Imitation and modification of bioactive lead structures via integration of boron clusters

Abstract

In medicinal chemistry, carbaboranes can be employed either as boron carriers for boron neutron capture therapy (BNCT) or as scaffolds for radiodiagnostic or therapeutic agents. We have developed a suitable synthesis employing the phosphoramidite method to connect meta-carbaboranyl bis-phosphonites with the 6'-OH group of isopropylidene-protected galactose, followed by oxidation or sulfurization to give the corresponding bis-phosphonates. Deprotection yielded water-soluble compounds. The corresponding disodium salts exhibit especially low cytotoxicity. Preliminary results on the in vivo toxicity and biodistribution of two compounds in mice indicated a lack of selectivity for the cotton rat lung (CRL) tumor chosen for the experiment. For the incorporation of carbaboranes into breast tumorselective modified neuropeptide Y, [F 7 , P 34 ]-NPY, a synthesis of a carbaborane-modified lysine derivative was developed. Linkage of the lysine to the boron cluster was achieved by using a propionic acid spacer. Incorporation of the amino acid derivatives into NPY and [F 7 , P 34 ]-NPY by solid-phase peptide synthesis was successful. Preliminary studies showed that the receptor binding affinity and signal transduction of the boron-modified peptides were very well retained.Asborin, the carbaborane analogue of aspirin, is a rather weak inhibitor of cyclooxygenase-1 (COX-1) and COX-2, but a highly potent aldo/keto reductase 1A1 (AKR1A1) inhibitor. Modification either at the carboxyl group or at the chlorophenyl ring in indomethacin with ortho-and meta-carbaboranyl derivatives gave active derivatives only for the ortho-carbaborane directly attached to the carboxyl group, while the corresponding adamantyl and meta-carbaboranyl derivatives were inactive.

2‐Carbaborane‐3‐phenyl‐1H‐indoles—Synthesis via McMurry Reaction and Cyclooxygenase (COX) Inhibition Activity

“…Carbaboranes are icosahedral clusters with ten BH and two CH vertices and a volume slightly larger than that of a rotating benzene ring. [1] Besides their use in catalysis and polymer chemistry, [2] carbaborane derivatives were developed for medicinal applications, primarily for use as boron neutron capture therapy (BNCT) agents; [3][4][5] however, their potency as novel pharmacophores in drug development [1,[6][7][8][9][10][11][12][13][14][15] has also been recognized. [16][17][18] In this context, dicarba-closo-dodecaboranes [closo-C 2 B 10 H 12 ] are regarded as promising candidates given their remarkable metabolic stability and low toxicity as well as their high hydrophobicity and three-dimensional aromaticity.…”

Modular triazine-based carborane-containing carboxylic acids – synthesis and characterisation of potential boron neutron capture therapy agents made of readily accessible building blocks

“…highly stable peptide bond between the carboxylic acid of boron-rich derivatives and an amino group of the biomolecule of interest (e.g. lysine in specific peptides) is a much-favoured coupling strategy 20,48,[50][51][52][53] and was also employed here for the thioglycolic acid derivative 4. Compound 4 could be incorporated up to three times into the breast cancer-selective peptide [F 7 ,P 34 ]-NPY at positions 4, 18 and 22.…”

(N,Se) and (Se,N,Se) Ligands Based on Carborane and Pyridine Fragments – Reactivity of 2,6‐[(1′‐Me‐1′,2′‐closo‐C2B10H10)SeCH2]2C5H3N towards Copper and Silver

“…Carboranes, a current hot research topic, have found versatile applications in catalysis, polymer chemistry, and in medicine as boron neutron capture therapy (BNCT) agents . Exhibiting unique structural features and properties such as high hydrophobicity and low toxicity in conjunction with high thermal and catabolic stabilities, carboranes are also regarded as suitable pharmacophores for drug delivery .…”