Open saccharin-based secondary sulfonamides as potent and selective inhibitors of cancer-related carbonic anhydrase IX and XII isoforms

Figures & data

Figure 1. Reductive ring opening approach to the synthesis of novel CAIs.

Scheme 1. Synthesis and structure of compounds 1–21. For R substituents see Table 1.

Table 1. Inhibitory activity of the open saccharin-based derivatives 1–21 and acetazolamide as a reference drug, against selected hCA isoforms by a stopped-flow CO₂ hydrase assay.

Compound	R		Ki (nM)*
		hCA I	hCA II	hCA IX	hCA XII
1	2-CH3	>10000	>10000	218	4.6
2	2-CF3	>10000	>10000	200	54
3	2-NO2	>10000	>10000	104	383
4	2-Br	>10000	>10000	113	323
5	3-CH3	>10000	>10000	223	4.3
6	3-CF3	>10000	>10000	238	4.4
7	3-NO2	>10000	>10000	176	382
8	3-F	>10000	>10000	268	247
9	3-Br	>10000	>10000	267	64
10	4-CH3	>10000	>10000	120	5.7
11	4-CF3	>10000	>10000	253	7.2
12	4-CN	>10000	>10000	126	57
13	4-NO2	>10000	>10000	20	54
14	4-F	>10000	>10000	26	63
15	4-Cl	>10000	>10000	154	48
16	4-Br	>10000	>10000	145	432
17	2,6-diF	>10000	>10000	296	45
18	3,4-diCl	>10000	>10000	298	40
19	2,3-Phenylene	>10000	>10000	294	345
20	H	>10000	>10000	224	64
21	3-OCH3	>10000	>10000	31	355
AAZ (acetazolamide)		250	12	25	6.0

* Mean from 3 different assays (errors were in the range of ±5–10% of the reported values).

Figure 2. Docked pose of compound 6 in the active site of hCA XII. Hydrogen bonds and interactions to the Zn²⁺-ion are depicted in red dashed lines. The Zn²⁺-ion is depicted as a turquoise sphere. The three zinc-binding Histidines (H94, H96 and H119) are depicted in light gray for clarity.