Computational investigation of the selectivity of salen and tetrahydrosalen compounds towards the tumor-associated hCA XII isozyme

Figures & data

Table 1. Inhibition of the cytosolic hCA II and tumor-associated hCA IX and XII enzymes by compounds 1A–8A and 1B–6B.

				Ki (µM)			Ratio/selectivity*
Cpd	N	R1	R2	hCA II	hCA IX	hCA XII	hCA II/hCA IX	hCA II/hCA XII	hCA IX/hCA XII
1A	1	OH	H	1.72	>100	0.28	hCA II	6.14	hCA XII
2A	2	OH	H	4.19	15.7	0.95	0.27	4.41	16.53
3A	3	OH	H	3.92	10.5	0.88	0.37	4.45	11.93
4A	4	OH	H	3.13	4.47	0.54	0.70	5.80	8.28
5A	5	OH	H	3.60	4.35	0.43	0.83	8.37	10.12
6A	–	–	–	3.42	2.45	1.17	1.40	2.92	2.09
7A	1	OH	OCH3	>100	>100	1.49	–	hCA XII	hCA XII
8A	5	NO2	H	>100	>100	15.6	–	hCA XII	hCA XII
1B	1	–	–	3.69	>100	0.17	hCA II	21.71	hCA XII
2B	2	–	–	0.39	3.37	0.04	0.12	9.75	84.25
3B	3	–	–	3.53	4.37	0.037	0.81	95.41	118.11
4B	4	–	–	3.39	4.19	0.17	0.81	19.94	24.65
5B	5	–	–	0.24	2.51	0.047	0.10	5.11	53.40
6B	–	–	–	0.31	0.22	0.37	1.41	0.84	0.59

All compounds show IC₅₀ > 100 µM for hCA I. Data are derived from Carradori et al.16

*The ratio between the IC₅₀ values of the two hCA enzymes is calculated. Otherwise, the enzyme for which the compound shows the lowest IC₅₀ value is given.

Table 2. Residues forming the binding pockets of hCA I, II, IX and XII.

hCA I	hCA II	hCA IX	hCA XII
Trp5	Trp5	Trp5	Trp5
Glu58	Arg58	Arg59	Leu58
Ile60	Leu60	Arg60	Thr60
Val62	Asn62	Asn62	Asn62
His64	His64	His64	His64
Ser65	Ala65	Ser65	Ser65
His67	Asn67	Gln67	Lys67
Asn69	Glu69	Thr69	Asn69
Phe91	Ile91	Leu91	Thr91
Gln92	Gln92	Gln92	Gln92
Ala121	Val121	Val121	Val121
Leu131	Phe131	Val131	Ala131
Ala135	Val135	Leu135	Ser135
Leu141	Leu141	Leu141	Leu141
Val143	Val143	Val143	Val143
Leu198	Leu198	Leu198	Leu198
Thr199	Thr199	Thr199	Thr199
His200	Thr200	Thr200	Thr200
Tyr204	Leu204	Ala204	Asn204

Figure 1. A representative docked pose of compound 3B (turquoise) within the active site of hCA XII. One of the ligand’s hydroxyl group is located at the position of the zinc-bound water molecule and interacts both with Zn²⁺ as well as the side chain of Thr199. The other hydroxyl group of the ligand forms hydrogen bonds (red-dotted lines) with the backbone carbonyl group of Pro201 while the phenyl group forms hydrophobic interactions with Trp5.

Figure 2. Docked poses of compounds 5A (panel A) and 8A (panel B) within the active site of hCA XII. Hydrogen bonds are indicated with dotted red lines.

Carradori S, De Monte C, D’Ascenzio M, et al. Salen and tetrahydrosalen derivatives act as effective inhibitors of the tumor-associated carbonic anhydrase XII-A new scaffold for designing isoform-selective inhibitors. Bioorg Med Chem Lett 2013;23:6759–63

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