article · Journal of Medicinal Chemistry
Common artificial sweeteners such as saccharin and acesulfame K can selectively inhibit tumour-associated human carbonic anhydrases IX and XII, leaving off-target enzymes unaffected. Building upon these two sweetener structures, a series of derivatives called 2H-benzo[e][1,2,4]thiadiazin-3(4H)-one-1,1-dioxides, or BTDs, was synthesised to improve potency and selectivity. Multiple candidate compounds demonstrated significantly improved inhibition and selectivity against carbonic anhydrases IX and XII compared to the original lead molecules. Detailed structural analysis using X-ray crystallography revealed precisely how these molecules bind to target enzymes. When evaluated in laboratory cell cultures, selected compounds inhibited the growth of lung, prostate, and colorectal cancer cell lines under both normal and oxygen-depleted conditions. Further testing confirmed that the top two compounds influenced key markers of programmed cell death, establishing them as strong leads for future cancer therapies.
Selectively targeting tumour-associated enzymes while sparing healthy tissues is a primary goal in cancer treatment. Carbonic anhydrases IX and XII are typically overexpressed in solid tumours, particularly in low-oxygen environments. Developing potent, selective inhibitors based on well-understood sweetener scaffolds provides a compelling starting point for therapies that could treat aggressive tumours while reducing adverse side effects on off-target tissues.
This research could support early-stage drug discovery pipelines for pharmaceutical developers seeking targeted oncology therapeutics, particularly for solid tumours such as lung, prostate, and colorectal cancers. As an early-stage study tested only in biochemical assays and laboratory cancer cell lines, the compounds are far from clinical application and require extensive preclinical efficacy, pharmacokinetic, and safety profiling before any commercial transition.
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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.
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DOI: 10.1021/acs.jmedchem.9b01669
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