Metallacarborane Sulfamides: Unconventional, Specific, and Highly Selective Inhibitors of Carbonic Anhydrase IX

Abstract

Carbonic anhydrase IX (CAIX) is a transmembrane enzyme that regulates pH in hypoxic tumors and promotes tumor cell survival. Its expression is associated with the occurrence of metastases and poor prognosis. Here, we present nine derivatives of the cobalt bis­(dicarbollide)(1−) anion substituted at the boron or carbon sites by alkysulfamide group(s) as highly specific and selective inhibitors of CAIX. Interactions of these compounds with the active site of CAIX were explored on the atomic level using protein crystallography. Two selected derivatives display subnanomolar or picomolar inhibition constants and high selectivity for the tumor-specific CAIX over cytosolic isoform CAII. Both derivatives had a time-dependent effect on the growth of multicellular spheroids of HT-29 and HCT116 colorectal cancer cells, facilitated penetration and/or accumulation of doxorubicin into spheroids, and displayed low toxicity and showed promising pharmacokinetics and a significant inhibitory effect on tumor growth in syngenic breast 4T1 and colorectal HT-29 cancer xenotransplants.

Synthesis and study ofC-substituted methylthio derivatives of cobalt bis(dicarbollide)

“…Acros Organics silica gel (0.060-0.200 mm) was used for column chromatography. The 1 H, 11 B, and 13 C NMR spectra were collected using Bruker Avance-400 spectrometer. The residual signal of the NMR solvent relative to tetramethylsilane was taken as the internal reference for 1 H NMR and 13 C NMR spectra.…”

“…The residual signal of the NMR solvent relative to tetramethylsilane was taken as the internal reference for 1 H NMR and 13 C NMR spectra. 11 Single crystal X-ray diffraction study X-ray diffraction study of (BEDT-TTF)[1,1 0 -(MeS) 2 -3,3 0 -Co(1,2-C 2 B 9 H 10 ) 2 ] was carried out at 150 K with an Xcalibur, Eos diffractometer. The structure was solved by direct method followed by Fourier difference synthesis and rened by the fullmatrix least-squares method in anisotropic approximation for all non-hydrogen atoms using SHELXL soware.…”

“…[1][2][3][4][5] Among the various derivatives of carboranes, special attention is paid to p-complexes of transition metals with carborane ligands, called metallacarboranes. The most known of them, cobalt bis(dicarbollide) [3,3 0 -Co(1,2-C 2 B 9 H 11 ) 2 ] À attracts increasing interest from researchers working in various elds from medical chemistry to [6][7][8][9][10][11] materials science [12][13][14][15][16][17][18] to due to its extraordinary high stability, low toxicity 19 and almost unlimited possibilities for chemical modication. 20,21 Recently, we suggested that cobalt bis(dicarbollide) can be used as a structural element in the design of molecular switches.…”

“…solution of K 2 CO 3 (50 ml). The organic fraction was combined and evaporated in vacuo to obtain 0.15 g (47%) of red solid 11. B NMR (acetone-d 6 , ppm): 104.2, 29.4, 9.9, À4.2, À11.5, À31.8, À36.1, À384.2, À556.5.…”

Focus on Chemistry of the 10-Dioxane-nido-7,8-dicarba-undecahydrido Undecaborate Zwitterion; Exceptionally Easy Abstraction of Hydrogen Bridge and Double-Action Pathways Observed in Ring Cleavage Reactions with OH− as Nucleophile

“…We have been involved in the design and exploration of building blocks based on boron polyhedra, which enable the facile merging of boron cages with various organic molecules or biomolecules, particularly those applicable in drug design [40,[46][47][48]. Herein we present an overview of the reactions of 1 with a variety of possible nucleophiles.…”