Synthesis and SAR of novel isoxazoles as potent c-jun N-terminal kinase (JNK) inhibitors

The design and synthesis of isoxazole 3 is described, a potent JNK inhibitor with two fold selectivity over p38. Optimization of this scaffold led to compounds 27 and 28 which showed greatly improved selectivity over p38 by maintaining the JNK3 potency of compound 3. Extensive SAR studies will be described as well as preliminary in vivo data of the two lead compounds.     

Synthesis and SAR studies of 1,4-diazabicyclo[3.2.2]nonane phenyl carbamates – subtype selective,high affinity α7 nicotinic acetylcholine receptor agonists

The synthesis and SAR studies about the bicyclic amine, carbamate linker and aromatic ring of a 1,4-diazabicyclo[3.2.2]nonane phenyl carbamate series of α7 nAChR agonists is described. The development of the medicinal chemistry strategy and SAR which led to the identification of 5 and 7aa as subtype selective, high affinity α7 agonists as excellent leads for further evaluation is discussed, along with key physicochemical and pharmacokinetic data highlighting their lead potential.     

Highly tunable thiosulfonates as a novel class of cysteine protease inhibitors with anti-parasitic activity against Schistosoma mansoni

The development of a new class of cysteine protease inhibitors utilising the thiosulfonate moiety as an SH specific electrophile is described. This moiety has been introduced into suitable amino acid derived building blocks, which were incorporated into peptidic sequences leading to very potent i.e. sub micromolar inhibitors of the cysteine protease papain in the same range as the vinyl sulfone based inhibitor K11777. Therefore, their inhibitory effect on Schistosoma mansoni, a human blood parasite, that expresses several cysteine proteases, was evaluated. The homophenylalanine side chain containing compounds 27–30 and especially 36 showed promising activities compared with K11777 and warrant further investigations of these peptidic thiosulfonate inhibitors as new potential anti-parasitic compounds.     

New quaternary ammonium camphor derivatives and their antiviral activity,genotoxic effects and cytotoxicity

The synthesis and biological evaluation of a novel series of dimeric camphor derivatives are described. The resulting compounds were studied for their antiviral activity, cyto- and genotoxicity. Compounds 3a and 3d in which the quaternary nitrogen atoms are separated by the C5H10 and С9H18 aliphatic chain, exhibited the highest efficiency as an agent inhibiting the reproduction of the influenza virus A(H1N1)pdm09. The cytotoxicity data of compounds 3 and 4 revealed their moderate activity against malignant cell lines; compound 3f had the highest activity for the CEM-13 cells. These results show close agreement with the data of independent studies on toxicity of these compounds, in particular that the toxicity of compounds strongly depends on spacer length.     

Synthesis and biological evaluation of new jasplakinolide (jaspamide) analogs

Synthesis and biological evaluation of jasplakinolide analogs are described. The synthesis of analogs utilized a diastereoselective syn-aldol reaction and an orthoester Claisen rearrangement as key steps. All synthetic analogs were evaluated for their ability to disrupt the actin cytoskeleton. Compounds 2, 3, and 4 essentially displayed similar activity to jasplakinolide.     

The free reducing oligosaccharides of angico branco (Anadenanthera colubrina) gum exudate: an aid for structural assignments in the heteropolysaccharide

A novel method is described for the determination of sequential side-chain structures in the complex, high-arabinose polysaccharide of the gum exudate of angico branco (Anadenanthera colubrina), using as basis the structurally similar reducing oligosaccharides present in small quantities. Of the ten detected, eight were characterized as disaccharides (2, 3, and 9), linear trisaccharides (1 and 4), branched pentasaccharides (5 and 6), and a doubly branched heptasaccharide (8). The oligosaccharides are substituents of the polysaccharide, which has a (1→3)-linked β- -galactopyranosyl main chain, and with two exceptions they had 6-O-substituted galactopyranosyl reducing ends, probably corresponding to its main-chain units. Characterization was effected through their 1D and 2D NMR correlation spectra, which were better resolved and more readily interpretable than those of the polysaccharide. These spectral data were supported by monosaccharide composition and rotation values. Controlled Smith degradations and methylation analyses were carried out when it was necessary. These data were confirmed by field-desorption MS.     

Synthesis and bioactivities evaluation of l-pyroglutamic acid analogues from natural product lead

A series of l-pyroglutamic acid analogues from natural product lead were designed and synthesized, as well as their antifungal activities against Phytophthora infestans, neuritogenic activities, antibacterial activities and anti-inflammatory activities are described. The bioassays and SAR study showed that the majority of l-pyroglutamic acid esters have a significant antifungal activity against P. infestans, especially 2d and 2j demonstrated the best activities with EC₅₀ values of 1.44 and 1.21?μg?mL^?1, which were about seven times that of commercial azoxystrobin (7.85?μg?mL^?1). Moreover, compounds 2e, 2g and 4d displayed anti-inflammatory activity against LPS-induced NO production in BV-2 microglial cells; neuritogenic activity in NGF-induced PC-12 cells is the same activity. This study demonstrates that compounds 2d and 2j are potential drugs to control P. infestans.     

