5-Arylisothiazol-3(2H)-one-1,(1)-(di)oxides: A new class of selective tumor-associated carbonic anhydrases (hCA IX and XII) inhibitors.

Sixteen 5-aryl-substituted isothiazol-3(2 H)-one-1,(1)-(di)oxide analogs have been prepared from the corresponding 5-chloroisothiazol-3(2 H)-one-1-oxide or −1,1-dioxide by a Suzuki-Miyaura cross-coupling reaction and screened for their inhibition potency against four human carbonic anhydrase isoenzymes: the transmembrane tumor-associated hCA IX and XII and the cytosolic off-target hCA I and II. Most of the synthesized derivatives inhibited hCA IX and XII isoforms in nanomolar range, whereas remained inactive or modestly active against both hCA I and II isoenzymes. In the N - tert -butylisothiazolone series, the 5-phenyl-substituted analog (1a) excelled in the inhibition of tumor-associated hCA IX and XII (K i = 4.5 and K i = 4.3 nM, respectively) with excellent selectivity against off target hCA I and II isoenzymes (S > 2222 and S > 2325, respectively). Since the highest inhibition activities were observed with N - tert -butyl derivatives, lacking a zinc-binding group, we suppose to have a new binding mode situated out of the active site. Additionally, three free-NH containing analogs (3a , 4a , 3i) have also been prepared in order to study the impact of free-NH containing N -acyl-sulfinamide- (-SO-NH-CO-) or N -acyl-sulfonamide-type (-SO 2 -NH-CO-) derivatives on the inhibitory potency and selectivity. Screening experiments evidenced 5-phenylisothiazol-3(2 H)-one-1,1-dioxide (4a), the closest saccharin analog, to be the most active derivative with inhibition constants of K i = 40.3 nM and K i = 9.6 nM against hCA IX and hCA XII, respectively. The promising biological results support the high potential of 5-arylisothiazolinone-1,(1)-(di)oxides to be exploited for the design of potent and cancer-selective carbonic anhydrase inhibitors. Image 1 • Sixteen 5-arylisothazol-3(2 H)-one-1,(1)-(di)oxide (5-Ar-ITZ) analogs have been synthesized. • Several 5-Ar-ITZ analogs were found to be potent and selective hCA IX/XII inhibitors. • 2- tert -Bu-5-Ph-isothazol-3(2 H)-one-1-oxide is the most active (K i ≈ 4 nM) and selective (S > 2222 vs. hCA I/II) on hCA IX/XII. • 5-Ar-ITZ analogs constitute a new class of potent cancer-selective CAIs. • Non Zn-binding mode, outside the active site may be involved for 2- tert -Bu-5-Ar-ITZ analogs. [ABSTRACT FROM AUTHOR]