Direct Introduction of an Alkylsulfonamido Group on C‐sites of Isomeric Dicarba‐closo‐dodecaboranes: The Influence of Stereochemistry on Inhibitory Activity against the Cancer‐Associated Carbonic Anhydrase IX Isoenzyme

Abstract

Carbonic anhydrase IX (CA IX), at umor-associated metalloenzyme, represents avalidated target for cancertherapy and diagnostics. Herein, we report the inhibition properties of isomeric families of sulfonamidopropyl-dicarba-closododecaboranes group(s) prepared using an ew direct fivestep synthesis from the correspondingp arent cages. The protocol offers ar eliable solutionf or synthesis of singly and doubly substituted dicarba-closo-dodecaboranes with ad ifferent geometric positiono fc arbon atoms. The closo-compounds from the ortho-and meta-series were then degraded to corresponding 11-vertex dicarba-nido-undecaborate(1À) anions. All compounds show in vitro enzymatic activity against CA IX in the low nanomolar or subnanomolar range. This is accompanied by clear isomer dependence of the inhibition constant(K i)a nd selectivity towardsC AI X. Decreasing trends in K i ands electivity index (S I)v alues are observed with increasing separation of the cage carbon atoms. Interactions of compounds with the active sites of CA IX were explored with X-ray crystallography,a nd eight high-resolution crystal structures uncovered the structuralb asis of inhibition potencya nd selectivity.

Determination of acidity constants, ionic mobilities, and hydrodynamic radii of carborane‐based inhibitors of carbonic anhydrases by capillary electrophoresis

“…1. Their synthesis, inhibitory constants ( K i ), and structures with CA‐II and CA‐IX mimic enzymes were described elsewhere [1–6].…”

“…The carborane (CB)‐based compounds are promising lead structures for the development of the potent inhibitors of human carbonic anhydrase (CA) IX and other CAs [1–6]. CAs belong to a family of zinc metalloenzymes.…”

“…It plays a significant role in tumor progression. Inhibitors of CA IX could be potentially used as anticancer drugs [1–6]. The traditional CAs inhibitors contain a sulfonamide‐ or sulfamide‐based moiety that coordinates the zinc cation located in the CA catalytic site [7].…”

Inhibitors of CA IX Enzyme Based on Polyhedral Boron Compounds

“…From this point, carborane chemistry offered several possible solutions for the synthesis of primary amines to use as building blocks. Several routes to alkylamines have been described in the literature comprising of the insertion of alkynes with a protected amino function into open‐cage precursors, [42] reactions of lithiated carborane with N‐protected haloalkyl amines [43] such as N ‐(ω‐bromoalkyl)phthalimides, [44] or synthesis proceeding via reactions of triflate esters [40e,45] with sodium amide [46] . It should be noted that carbon substituted amines with an −NH 2 group directly connected to the cage were excluded from consideration (with the exception of 1‐H 3 N−1‐CB 11 H 11 ), since docking studied proposed that a short linker, such as methylene moiety is necessary condition for attaining high affinity towards CA IX.…”

“…Nido‐carboranes were also further used as structural blocks in the synthesis of metallacarboranes. B) Reaction route to isomeric series of inhibitors based on alkylsulfonamido substituted ortho‐, meta‐, and para‐ carboranes, which proceeds via direct substitutions on the cages [40e] . Only the reaction sequence for the monosubstituted ortho‐family is shown in full; the other series were prepared in analogy.…”