PEGylated Bis-Sulfonamide Carbonic Anhydrase Inhibitors Can Efficiently Control the Growth of Several Carbonic Anhydrase IX-Expressing Carcinomas

A series of aromatic/heterocyclic
bis-sulfonamides were synthesized
from three established aminosulfonamide carbonic anhydrase (CA, EC
4.2.1.1) inhibitor pharmacophores, coupled with either ethylene glycol
oligomeric or polymeric diamines to yield bis-sulfonamides with short
or long (polymeric) linkers. Testing of novel inhibitors and their
precursors against a panel of membrane-bound CA isoforms, including
tumor-overexpressed CA IX and XII and cytosolic isozymes, identified
nanomolar-potent inhibitors against both classes and several compounds
with medium isoform selectivity in a detailed structure–activity
relationship study. The ability of CA inhibitors to kill tumor cells
overexpressing CA IX and XII was tested under normoxic and hypoxic
conditions, using 2D and 3D in vitro cellular models. The study identified
a nanomolar potent PEGylated bis-sulfonamide CA inhibitor (25) able to significantly reduce the viability of colon HT-29, breast
MDA-MB231, and ovarian SKOV-3 cancer cell lines, thus revealing the
potential of polymer conjugates in CA inhibition and cancer treatment.