Discovery of novel 1,3-diaryltriazene sulfonamides as carbonic anhydrase I, II, VII, and IX inhibitors

Figures & data

Figure 1. Clinically used triazene substituted compounds (TMZ and DTIC) and efficient CAI SLC-0111 (phase I/II trials for the advanced metastatic solid tumours).

Figure 2. Ribbon diagram (a) and active site detail of the adducts with ureido-substituted benzenesulfonamide CAIs (b); SLC-0111 (cyan, pdb: 3N4B), 4–(3-(3-nitrophenyl)ureido) benzenesulfonamide (pink, pdb: 3N2P), 4–(3-(2-isopropylphenyl)ureido) benzenesulfonamide (yellow, pdb: 3N3J) and 4–(3-cyclopentylureido) benzenesulfonamide (light orange, pdb: 3MZC) (superimposed)⁹. Figure made using PyMol (Delano Scientific).

Figure 3. General CA inhibitor design structure and design strategy of the reported 1,3-diaryltriazen-substituted sulfonamide derivatives starting from SLC-0111.

Scheme 1. General synthetic route for the synthesis of the 1,3-diaryltriazene sulfonamide derivatives 4(a–h). Reagent and conditions: (i) H₂O, HCl, NaNO₂, 0–5 °C, 30 min, (ii) Substituted aromatic anilines 3(a–h), MeOH, H₂O, sodium acetate, 0–5 °C 3h, r.t. overnight.

Table 1. In vitro hCA I, hCA II, hCA VII, and hCA IX inhibition data with 1,3diaryltriazene-substituted sulfonamides 4(a–h) investigated here, and standard sulfonamide inhibitor Acetazolamide (AAZ) by a stopped flow CO₂ hydrase assay¹².

Compound	KI^a (nM)
	R	hCA I	hCA II	hCA VII	hCA IX
4a	4-F	365 ± 15	858 ± 43	9478 ± 348	8051 ± 126
4b	4-COOH	92.3 ± 7.1	68.7 ± 5.1	967 ± 54	835 ± 47
4c	4-CN	501 ± 31	605 ± 34	7897 ± 456	8963 ± 348
4d	4-BuO	618 ± 40	519 ± 39	5866 ± 314	7428 ± 216
4e	4-MeO	416 ± 32	877 ± 62	5761 ± 324	7232 ± 159
4f	3,5-diMe	277 ± 18	4.3 ± 0.2	15.6 ± 0.9	50.8 ± 3.6
4g	3,4-diMeO	3854 ± 179	6461 ± 310	2557 ± 129	84.9 ± 4.5
4h	3,4-diCl	8371 ± 601	9194 ± 504	7834 ± 418	9268 ± 451
AAZ	–	250 ± 12	12 ± 0.8	2.5 ± 0.1	25 ± 1.1

^a Errors in the range of ± standard error, from three different assays, by a stopped-flow technique.

Pacchiano F, Aggarwal M, Avvaru BS, et al. Selective hydrophobic pocket binding observed within the carbonic anhydrase II active site accommodate different 4-substituted-ureido-benzenesulfonamides and correlate to inhibitor potency. Chem Commun (Camb) 2010;46:8371.

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