New keys for old locks: carborane-containing drugs as platforms for mechanism-based therapies

Abstract

Icosahedral carboranes in medicine are still an emerging class of compounds with potential beneficial applications in drug design. These highly hydrophobic clusters are potential ''new keys for old locks'' which open up an exciting field of research for well-known, but challenging important therapeutic substrates, as demonstrated by the numerous examples discussed in this review.Key learning points 1. Highlight important receptors (''old locks'') as targets for efficient therapeutic treatments and propose carboranes as new class of drugs (''new keys''). 2. Present the benefits of carboranes as building block in drug design and outline novel carborane-based receptor ligands. 3. Guideline for readers through the versatility of potential medical applications of carborane-containing agents. 4. Current challenges of this novel strategy and the possibilities for structural modifications for enhancing drug properties and effects. 5. Molecular docking strategies available for carborane-based receptor ligands.

Quinoline‐Conjugated Ruthenacarboranes: Toward Hybrid Drugs with a Dual Mode of Action

“…Polyhedral molecular boron‐carbon clusters (carboranes) of type closo ‐C 2 B 10 H 12 , nido ‐[C 2 B 9 H 12 ] − , nido ‐[C 2 B 9 H 11 ] 2− and their metal complexes, are already well‐established scaffolds in the medicinal inorganic chemistry . By far the most extensively studied application of carboranes in medicine is their use as high‐boron carriers for boron neutron capture therapy (BNCT), followed by pharmacophores in drug design and radio‐imaging agents . Regardless the particular type of cluster, carborane‐containing molecules and complexes have been intensively studied for targeting cells and tissues within the central nervous system (CNS),– because they are able to efficiently cross the blood‐brain‐barrier (BBB, the “brain keeper”), thanks to the presence of hydridic B−H bonds, which make the cluster highly hydrophobic …”

Carborane‐Containing Matrix Metalloprotease (MMP) Ligands as Candidates for Boron Neutron‐Capture Therapy (BNCT)

“…[45,46] There are many examples of closo-carboranes having been used as bioisosteric replacements for heteroaromatic or heteroaliphatic rings. [47][48][49][50][51][52][53][54][55][56] Due to the complexity of substituting each individual boron atom within the carborane cluster with carbon atoms, we considered an alternative approach, where the entire carborane cluster is replaced with a simple phenyl ring for molecular docking experiments, given the similar 3D sweep volume and high lipophilicity of both moieties.…”

Neutral Rhenadicarbaboranes with Re(CO)2(NO) Vertices: A Theoretical Study of Building Blocks for Rhenacarborane-Based Drug Delivery Agents

“…Carboranes as hydrophobic units can be incorporated into a host of other proteins. These include the androgen receptors (e.g., with testosterone as target, leading to carborane-containing derivatives shown to outperform currently used drugs against prostate cancer) [10], retinoic acid receptors (with successful tests performed on human promyelelocytic leukemia HL-60 cells-thus again with anti-cancer potential) [11]. Other such proteins include transthyretin (a target of non-steroidal anti-inflammatory drugs), NSAIDS, where carborane derivatives have the unique advantage of not showing concomitant affinity for cyclooxygenase enzymes, COX, and hence displaying reduced side-effects as anti-inflammatory agents compared to typical NSAIDS.…”

“…Rhenium (and hence rhenacarboranes) has been proposed as a convenient substitute for technetium for preliminary laboratory and in vitro studies, since the two metals are reasonably similar in properties insofar their metallacarboranes are concerned. In addition, rhenium is much more readily available and non-radioactive [1,10,11].…”