Cobalt Bis(dicarbollide) Alkylsulfonamides: Potent and Highly Selective Inhibitors of Tumor Specific Carbonic Anhydrase IX

Abstract

The most significant result of this study is design and synthesis of boron-cluster-containing compounds that inhibit activity of the cancer-associated enzyme CA IX with picomolar inhibition constants. Moreover,X-ray crystallography,w as used to help understand their interactions at the active site of the enzyme on an atomic level.

Inhibitors of CA IX Enzyme Based on Polyhedral Boron Compounds

“… Synthesis of alkylsulfonamido substituted cobalta bis(dicarbollide)(1‐) derivatives using two methods: A. cobalt insertion reaction into modified 7,8‐dicarba‐ nido ‐undecaborate ion; B. direct modification of the metallacarborane cage [40c] …”

“…The synthesis of the corresponding 11‐vertex ligands is outlined in paragraph 4.1.2. Suitable reaction conditions enabling insertion of the Co(III) central atom were found, which prevented cleavage of the substituent during the reaction and provided the respective di(sulfonamidoalkyl) cobalt bis(dicarbollide) ions of formula [(NH 2 −S(O) 2 −(CH 2 ) n −1,2‐C 2 B 9 H 10 ) 2 −3,3‘‐Co] − ( 44 – 50 ) in moderate (for n=1, 4) or excellent yields (for n=2 and 3) [40c] . As follows from their genesis, it was possible to obtain mainly disubstituted compounds.…”

“…Also, compounds from the monosubstituted series of formula [(1‐H 2 NSO 2 −(CH 2 ) n −1,2‐C 2 B 9 H 10 )(1,2‐C 2 B 9 H 11 )−3,3’‐Co] − ( 41 ) (Scheme 3A, bottom) could be prepared using a similar indirect method of reacting the sulfonamide‐substituted eleven vertex ligand together with the parent unsubstituted [C 2 B 9 H 12 ] − ion; [40c] however, reaction kinetics disfavor the formation of the mixed ligands complex. The reaction rate to the parent unsubstituted sandwich is visibly faster, and only small yields of the assumed product formed, even when [C 2 B 9 H 12 ] − was used in excess.…”

“…No other chlorinated side products formed using this method, thus it was possible to isolate the corresponding sulfamoyl chlorides and sulfonamides as chemically pure species. These were then smoothly converted by reaction with aqueous NH 4 OH to corresponding alkylsulfonamides of formula [(1‐H 2 NSO 2 −(CH 2 ) n −‐8‐Cl−1,2‐C 2 B 9 H 9 )(8’‐Cl−1’,2’‐C 2 B 9 H 10 )−3,3’‐Co] − Compounds with ethylene and propylene connectors ( 42 , 43 , Scheme 3B) were prepared in good yield and tested [40c] …”

“…The sulfamide moiety was used in the pilot series of carborane inhibitors [37,40a] . Later, series containing a sulfonamide group were prepared and explored [40b–e] . It is known from the field of classical CA inhibitors that a sulfonamide head group binds to the catalytic zinc ion with a higher interaction energy than sulfamide, [59] and this proved to be true also for carborane‐containing compounds.…”