Recent advances in the discovery of zinc-binding motifs for the development of carbonic anhydrase inhibitors

Figures & data

Figure 1. Structure of trithiocarbonate and dithiocarbamate zinc-binding motif. Electron density of trithiocarbonate (yellow and gold) bound within the hCA II active site. The electron density of the two water molecules (w162 and w179) making hydrogen bonds with the bound inhibitor are also presented. The catalytically critical Zn(II) ion is shown as the violet sphere, and its three protein ligands, His94, His96 and His119 in CPK colors. Thr199, a conserved amino acid residue involved in catalysis and binding of inhibitors is also shown, whereas the protein backbone is in green.

Table 1. CA I, II, IX, and XII inhibition data with some examples of DTCs from the work by Carta et al.12

			KI (nM)^a
	R1	R2	hCAI	hCAII	hCAIX	hCAXII
1	Ph–	H–	4.8	4.5	4.2	4.3
2	O[(CH2CH2)2]N–	H–	4.8	3.6	29.1	9.2
3	Ph–CH2–	H–	4.1	0.7	19.2	11.5
4	O[(CH2CH2)2]		0.88	0.95	6.2	3.4
5	HO(CH2)2–	HO(CH2)2–	9.2	4	4.3	4.2
6	Iso-Bu–	Iso-Bu–	0.97	0.95	4.5	0.99

^aMeans from three different assays. Errors were within ±5–10% of the reported values (data not shown).

Figure 2. Structure of the three N,N-disubstituted dithiocarbamates.

Figure 3. Electronic density for the adduct of dithiocarbamate 4 bound within the active site of human carbonic anhydrase (hCA II). The zinc ion is shown as the central sphere, and the amino acid residues involved in the binding are evidenced and numbered12.

Table 2. CA I, II, IX, and XII Inhibition data with some examples of xanthate and thioxanthate from the work by Carta et al16.

			KI (nM)^a
	R		hCAI	hCAII	hCAIX	hCAXII
9	Boc-NH–(CH2)4–		5.6	9.5	622	705
10	Boc-NH–(CH2)6–		6.3	59	765	744
11	Ph-CH2-		76.1	45.1	8.1	6.0
12	2-Pyridyl-(CH2)2–		74.2	13.1	4.3	3.6
13	–		63.4	6.6	643	835
14	Ph2CH–CH2–		64.1	5.4	58	63.3
15	Ph–CH2–		73.5	75.7	7.8	6.7

^aMeans from three different assays. Errors were within ±5–10% of the reported values (data not shown).

Figure 4. (A) Active site region in the hCA II – 16 complex. (B) Zn²⁺ coordination geometry of N-(hydroxy)-benzamide 16²⁰.

Figure 5. Structure of compounds 16 and 17.

Figure 6. Structures of salicylaldoxime 18–20.

Carta F, Aggarwal M, Maresca A, et al. Dithiocarbamates strongly inhibit carbonic anhydrases and show antiglaucoma action in vivo. J Med Chem 2012;55:1721–30

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Carta F, Akdemir A, Scozzafava A, et al. Xanthates and trithiocarbonates strongly inhibit carbonic anhydrases and show antiglaucoma effects in vivo. J Med Chem 2013;56:4691–700

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Di Fiore A, Maresca A, Supuran CT, De Simone G. Hydroxamate represents a versatile zinc binding group for the development of new carbonic anhydrase inhibitors. Chem Comm 2012;48:8838–40

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