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

Abstract

Capillary electrophoresis (CE) has been applied for determination of the thermodynamic acidity constants (pKa) of the sulfamidoalkyl and sulfonamidoalkyl groups, the actual and limiting ionic mobilities and hydrodynamic radii of important compounds, eight carborane‐based inhibitors of carbonic anhydrases, which are potential new anticancer drugs. Two types of carboranes were investigated, (i) icosahedral cobalt bis(dicarbollide)(1‐) ion with sulfamidoalkyl moieties, and (ii) 7,8‐nido‐dicarbaundecaborate with sulfonamidoalkyl side chains. First, the mixed acidity constants, pKamix, of the sulfamidoalkyl and sulfonamidoalkyl groups of the above carboranes and their actual ionic mobilities were determined by nonlinear regression analysis of the pH dependences of their effective electrophoretic mobility measured by capillary electrophoresis in the pH range 8.00−12.25, at constant ionic strength (25 mM), and constant temperature (25°C). Second, the pKamix were recalculated to the thermodynamic pKas using the Debye–Hückel theory. The sulfamidoalkyl and sulfonamidoalkyl groups were found to be very weakly acidic with the pKas in the range 10.78−11.45 depending on the type of carborane cluster and on the position and length of the alkyl chain on the carborane scaffold. These pKas were in a good agreement with the pKas (10.67−11.27) obtained by new program AnglerFish (freeware at https://echmet.natur.cuni.cz), which provides thermodynamic pKas and limiting ionic mobilities directly from the raw CE data. The absolute values of the limiting ionic mobilities of univalent and divalent carborane anions were in the range 18.3−27.8 TU (Tiselius unit, 1 × 10−9 m2/Vs), and 36.4−45.9 TU, respectively. The Stokes hydrodynamic radii of univalent and divalent carborane anions varied in the range 0.34−0.52 and 0.42−0.52 nm, respectively.

Determination of acidity constants of pyridines, imidazoles, and oximes by capillary electrophoresis

“…By rearranging the equation, the pK a can be directly obtained from p𝐾 a, AN = p𝐾 a, IS + log 𝑄 AN − log 𝑄 IS (12) Similarly, the acidity constants of monoprotic bases are calculated via the following equation: p𝐾 a, AN = p𝐾 a, IS − log 𝑄 AN + log 𝑄 IS (13)…”

“…Malý et al developed the software AnglerFish to determine thermodynamic pK a s and limiting ionic mobilities using measured effective mobilities at a known buffer composition without the need for a constant ionic strength in the experiments [11]. This program was applied to the determination of thermodynamic pK a values of carborane-based inhibitors [12] and ampholytes [13].…”

Inhibitors of CA IX Enzyme Based on Polyhedral Boron Compounds

“…The value of the acid dissociation constant p K a of the head group has impact on the strength of covalent bond of sulfonamide or sulfamide inhibitors to Zn 2+ ion in the CA active site [60] . The p K a values were determined for set of metallacarborane sulfamides ( 34 , 35 , 36 , 38 , and 40 ) and nido‐ carborane sulfonamides ( 22 , 23 , and 24 ) by capillary electrophoresis [61] . The sulfamidoalkyl and sulfonamidoalkyl groups were found to be very weakly acidic with the p K a values around 11 and thus in the physiological conditions, these compounds are present in solution as monovalent anions.…”

“…The sulfamidoalkyl and sulfonamidoalkyl groups were found to be very weakly acidic with the p K a values around 11 and thus in the physiological conditions, these compounds are present in solution as monovalent anions. The acidity of carborane‐containing compounds is mainly affected by electronegativity of carborane cage and this effect is marginally weakened by the increasing length of the linker between head group and the cluster [61] …”