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

Figures & data

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; His⁶⁴ 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.

Table 1. Activation data of human CA isoforms I, II, IV and VII with amino alcohols 1–16 and histamine as reference CAA by a stopped flow CO₂ hydrase assay³⁴.

Compound	R1	R2	Ref	KA (µM)^a
				hCA I	hCA II	hCA IV	hCA VII
1		tBu	6	0.94	0.76	1.42	0.89
2		tBu	1,6	4.25	0.98	6.13	0.95
3		tBu	6,7	7.54	7.19	5.94	1.03
4		tBu	1	1.37	6.35	4.20	2.40
5		tBu	1	7.10	0.079	6.01	0.42
6		tBu	1	1.26	0.31	5.29	0.13
7		tBu	―	6.02	2.48	1.01	0.74
8		tBu	―	0.92	0.47	7.13	0.24
9		iPr	2,6	12.1	2.50	7.73	0.082
10		iPr	3,6	8.15	1.94	1.08	0.091
11		iPr	6,7	8.14	3.27	12.9	8.86
12		iPr	4	9.20	4.02	3.24	1.02
13		iPr	5	4.57	5.90	3.01	0.51
14		iPr	1	n.d	n.d	n.d	n.d
15		tBu	1	n.d	n.d	n.d	n.d
16		iPr	1	n.d	n.d	n.d	n.d
Histamine	–			2.1	125	25.3	37.5

^aFrom three different assays (errors within ± 10% of the reported values).

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