3H-1,2-benzoxathiepine 2,2-dioxides: a new class of isoform-selective carbonic anhydrase inhibitors

Figures & data

Figure 1. Chemical structure of sulfocoumarins A and B.

Scheme 1. Active site, CA-mediated hydrolysis of A2 to D1.

Scheme 2. Reagents and conditions: (i) MePPh₃Br, tBuOK, THF, RT, 24 h; (ii) NEt₃, CH₂Cl₂, RT, 20 h; (iii) 5, toluene, 70 °C, 4 h; (iv) Fe, AcOH, EtOH, H₂O, 70 °C, 1 h, 98%; (v) 1) NaNO₂, H₂O, TFA, 2) NaN₃, H₂O, 69%; (vi) alkyne, tBuOH/H₂O (1:1), CuSO₄, sodium ascorbate, acetic acid, 30 min.

Figure 2. Single-crystal X-ray structure of 6c (CCDC deposition number 1526002). Thermal ellipsoids are drawn at the 50% probability level (see Experimental for details).

Table 1. CA inhibition data against isoforms hCA I, II, IX and XII with homo-sulfocoumarins 6–17 and acetazolamide (AAZ) as standard, by a stopped-flow CO₂ hydrase assay14.

	KI (μM)^a
Compound	hCA I	hCA II	hCA IX	hCA XII
6c	>50	>50	0.027	0.64
7	>50	>50	3.57	>50
9	>50	>50	1.71	>50
10	>50	>50	3.59	>50
11	>50	>50	2.56	>50
12	>50	>50	1.75	>50
13	>50	5.77	0.34	1.72
14	>50	>50	1.15	>50
15	>50	>50	0.46	2.32
16	>50	>50	0.87	>50
17	>50	>50	0.43	>50
AAZ	0.25	0.012	0.025	0.006

^a Errors in the range of ±5% of the reported values, from three different assays.

a) Grandane A, Belyakov S, Trapencieris P, et al. Facile synthesis of coumarin bioisosteres – 1,2-benzoxathiine 2,2-dioxides. Tetrahedron 2012;68:5541–6. b) Tars K, Vullo D, Kazaks A, et al. Sulfocoumarins (1,2-benzoxathiine-2,2-dioxides): a class of potent and isoform-selective inhibitors of tumor-associated carbonic anhydrases. J Med Chem 2013;56:293–300.

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