Aryl derivatives of 3H-1,2-benzoxaphosphepine 2-oxides as inhibitors of cancer-related carbonic anhydrase isoforms IX and XII

Figures & data

Scheme 1. Reagents and conditions: (1) MePPh₃Br, tBuOK, THF, rt, 18 h; (2) NEt₃, CH₂Cl₂, 0 °C to rt, 18 h; (3) 5 (CAS: 250220–36-1), PhMe, 70 °C, 4 h; (iv) TMSBr, CH₂Cl₂, rt, 24 h.

Scheme 2. Reagents and conditions: (1) Pd(dppf)Cl₂, K₂CO₃, 1,4-dioxane/H₂O (5:1), 80 °C, 16 h, 54–63%.

Scheme 3. Reagents and conditions: (1) Pd(dppf)Cl₂, K₂CO₃, 1,4-dioxane/H₂O (5:1), 80 °C, 16 h, 57–69%.

Scheme 4. Reagents and conditions: (1) Pd(dppf)Cl₂, K₂CO₃, 1,4-dioxane/H₂O (5:1), 80 °C, 16 h, 66–89%.

Table 1. Inhibition data of compounds 7–10 and the standard inhibitor acetazolamide (AAZ) against human CA isoforms I, II, IX and XII by the stopped-flow CO₂ hydrase assay.

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Cmpd	Substitution position (7 / 8 / 9)	R	KI (µM)^a^,^b
			CA I	CA II	CA IX	CA XII
7a^19	7	I	>100	>100	0.88	0.68
8a	7	H	>100	>100	0.77	0.95
8b	7	4-OMe	>100	>100	4.6	1.7
8c	7	4-CO2Et	>100	>100	6.0	6.7
8d	7	4-F	>100	>100	0.86	0.25
8e	7	4-Cl	>100	>100	8.6	1.1
8f	7	4-CF3	>100	>100	3.7	0.59
8g	7	3,5-diCl	>100	>100	7.3	4.2
8h	7	3-F	>100	>100	0.63	0.56
8i	7	4-Me	>100	>100	1.5	0.94
8j	7	3-CO2Me	>100	>100	9.5	1.5
8k	7	3-NO2	>100	>100	7.6	0.64
8l	7	4-tBu	>100	>100	4.9	0.97
7b	8	Br	>100	>100	3.4	1.5
9a	8	H	>100	>100	1.8	2.7
9b	8	4-OMe	>100	>100	2.1	5.6
9c	8	4-CO2Et	>100	>100	10.2	3.8
9d	8	4-Cl	>100	>100	5.0	7.1
9e	8	3,5-diCl	>100	>100	0.98	0.84
9f	8	2-NO2	>100	>100	12.9	0.67
7c^19	9	Br	>100	>100	2.5	1.8
10a	9	H	>100	>100	16.5	25.5
10b	9	4-OMe	>100	>100	39.4	52.4
10c	9	4-CO2Et	>100	>100	55.3	>100
10d	9	4-Cl	>100	>100	48.9	65.3
10e	9	3,5-diCl	>100	>100	22.4	28.2
10f	9	4-NO2	>100	>100	38.4	35.1
AAZ	–		0.25	0.012	0.025	0.006

^a Values are mean from three different assays using the stopped-flow technique (errors were in the range of ± 5–10% of the reported values).

^b Incubation time: 6 h.

Pustenko A, Balašova A, Nocentini A, Supuran CT, Žalubovskis R. 3H-1,2-Benzoxaphosphepine 2-oxides as selective inhibitors of carbonic anhydrase IX and XII. J Enzyme Inhib Med Chem. 2023;38(1):216–224.

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