Prediction of the doubly charged ion pattern by modelling the high- and low-resolution mass spectra of isotopomeric forms

The presence of doubly charged ions in mass spectra is detected only occasionally because their clusters are observed more rarely than singly charged ones. The patterns connected with doubly charged ions are located in the spectrum below M/2. The narrow shapes of such patterns as well as overlapping with other bands generate significant problems in their interpretation. The method described here is based on modelling of the isotopomeric form of single- and double-charged mass ion clusters. The present work attempts to explain the generation of the double charge disotopomeric patterns of high- as well as low-resolution spectra. Predicting the high-resolution mass cluster is simpler than calculations of the low-resolution cluster. The high-resolution cluster may represent the initial form of low-resolution pattern formation.

Sodium/calcium exchanger as main effector of endogenous neuroprotection elicited by ischemic tolerance

The ischemic tolerance (IT) paradigm represents a fundamental cell response to certain types or injury able to render an organ more “tolerant” to a subsequent, stronger, insult. During the 16th century, the toxicologist Paracelsus described for the first time the possibility that a noxious event might determine a state of tolerance. This finding was summarized in one of his most important mentions: “The dose makes the poison”. In more recent years, ischemic tolerance in the brain was first described in 1991, when it was demonstrated by Kirino and collaborators that two minutes of subthreshold brain ischemia in gerbils produced tolerance against global brain ischemia.Based on the time in which the conditioning stimulus is applied, it is possible to define preconditioning, perconditioning and postconditioning, when the subthreshold insult is applied before, during or after the ischemic event, respectively. Furthermore, depending on the temporal delay from the ischemic event, two different modalities are distinguished: rapid or delayed preconditioning and postconditioning. Finally, the circumstance in which the conditioning stimulus is applied on an organ distant from the brain is referred as remote conditioning.Over the years the “conditioning” paradigm has been applied to several brain disorders and a number of molecular mechanisms taking part to these protective processes have been described. The mechanisms are usually classified in three distinct categories identified as triggers, mediators and effectors. As concerns the putative effectors, it has been hypothesized that brain cells appear to have the ability to adapt to hypoxia by reducing their energy demand through modulation of ion channels and transporters, which delays anoxic depolarization. The purpose of the present review is to summarize the role played by plasmamembrane proteins able to control ionic homeostasis in mediating protection elicited by brain conditioning, particular attention will be deserved to the role played by Na⁺/Ca²⁺ exchanger.     

Antifungal activity of 1′-homo-N-1,2,3-triazol-bicyclic carbonucleosides: A novel type of compound afforded by azide-enolate (3+2) cycloaddition

The first report of 1′-homo-N-1,2,3-triazol-bicyclic carbonucleosides (7a and 7b) is described herein. Azide-enolate (3+2) cycloaddition afforded the synthesis of this novel type of compound. Antifungal activity was evaluated in vitro against four filamentous fungi (Aspergillus fumigatus, Trichosporon cutaneum, Rhizopus oryzae and Mucor hiemalis) as well as nine species of Candida spp. as yeast specimens. These pre-clinical studies suggest that compounds 7a and 7b are promising candidates for complementary biological studies due to their good activity against Candida spp.     

Synthesis and structure–activity relationships of 2-aryl-4-oxazolylmethoxy benzylglycines and 2-aryl-4-thiazolylmethoxy benzylglycines as novel,potent PPARα selective activators- PPARα and PPARγ selectivity modulation

The synthesis and follow-up SAR studies of our development candidate 1 by incorporating 2-aryl-4-oxazolylmethoxy and 2-aryl-4-thiazolylmethoxy moieties into the oxybenzylglycine framework of the PPARα/γ dual agonist muraglitazar is described. SAR studies indicate that different substituents on the aryloxazole/thiazole moieties as well as the choice of carbamate substituent on the glycine moiety can significantly modulate the selectivity of PPARα versus PPARγ. Potent, highly selective PPARα activators 2a and 2l, as well as PPARα activators with significant PPARγ activity, such as 2s, were identified. The in vivo pharmacology of these compounds in preclinical animal models as well as their ADME profiles are discussed.     

Structure-based design of novel dihydroisoquinoline BACE-1 inhibitors that do not engage the catalytic aspartates

The structure–activity relationship of a series of dihydroisoquinoline BACE-1 inhibitors is described. Application of structure-based design to screening hit 1 yielded sub-micromolar inhibitors. Replacement of the carboxylic acid of 1 was guided by X-ray crystallography, which allowed the replacement of a key water-mediated hydrogen bond. This work culminated in compounds such as 31, which possess good BACE-1 potency, excellent permeability and a low P-gp efflux ratio.     

