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.
Organoboron reagents represent a unique class of compounds because of their utility in modern synthetic organic chemistry, often affording unprecedented reactivity. The transformation of the carbon−boron bond into a carbon−X (X = C, N, and O) bond in a stereocontrolled fashion has become invaluable in medicinal chemistry, agrochemistry, and natural products chemistry as well as materials science. Over the past decade, first-row dblock transition metals have become increasingly widely used as catalysts for the formation of a carbon−boron bond, a transformation traditionally catalyzed by expensive precious metals. This recent focus on alternative transition metals has enabled growth in fundamental methods in organoboron chemistry. This review surveys the current state-of-the-art in the use of first-row d-block element-based catalysts for the formation of carbon−boron bonds.
Metallacarboranes are a class of
inorganic boron clusters that
have recently been recognized as biologically active compounds. Herein,
we report on the host–guest complexation of several cobalt
bis(1,2-dicarbollide) anions (COSANs) with cyclodextrins (CDs) in
aqueous solution. The binding affinities reach micromolar values,
which are among the highest known values for native CDs, and exceed
those for neutral hydrophobic organic guest molecules. The entrapment
of the COSANs inside the cavity of CDs was confirmed using NMR and
UV–visible spectroscopy, mass spectrometry, cyclic voltammetry,
and isothermal titration calorimetry. Complexation by CDs greatly
influences the photophysical and electrochemical properties of COSANs.
In combination with indicator displacement assays, a label-free fluorescence-based
method was developed to allow real-time monitoring of the translocation
of COSANs through lipid bilayer membranes.
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