Dithiocarbamates Strongly Inhibit Carbonic Anhydrases and Show Antiglaucoma Action in Vivo

Abstract

A series of dithiocarbamates was prepared by reaction of primary/secondary amines with carbon disulfide in the presence of bases. These compounds were tested for the inhibition of 4 human (h) isoforms of the zinc enzyme carbonic anhydrase, CA (EC 4.2.1.1), hCA I, II, IX and XII, involved in pathologies such as glaucoma (CA II and XII) or cancer (CA IX). Several low nanomolar inhibitors targeting these CAs were detected. X-ray crystal structure of hCA II adduct with morpholine dithiocarbamate evidenced the inhibition mechanism of these compounds, which coordinate to the metal ion through a sulfur atom from the dithiocarbamate zinc-binding function. Some dithiocarbamates showed effective intraocular pressure lowering activity in an animal model of glucoma.

Structure-based drug discovery of carbonic anhydrase inhibitors

“…The x-ray crystal structures were also reported for three DTCs complexed to hCA II, compounds 28-30 ( Figure 5). DTCs 28-30 inhibited hCA II with K I s of 25, 41 and 0.95 nM, respectively, and hCA IX with K I s of 53, 757 and 6.2 nM, respectively 66 . As seen from Figure 5, the binding mode of the ZBG present in 29 is identical to that of trithiocarbonate (with one sulphur coordinated to the metal ion), but the organic scaffold present in the DTC was observed to make extensive contacts with many amino acid residues from the active site, which explains the wide range of inhibitory power of these derivatives (from the subnanomolar to the micromolar, for the entire series of around 30 DTC reported thus far 59,66 ).…”

“…DTCs 28-30 inhibited hCA II with K I s of 25, 41 and 0.95 nM, respectively, and hCA IX with K I s of 53, 757 and 6.2 nM, respectively 66 . As seen from Figure 5, the binding mode of the ZBG present in 29 is identical to that of trithiocarbonate (with one sulphur coordinated to the metal ion), but the organic scaffold present in the DTC was observed to make extensive contacts with many amino acid residues from the active site, which explains the wide range of inhibitory power of these derivatives (from the subnanomolar to the micromolar, for the entire series of around 30 DTC reported thus far 59,66 ). Interestingly, the highly water-soluble DTC 30 was also effective in vivo as an anti-glaucoma agent when administered topically directly to the eye of hypertensive rabbits 66 , a widely used animal model of glaucoma 39 .…”

“…However, very recently, new important chemotypes emerged. Among them, the DTCs are undoubtedly the most interesting ones 59,[66][67][68] . These compounds have been rationally discovered as CAIs after our report of trithiocarbonate (CS 3 2− ) as an interesting (milli -micromolar) CAI 14 .…”

“…Thus, the CS 2 − was detected as a new zinc-binding group (ZBG). As DTCs incorporate this new ZBG, a rather large series of such compounds was prepared and evaluated for their inhibitory activity against several mammalian, fungal and bacterial CAs 59,[66][67][68] . Several low nanomolar and subnanomolar CAIs were thus detected against all these isoforms.…”

Inhibition of Bacterial Carbonic Anhydrases as a Novel Approach to Escape Drug Resistance

“…Dithiocarbamates (DTCs) were discovered as a completely new class of CAIs only recently, after the investigation of some inorganic anions acting in this way [45][46][47][48][49][50]. Indeed, the simple inorganic compound trithiocarbonate (TTC, CS 3 2-), [51] for which an X-ray crystal structure in complex with the isoform hCA II was available, showed that the inhibitor is bound to the Zn(II) ion from the enzyme catalytic site through one of its three equivalent sulfur atoms, whereas a second such atom interacted with the conserved Thr199 amino acid residue.…”