Activation of carbonic anhydrases from human brain by amino alcohol oxime ethers: towards human carbonic anhydrase VII selective activators

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 K_As 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.

Keywords: CNS-disease; Metalloenzyme; activation; cognition; selectivity.

Figure 1.

Natural amino acids and amines investigated for the activation of catalytically active hCA isoforms.

Figure 2.

Superimposition of CAA – hCA II complexes as determined by X-ray crystallography. (A) Surface view: the hydrophobic half of the active site is coloured red; His is coloured green and the hydrophilic half in blue. (B) Ribbon active site view. The activators are histamine, in green (PDB 1AVN); L-His, in magenta (PDB 2ABE); L-Phe, in gold (PDB 2FMG); adrenaline, in cyan (PDB 2HKK).

Figure 3.

Histamine-based carbonic anhydrase activators.

Figure 4.

Other pharmacological agents showing hCAs activating properties.

Scheme 1.

Preparation of Amino alcohols 1–13. Reagents and conditions: (i) epichlorohydrin, MeONa/MeOH, dry DMF, 60 °C, 1 h; (ii) iPrNH₂ or tBuNH₂, Benzene, 90 °C, 12 h.

Scheme 2.

Preparation of Amino alcohols 14–16. Reagents and conditions: (i) epichlorohydrin, Et₃N, dry DMF, rt, 18 h; (ii) iPrNH₂ or tBuNH₂, Benzene, 50 °C, 4 h; (iii) NH₃ MeOH 7 N, rt, 2 h; (iv) o-, m-, p-hydroxybenzaldehyde, EtOH, 90 °C, 12 h.