ChemInform Abstract: 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-pro- tected galactose, followed by oxidation or sulfurization to give the corresponding bis-phos- phonates. Deprotection yielded water-soluble compounds. The corresponding disodium salts exhibit especially low cytotoxicity. Preliminary results on the in vivo toxicity and biodistribu - tion 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 tumor- selective 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 cyclo - oxygenase-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.