Design and synthesis of benzothiazole-based SLC-0111 analogues as new inhibitors for the cancer-associated carbonic anhydrase isoforms IX and XII

Figures & data

Figure 1. SLC-0111 chemical structure, and some of the previously reported SLC-0111 analogues.

Figure 2. Design of the target benzothiazole-based SLC-0111 analogues as CAIs.

Scheme 1. Synthesis of target benzothiazole-derived sulphonamides 8a-c.

Scheme 2. Synthesis of target benzothiazole-derived sulphonamides 10 and 12.

Scheme 3. Synthesis of target benzothiazole-derived carboxylic acids 14a-c and sulphonamides 16a-b.

Table 1. Inhibition constants for benzothiazole-based derivatives (8a-c, 10, 12, 14a-c and 16a-b) and the standard sulphonamide inhibitor acetazolamide (AAZ) towards hCA I, II, IX and XII, determined with a stopped-flow CO₂ hydrase assay.

Cmpd	n	R	KI (nM)^a
			hCA I	hCA II	hCA IX	hCA XII
8a	0	o-SO2NH2	12590	785.2	65.3	41.2
8b	0	m-SO2NH2	4040	652.7	48.9	57.5
8c	0	p-SO2NH2	361.7	54.1	31.5	29.3
10	1	p-SO2NH2	945.9	204.3	58.8	51.2
12	2	p-SO2NH2	61.5	28.5	16.4	34.7
14a	0	o-COOH	68090	75940	44620	39860
14b	0	m-COOH	82750	94130	16280	9140
14c	0	p-COOH	11820	9470	2410	8540
16a	–	–	>100000	>100000	56090	32500
16b	–	–	>100000	>100000	>100000	>100000
AAZ			250.0	12.5	25.0	5.7
SLC-0111			5080.0	960.0	45.0	4.5

^aMean from three different assays (errors were in the range of ± 5–10% of the reported values).

Figure 3. The cancer cell lines that are most vulnerable to the effects of sulphonamide 8b.

Table 2. Anticancer activity of target benzothiazole-based sulphonamide 8b towards breast T-47D and MCF-7 cancer cell lines under hypoxic conditions.

Com.	IC50 (µM)
	T-47D	MCF-7
8b	6.73 ± 0.28	9.16 ± 0.70
Doxorubicin	7.31 ± 0.49	6.52 ± 0.38