Saccharin: A lead compound for structure-based drug design of carbonic anhydrase IX inhibitors

Abstract

Carbonic anhydrase IX (CA IX) is a key modulator of aggressive tumor behavior and a prognostic marker and target for several cancers. Saccharin (SAC) based compounds may provide an avenue to overcome CA isoform specificity, as they display both nanomolar affinity and preferential binding, for CA IX compared to CA II (>50-fold for SAC and >1000-fold when SAC is conjugated to a carbohydrate moiety). The X-ray crystal structures of SAC and a SAC-carbohydrate conjugate bound to a CA IX-mimic are presented and compared to CA II. The structures provide substantial new insight into the mechanism of SAC selective CA isoform inhibition.

Mapping Selective Inhibition of the Cancer-Related Carbonic Anhydrase IX Using Structure–Activity Relationships of Glucosyl-Based Sulfamates

“…Using the current structural data within our model system of the hCA IX active site (via the hCA IX-mimic), in combination with previously published results, it is possible to map out key attributes of the hCA IX active site to exploit for isoform specific inhibition of the enzyme. 21,28,31 It has been determined that the least selective inhibitors utilize mostly hydrophilic interactions in the hCA active site ( Figure 5A). The most important interaction in the hydrophilic pocket appears to be with Gln67 in the hCA IX active site, as this forms stabilizing hydrogen bonding networks that are not present in the hCA II active site.…”

Targeting Aggressive Cancers with an Artificial Sweetener: Could Saccharin be a Lead Compound in Anticancer Therapy?

“…This comes from data that have shown saccharin's ability to inhibit the carbonic anhydrase (CA) family of enzymes, and especially the cancer-related isoforms IX and XII [8][9][10][11]. CAs are zinc metalloproteins that catalyze the interconversion of CO 2 to bicarbonate and a proton, a reaction that is important for many physiological processes including respiration, fluid secretion and pH regulation [12].…”

“…Much like its discovery, saccharin has serendipitously shown to be useful in terms of designing selective CA IX and XII inhibitors. This comes as the compounds ability to not only inhibit CA IX and XII but also do so in a selective manner over the other off-target CAs [8,23]. X-ray crystallographic analysis shows that saccharin binds directly to the catalytic zinc in the CA active site similarly to clinically used sulfonamide-based compounds [8,[23][24].…”

“…This comes as the compounds ability to not only inhibit CA IX and XII but also do so in a selective manner over the other off-target CAs [8,23]. X-ray crystallographic analysis shows that saccharin binds directly to the catalytic zinc in the CA active site similarly to clinically used sulfonamide-based compounds [8,[23][24]. Therefore, the small size of saccharin coupled with its ability to act as CA IX/XII zinc-binding group (ZBG), suggests it can be used as a lead compound for drug design [12,14,21].…”

“…The use of saccharin as a lead compound has already been implemented by several groups that have developed saccharin-derivative compounds in attempts to produce a promising drug candidate to target both CA IX and XII [8][9][10][11]24]. Strategies to develop saccharin-derivative compounds have utilized either the primary cyclic amide or the ortho-position of the phenol ring of saccharin to add chemical groups.…”