Carbaboranes as pharmacophores: Similarities and differences between aspirin and asborin

• Published in: European journal of medicinal chemistry Vol. 46; no. 4; pp. 1131 - 1139
• Main Authors: Scholz, Matthias, Kaluđerović, Goran N., Kommera, Harish, Paschke, Reinhard, Will, Joanna, Sheldrick, William S., Hey-Hawkins, Evamarie
• Format: Journal Article
• Language: English
• Published: Kidlington Elsevier Masson SAS 01.04.2011; Elsevier
• Subjects: Acetates - chemistry; Acetates - pharmacology; Apoptosis - drug effects; Asborin; Aspirin; Aspirin - chemistry; Aspirin - pharmacology; Biological and medical sciences; Bones, joints and connective tissue. Antiinflammatory agents; Boron Compounds - chemistry; Boron Compounds - pharmacology; Carbaborane; Carborane; Caspases - metabolism; Catalytic Domain; Cell Line, Tumor; Cyclooxygenase 1 - chemistry; Cyclooxygenase 1 - metabolism; Cyclooxygenase 2 - chemistry; Cyclooxygenase 2 - metabolism; Cyclooxygenase 2 Inhibitors - chemistry; Cyclooxygenase 2 Inhibitors - pharmacology; Cytotoxicity; Drug Discovery; Humans; Hydrolysis; Isomerism; Medical sciences; Models, Molecular; Pharmacology. Drug treatments; Pharmacophore; Rhodamines - metabolism; Cytotoxicity; Aspirin; Carbaborane; Carborane; Asborin; Pharmacophore; Prostaglandin-endoperoxide synthase; Cage compound; Similarity; Enzyme; Enzyme inhibitor; Acetylsalicylic acid; Biological activity; Hydrolysis; Structure activity relation; Cell death; Molecular model; Boron Organic compounds; Oxidoreductases; Salicylates; Degradation product; Comparative study; Apoptosis
• ISSN: 0223-5234; 1768-3254; 1768-3254
• DOI: 10.1016/j.ejmech.2011.01.030

In medicinal chemistry carbaboranes have been used almost exclusively as boron carriers for boron neutron capture therapy (BNCT). Recent developments extended the carrier approach and use carbaboranes as scaffolds for radiodiagnostic or therapeutic agents. Most recent studies, however, focus on carbaboranes as modern hydrophobic pharmacophores. This research employs preferably meta- and para-carbaborane, because these isomers are extremely hydrophobic and very stable. In this paper we therefore investigated the pharmacophoric behavior of the ortho isomer as putative phenyl mimetic by comparing aspirin to asborin, its ortho-carbaborane analogue. Special emphasis is placed on the impact of the cluster properties on the pharmacological profile. Subjects under study are the mode of cyclooxygenase (COX) inhibition, stability, and toxicity. The straightforward syntheses of the corresponding nido compounds as well as their contribution to the pharmacology of the closo precursors will be highlighted. Finally, proof will be given that the ortho-carbaborane core of asborin merits the designation “pharmacophore” by definition and is a multifunctional group rather than just a hydrophobic, bulky spectator. [Display omitted] ► Carbaboranes are used as modern hydrophobic pharmacophores. ► Comparison of aspirin to asborin, its ortho-carbaborane analogue, in mode of cyclooxygenase (COX) inhibition, stability, and toxicity. ► Syntheses of the corresponding nido compounds and their contribution to the pharmacology of the closo precursors are highlighted.