Abstract
The synthesis and carbonic anhydrase (CA; EC 4.2.1.1) activating effects of a series of oxime ether-based amino alcohols towards four human (h) CA isoforms expressed in human brain, hCA I, II, IV and VII, are described. Most investigated amino alcohol derivatives induced a consistent activation of the tested CAs, with KAs spanning from a low micromolar to a medium nanomolar range. Specifically, hCA II and VII, putative main CA targets when central nervous system (CNS) diseases are concerned, were most efficiently activated by these oxime ether derivatives. Furthermore, a multitude of selective hCA VII activators were identified. As hCA VII is one of the key isoforms involved in brain metabolism and other brain functions, the identified potent and selective hCA VII activators may be considered of interest for investigations of various therapeutic applications or as lead compounds in search of even more potent and selective CA activators.
Highlights
Activators of the metalloenzymes carbonic anhydrases (CAs; EC 4.2.1.1, CAAs) have been lately going through a second youth in drug discovery processes[1]
We extend the knowledge of CAA chemotypes by describing the synthesis and CA activating effects of a series of oxime ether based amino alcohols towards four hCA isoforms expressed in human brain
Amino alcohols [1,2,3,4,5,6,7,8,9,10,11,12,13,14,15,16] were here assayed for their activating properties of 4 catalytically active and physiologically relevant hCA isoforms expressed in human brain, that are: the cytosolic hCA I, II, and VII, and the membrane associated hCA IV58
Summary
Activators of the metalloenzymes carbonic anhydrases (CAs; EC 4.2.1.1, CAAs) have been lately going through a second youth in drug discovery processes[1]. CA I, II, IV, VA, XII and XIV) have been reported in the last decades, associated to diseases such as osteopetrosis, cerebral calcifications, retinal problems, hyperammonaemia, hyperchlorhydrosis[12,13,14,15], and hydration (Equations 1 and 2), that is the regeneration of the catalytically active, zinc hydroxide species, by a proton transfer reaction from the Zn2þ – bound water molecule to the external medium (Equation 2)[6,7,8] This process is assisted by active site residues acting as proton shuttle, such as His residues placed in the middle or at the entrance of the active site cavity of the a-class human CAs4. CAs represent a þ HCOÀ3 crucial family of new targets for improving cognition, and in (1) therapeutic areas, such as phobias, obsessive-compulsive disorder, EZn2þÀÂOH2
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