Carbonic anhydrase activators: high affinity isozymes I, II, and IV activators, incorporating a beta-alanyl-histidine
Andrea Scozzafava1, Claudiu T Supuran
1Università degli Studi, Laboratorio di Chimica Inorganica e Bioinorganica, Via Gino Capponi 7, I-50121 Florence, Italy.
Abstract:
A novel class of tight binding carbonic anhydrase (CA) activators was designed by using histamine and histidine as lead molecules. Carnosine (beta-Ala-His) derivatives were synthesized by reaction of appropriately derivatized beta-alanines with imidazole/carboxy-protected histidine in the presence of carbodiimides, followed by removal of the various protecting groups. The derivatized beta-alanines mentioned above were in turn obtained by coupling of 4-fluorophenylsulfonylureido amino acids (fpu-AA) or 2-toluenesulfonylureido amino acids (ots-AA) with beta-Ala. Some structurally related dipeptides with the general formula fpu/ots-AA1-AA2 (AA, AA1, and AA2 represent amino acyl moieties) were also prepared by a similar strategy and used thereafter for obtaining CA activators incorporating a modified tetrapeptide scaffold. Many of the new tri-/tetrapeptide derivatives reported here proved to be efficient in vitro activators of three CA isozymes. Very good activity was detected against hCA I and bCA IV, for which some of the new compounds showed affinities in the 1-20 nM range (h = human; b = bovine isozymes), whereas against hCA II, their affinities were in the range of 10-40 nM. Ex vivo experiments showed some of the new activators to strongly enhance cytosolic red cell CA activity after incubation with human erythrocytes. This new class of CA activators might lead to the development of drugs/diagnostic tools for the management of CA deficiency syndromes, as well as for the pharmacological enhancement of synaptic efficacy, spatial learning, and memory. This may constitute a new approach for the treatment of Alzheimer's disease and other conditions in need of achieving memory therapy.
Related Concept Videos
02:34Regioselectivity and Stereochemistry of Acid-Catalyzed Hydration
01:19Allosteric Proteins-ATCase
Aspartate transcarbamoylase (ATCase) is a cytosolic enzyme that catalyzes the condensation of L-aspartate and carbamoyl phosphate to N-carbamoyl-L-aspartate. This reaction is the first step in pyrimidine biosynthesis. UTP and CTP, the end products of the pyrimidine synthesis pathway,...
01:20Aldehydes and Ketones with Water: Hydrate Formation
The formation of hydrates is a reversible reaction. Hydrate formation is influenced by steric and electronic factors accompanying the alkyl substituents on the carbonyl group: The rate of hydrate formation increases with a decrease in the number of alkyl groups attached to the carbonyl carbon. Hence,...
01:29Indirect-Acting Cholinergic Agonists: Chemistry and Structure-Activity Relationship
Reversible inhibitors display short to medium durations of action. Short-acting agents include simple alcohols with...
01:18Indirect-Acting Cholinergic Agonists: Mechanism of Action
Reversible inhibitors like edrophonium bind to a specific part of the enzyme called the anionic catalytic site. They form noncovalent bonds, which means they are not strongly attached to the enzyme. This creates a temporary and less stable enzyme–inhibitor complex, leading to...
01:30Antihypertensive Drugs: Angiotensin-Converting Enzyme Inhibitors