A 9,13-epoxylabdane from Colophospermum mopane

A new diterpene, 8(S),13(S)-dihydrogrindelic acid (2) was isolated from the seeds of Colophospermum mopane along with its previously described C-13 epimer (1). The structure of 2 was established primarily by NMR which required some revisions on the NMR shift assignments of 1. The importance of 1 and 2 as the missing links in the biosynthesis of 9,13-epoxylabdanes is briefly discussed.     

Synthesis,cytotoxicity, and haemolytic activity of chacotrioside lupane-type neosaponins and their germanicane-type rearrangement products

The concise synthesis, via a stepwise glycosylation approach, of lupeol, betulin and betulinic acid O-glycosides bearing a chacotriosyl moiety at the C-3 position is described. All neosaponins as well as their rearrangement products of the germanicane-type were evaluated in vitro for their anticancer and haemolytic activities. Although betulinic acid and betulin 3β-O-chacotriosides were neither cytotoxic nor haemolytic, their rearrangement products allobetulin and 28-oxoallobetulin 3β-O-chacotriosides (9 and 10) exhibited a cytotoxicity profile up to fourfold superior to betulinic acid against human breast (MCF7) and prostate (PC-3) adenocarcinomas cell lines (IC₅₀ = 10–18 μM). One important result was that only chacotriosides featuring non-polar functions at the C-28 position (6, 9 and 10) exerted a haemolytic activity against red blood cells.     

A revision of Vernonia series Buddleiifoliae (Compositae: Vernonieae)

SeriesBuddleiifoliae of the genusVernonia of southeastern South America consists of 18 species which are keyed, described, discussed and mapped.Vernonia goiasensis is proposed as a new name, whileV. wasshausenii andV. monocephala subsp.irwinii are described as new taxa, and V.asteriflora subsp.kuntzei is presented as a new combination.     

SPION-Smac mimetic nano-conjugates: Putative pro-apoptotic agents in oncology

Non-covalent (NP-1/3) and covalent (NP-A-1/3) pro-apoptotic SPION-Smac mimetic nano-conjugates antitumor agents are reported. The solution synthesis of key Smac mimetics, their support onto SPIONs through non-covalent adsorption (NP-1/3) or APTES-mediated covalent binding (NP-A-1/3), the analytical characterization of SPION-Smac mimetic conjugates, their target affinity in cell-free assays, and their cytotoxicity against tumor cells are thoroughly described.     

The use of boric and benzeneboronic acids in the partial acetonation of monosaccharides

The preparation of mono-O-isopropylidene derivatives and mono-O-isopropylidene benzeneboronates of monosaccharides in one step is described, together with their p.m.r. and mass-spectral characteristics. In particular, the use of boric acid in the synthesis of the new acetal 1,2-O-isopropylidene-β-L-arabinopyranose (8) is described, together with improved procedures for the preparation of 2,3-O-isopropylidene-D-mannofuranose (5) and 3,4-O-isopropylidene-L-arabinopyranose (10). The use of boric acid in the partial hydrolysis of 1,2:3,4-di-O-isopropylidene-β-L-arabinopyranose to give the 1,2-acetal is reported.     

Les relations ontogenèse-phylogenèse:Applications paléontologiques

After a short historical introduction, the principal notions used to study the connections between ontogeny and phylogeny are desribed. The three fondamental standards (shape, age, size) upon which are made ontogenetic comparisons are defined and discussed.The different ontogenetic heterochronies are described and illustrated with concrete paleontological examples. Successively are studied:u

1. -dwarfirsm and giantism which are particularcases;
2. -the 4 types of heterochrony which affect somatic development (neoteny and acceleration) or sexual maturation (hypermorphosis and progenesis);
3. -the innovations which are a fast appearence of a new character and their associations with the 4 elementary heterochronies.

The heterochronies are connected with phylogeny. This leads to the definition of two fondamental tendancies: paedomorphosis and peramorphosis; the terms proterogenesis and palingenesis are redefined. To conclude, this study is inserted in a more wider context that shows the importance of ontogenetic knowledge to understand numerous evolutif processes (tempos in evolution, demographic strategies, cladism).     

Discovery of N-substituted pyridinones as potent and selective inhibitors of p38 kinase

The identification and evolution of a series of potent and selective p38 inhibitors is described. p38 inhibitors based on a N-benzyl pyridinone high-throughput screening hit were prepared and their SAR explored. Their design was guided by ligand bound co-crystals of p38α. These efforts resulted in the identification of 12r and 19 as orally active inhibitors of p38 with significant efficacy in both acute and chronic models of inflammation.     

Four new species of Ixora (Rubiaceae, Ixoreae) from Brazil

Four new species of Ixora (Rubiaceae, Ixoreae) from Brazil are described and illustrated and their relationships to morphologically similar species as well as their conservation status are discussed. The new species, Ixora cabraliensis, Ixora emygdioi, Ixora grazielae, and Ixora pilosostyla are endemic to the Atlantic Forest of southern Bahia and Espirito Santo.