Carnosine is a histidine-containing dipeptide (β-alanyl-L-hystidine) which in humans is principally present in muscle and nerve tissues. It is rapidly cleaved into its constituents, in both cells and serum, under the action of carnosinases, a group of dipeptidases belonging to the family of metalloproteases. At present, the physiological role of carnosine remains unclear. In vitro, it triggers a variety of biological actions. In particular, it exerts protection against oxidative stress, being a scavenger of reactive oxygen species (ROS), which are responsible for oxidative damage of cellular lipids, enzymes, proteins and DNA. In addition, carnosine can trap toxic electrophilic α,β- unsaturated aldehydes (e.g., (E) 4-hydroxy-trans-2,3-nonenal (HNE) and malondialdehyde) deriving from the oxidation of unsaturated membrane lipids. It protects proteins from glycation, thus inhibiting the formation of toxic advanced glycation end-products (AGEs). Since oxidative stress and AGEs are involved in the development and progression of some cardiovascular and neurodegenerative diseases, as well as in ageing, there is currently great interest in carnosine and its derivatives. One possible limitation in the use of carnosine as a protective drug is that it is rapidly inactivated by carnosinases. A number of carnosinase-stable derivatives were developed, including some new carnosine amides, recently described by our group. These products share a number of properties with carnosine, further, in contrast with the lead, they also display high serum stability. The ether derivative, described in the same work, maintains good HNE scavenging properties as well as stability to carnosinase, but loses antioxidant capacity. Since ROS generation is fundamental in the pathogenesis of several diseases we tried to obtain a series of ether-carnosine-derivatives, endowed with potent antioxidant activity. We chose different phenol functions, known for their radical scavenging properties, to be joined to carnosine through an ether bridge. Synthesis, serum stability, ability to scavenge reactive carbonyl species (HNE) as well as preliminary antioxidant activity profile of these products are reported. [
Carnosine analogues containing Phenol substructures
GIORGIS, Marta;BERTINARIA, Massimo;ROLANDO, Barbara;MONTANARO, GABRIELE;FRUTTERO, Roberta;GASCO, Alberto
2012-01-01
Abstract
Carnosine is a histidine-containing dipeptide (β-alanyl-L-hystidine) which in humans is principally present in muscle and nerve tissues. It is rapidly cleaved into its constituents, in both cells and serum, under the action of carnosinases, a group of dipeptidases belonging to the family of metalloproteases. At present, the physiological role of carnosine remains unclear. In vitro, it triggers a variety of biological actions. In particular, it exerts protection against oxidative stress, being a scavenger of reactive oxygen species (ROS), which are responsible for oxidative damage of cellular lipids, enzymes, proteins and DNA. In addition, carnosine can trap toxic electrophilic α,β- unsaturated aldehydes (e.g., (E) 4-hydroxy-trans-2,3-nonenal (HNE) and malondialdehyde) deriving from the oxidation of unsaturated membrane lipids. It protects proteins from glycation, thus inhibiting the formation of toxic advanced glycation end-products (AGEs). Since oxidative stress and AGEs are involved in the development and progression of some cardiovascular and neurodegenerative diseases, as well as in ageing, there is currently great interest in carnosine and its derivatives. One possible limitation in the use of carnosine as a protective drug is that it is rapidly inactivated by carnosinases. A number of carnosinase-stable derivatives were developed, including some new carnosine amides, recently described by our group. These products share a number of properties with carnosine, further, in contrast with the lead, they also display high serum stability. The ether derivative, described in the same work, maintains good HNE scavenging properties as well as stability to carnosinase, but loses antioxidant capacity. Since ROS generation is fundamental in the pathogenesis of several diseases we tried to obtain a series of ether-carnosine-derivatives, endowed with potent antioxidant activity. We chose different phenol functions, known for their radical scavenging properties, to be joined to carnosine through an ether bridge. Synthesis, serum stability, ability to scavenge reactive carbonyl species (HNE) as well as preliminary antioxidant activity profile of these products are reported. [
I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
