II than that of Aβ(1‐40). Furthermore, HWH , HK^CH , and HAH act as very efficient inhibitors of copper‐mediated reactive oxygen species (ROS) generation and prevent the copper‐induced overproduction of toxic oligomers in the initial steps of amyloid aggregation in the presence of Cu^II ions. These tripeptides, and more generally small peptides including the sequence His‐Xaa‐His at the N‐terminus, may therefore be considered as promising motifs for the future development of new and efficient anti‐Alzheimer drugs.