Discovery of 4‑Hydroxy-3-(3-(phenylureido)benzenesulfonamides as SLC-0111 Analogues for the Treatment of Hypoxic Tumors Overexpressing Carbonic Anhydrase IX

Herein
we report the 2-aminophenol-4-sulfonamide 1 and its ureido
derivatives 2–23 as inhibitors of
the carbonic anhydrase (CA, EC 4.2.1.1) enzymes
as analogues of the hypoxic tumor phase II entering drug SLC-0111. This scaffold may determine preferential rotational isomers to
selectively interact within the tumor-associated CAs. Most of the
compounds indeed showed in vitro selective inhibition
of the tumor associated CA isoforms IX and XII. The most potent derivative
within the series was 11 (KIs of 2.59 and 7.64 nM on hCA IX and XII, respectively), which shares
the 4-fluorophenylureido tail with the clinical candidate. We investigated
by means of X-ray crystallographic studies the binding modes of three
selected compounds of this series to CA I. The evaluation of therapeutic
efficacy of compound 11 in an orthotopic, syngeneic model
of CA IX-positive breast cancer in vivo showed close
matching antitumoral effects and tolerance with SLC-0111.