“A Sweet Combination”: Developing Saccharin and Acesulfame K Structures for Selectively Targeting the Tumor-Associated Carbonic Anhydrases IX and XII

The sweeteners saccharin (SAC) and acesulfame
K (ACE) recently entered the topic of anticancer human
carbonic
anhydrase (CA, EC 4.2.1.1) inhibitors, as they showed to selectively
inhibit the tumor-associated CAs IX/XII over ubiquitous CAs. A drug
design strategy is here reported, which took SAC and ACE as leads and produced a series of 2H-benzo­[e]­[1,2,4]­thiadiazin-3­(4H)-one-1,1-dioxides
(BTD). Many derivatives showed greater potency (KIs-CA IX 19.1–408.5
nM) and selectivity (II/IX SI 2–76) than the leads (KIs-CA IX 103, 2400 nM; II/IX-SI 56, >4) against
CA IX/XII over off-target isoforms. A thorough X-ray crystallographic
study depicted their binding mode to both CA II and IX-mimic. The
most representative BTDs were characterized in vitro
for their antitumor activity against A549, PC-3, and HCT-116 cancer
cell lines both in normoxia and hypoxia. The two most effective compounds
were assayed for their effect on several apoptosis markers, identifying
promising leads for the development of new anticancer drugs.