Nitric Oxide Synthases Activation and Inhibition by Metallacarborane-Cluster-Based Isoform-Specific Affectors

Abstract

A small library of boron cluster and metallacarborane cluster-based ligands was designed, prepared and tested for isoform-selective activation or inhibition of the three nitric oxide synthase isoforms. Based on the concept of creating a hydrophobic analog of a natural substrate, a stable and non-toxic basic boron cluster system, previously used for boron neutron capture therapy, was modified by the addition of positively charged moieties to its periphery, providing hydrophobic and non-classical hydrogen bonding interactions with the protein. Several of these compounds show efficacy for inhibition of NO synthesis with differential effects on the various nitric oxide synthase isoforms.

2,2′‐Bipyridine‐Modified Tamoxifen: A Versatile Vector for Molybdacarboranes

“…Either it scavenges ROS/ RNS and thus generates NO, or it interacts with one or more of the nitric oxide synthases (NOS), as known for other mixedsandwich ferracarborane or COSAN-type structures. [7] This effect is in high contrast to the other two tested compounds (6 and Fc-diOH) in flow cytometry analysis. Also, nitric oxide has an ambivalent role in healthy and cancer cell correlation.…”

“…Remarkably, compound 10 strongly upregulates the NO production in MCF‐7 cells (Figure B). Either it scavenges ROS/RNS and thus generates NO, or it interacts with one or more of the nitric oxide synthases (NOS), as known for other mixed‐sandwich ferracarborane or COSAN‐type structures . This effect is in high contrast to the other two tested compounds ( 6 and Fc‐diOH) in flow cytometry analysis.…”

“…Thus, a deboronation (i. e. formal loss of a B + unit) of the closo ‐C 2 B 10 H 12 cluster and deprotonation, the so‐called dicarbollide, [C 2 B 9 H 11 ] 2− , is obtained and can be employed in the preparation of a large variety of transition metal complexes resulting in full‐, mixed‐ or half‐sandwich structures . Potential applications of the full‐sandwich cobalt bis(dicarbollide) ([3,3′‐Co(1,2‐C 2 B 9 H 11 ) 2 ] − , COSAN) derivatives in medicine are well investigated, but not as a pharmacophore. Also cytotoxic/cytostatic icosahedral mixed‐sandwich metallacarboranes, e.g.…”

Biological interaction of living cells with COSAN-based synthetic vesicles

“…We note however the association between membrane fluidity, cell proliferation arrest and apoptosis seen with other small molecules, such as methyl jasmonate 17 , and it is possible that all the biological effects we observe could arise due to membrane interactions. Alternatively, COSAN may mediate its effects due to protein interactions either by enzyme inhibition via active site binding, such the modified COSAN molecules that inhibit enzymes 18 19 , or more general interference by binding to protein surfaces. More detailed analysis is required to resolve these mechanistic possibilities.…”

Deciphering the Binding of Caveolin-1 to Client Protein Endothelial Nitric-oxide Synthase (eNOS)

“…The supernatant was stored at Ϫ80°C until required. The baculovirus-derived bovine eNOS used for GST pulldowns was from Cayman Chemicals, whereas highly purified eNOS protein of bacterial origin (38) was used for fluorescence experiments and to reproduce GST pulldown results.…”