Controlling the stereochemistry in 2-oxo-aldehyde-derived Ugi adducts through the cinchona alkaloid-promoted electrophilic fluorination.

In this report, we introduce a new strategy for controlling the stereochemistry in Ugi adducts. Instead of controlling stereochemistry directly during the Ugi reaction we have attempted to stereodefine the chiral center at the peptidyl position through the post-Ugi functionalization. In order to achieve this, we chose to study 2-oxo-aldehyde-derived Ugi adducts many of which partially or fully exist in the enol form that lacks the aforementioned chiral center. This in turn led to their increased nucleophilicity as compared to the standard Ugi adducts. As such, the stereocenter at the peptidyl position could be installed and stereodefined through the reaction with a suitable electrophile. Towards this end, we were able to deploy an asymmetric cinchona alkaloid-promoted electrophilic fluorination producing enantioenriched post-Ugi adducts fluorinated at the peptidyl position.

Studying the mechanisms and targets of glycation and advanced glycation end-products in simple eukaryotic model systems.

Biological systems are usually astonishingly complex. This complexity makes it often difficult if not impossible to study their inner workings. In order to address complex research questions more simply structured models (e.g., microorganisms, plants, non-vertebrate animals) are utilized. Findings from these studies can then be translated to more complex systems like mammals. This strategy facilitates the identification of relevant 'leads' that can be specifically addressed in the higher organism. In this review studies to elucidate the relevance, modes of action and molecular targets of reactive carbonyl species using simple model systems are discussed. These dicarbonyls are formed during metabolic activity in all organisms as toxic by-products that lead to the dysfunction of essential cellular components by a process termed glycation, resulting ultimately in the generation of advanced glycation end-products. Understanding how both dicarbonyls and advanced glycation end-products are formed, which environmental conditions influence their levels and what cellular pathways they affect is paramount to develop efficient strategies targeting diseases that are related to reactive carbonyl species, like diabetes, neurodegenerative disorders and cancer. This contribution presents important findings in the field of dicarbonyls and glycation from fungi, plants, the nematode Caenorhabditis elegans and the fruit fly Drosophila melanogaster.

Biological Effects Induced by Specific Advanced Glycation End Products in the Reconstructed Skin Model of Aging.

Advanced glycation end products (AGEs) accumulate in the aging skin. To understand the biological effects of individual AGEs, skin reconstructed with collagen selectively enriched with N(ɛ)-(carboxymethyl)-lysine (CML), N(ɛ)-(carboxyethyl)-lysine (CEL), methylglyoxal hydroimidazolone (MG-H1), or pentosidine was studied. Immunohistochemistry revealed increased expression of α6 integrin at the dermal epidermal junction by CEL and CML (p<0.01). Laminin 5 was diminished by CEL and MG-H1 (p<0.05). Both CML and CEL induced a robust increase (p<0.01) in procollagen I. In the culture medium, IL-6, VEGF, and MMP1 secretion were significantly decreased (p<0.05) by MG-H1. While both CEL and CML decreased MMP3, only CEL decreased IL-6 and TIMP1, while CML stimulated TIMP1 synthesis significantly (p<0.05). mRNA expression studies using qPCR in the epidermis layer showed that CEL increased type 7 collagen (COL7A1), ß1, and α6 integrin, while CML increased only COL7A1 (p<0.05). MG-H1-modified collagen had no effect. Importantly, in the dermis layer, MMP3 mRNA expression was increased by both CML and MG-H1. CML also significantly increased the mRNAs of MMP1, TIMP1, keratinocyte growth factor (KGF), IL-6, and monocyte chemoattractant protein 1 (MCP1) (p<0.05). Mixed effects were present in CEL-rich matrix. Minimally glycoxidized pentosidine-rich collagen suppressed most mRNAs of the genes studied (p<0.05) and decreased VEGF and increased MCP1 protein expression. Taken together, this model of the aging skin suggests that a combination of AGEs tends to counterbalance and thus minimizes the detrimental biological effects of individual AGEs.

Three-component reaction of a 2-aminoazine, a 2-oxoaldehyde, and a cyclic 1,3-dicarbonyl compound for the synthesis of imidazo[1,2-a]azine derivatives.

A three-component reaction of a 2-aminoazine, a 2-oxoaldehyde, and a cyclic 1,3-dicarbonyl compound providing access toward a novel class of imidazo[1,2-a]azine derivatives was developed and studied. The scope of the process was thoroughly explored under three different reaction conditions resulting in the generation of a small library of title compounds and highlighting the possibility of case-specific approach.

The relationship between glyoxalaseⅠand diabetic complications / 中国药理学通报

GlyoxalaseⅠthat presents in all human tissues detoxifies α-oxoaldehydes and prevents the formation of advanced glycation end products(AGEs).AGEs and their main precursor namely methylglyoxal(MG)produce cytotoxicity and have extensive relationship with diabetic complications.Therefore,to elevate glyoxalaseⅠactivity may be a new path to release such complications.

Glyoxalase I-structure,function and role in Alzheimer′s disease / 中国药理学通报

Glyoxalase system,a most effective defence system is present in cytosol of cells to scavenge ?-oxoaldehydes,which are reactive intermediates of AGEs formation.Glyoxalase Ⅰ is the key enzyme of this system.?-oxoaldehydes and AGEs are involved in the development of Alzheimer′s disease (AD). Therefore,the expression level and activity of glyoxalase I are essential to pathogenesis of AD.