Synthesis and pharmacological activities of amine-boranes.
A number of amine-boranes and related derivatives possess a wide range of biological activities including antineoplastic, antiviral, hypolipidemic, anti-inflammatory activities, anti-osteoporotic and dopamine receptor antagonist activities. The compounds include borane complexes of alpha-amino acids, aromatic, aliphatic and heterocyclic amines, and nucleosides. The syntheses of amine-borane derivatives are generally carried out by first preparing a tertiary amine- or phosphine-cyano- or carboxyborane to serve as a borane donor for a subsequent Lewis acid exchange reaction. Borane adducts of simple aliphatic amines, heterocyclic amines and nucleic acids demonstrated potent cytotoxic activity in vitro and in vivo against murine and human tumor models. These boron-containing compounds were shown to inhibit DNA synthesis; such inhibition was caused primarily by reducing de novo purine biosynthesis via inhibition of PRPP amidotransferase, IMP dehydrogenase and dihydrofolate reductase activities. Aliphatic, heterocyclic and nucleoside amine-boranes have also been shown to possess hypolipidemic activity in mice and rats. Many boron derivatives from different chemical classes demonstrated both cytotoxic and hypolipidemic activities. They decreased low-density lipoprotein (LDL) cholesterol while increasing high-density lipoprotein (HDL) cholesterol levels. The mode of action of these compounds in the 50-100 microM concentration range appeared to be by increasing lipid excretion from the body and by inhibiting rate-limiting enzyme activities for the de novo synthesis of lipids and cholesterol (e.g., phosphatidylate phosphohydrolase, ATP-dependent citrate lyase, cytoplasmic acetyl coenzyme A [CoA] synthetase, HMG CoA reductase, and acetyl CoA carboxylase). Selected amine-boranes (e.g., trimethylamine-cyanoborane, N-methylmorpholine-cyanoborane, and the base-boronated 2'-deoxynucleosides) have anti-inflammatory, analgesic, anti-arthritic and anti-osteoporotic activities.
Burnham
Bruce S
BS
Rider University, Department of Chemistry, Biochemistry and Physics, 2083 Lawrenceville Road, Lawrenceville, NJ 08648, USA. bburnham@rider.edu
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000138:chemical synthesis / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000494:pharmacology; D000998:Antiviral Agents / Q000138:chemical synthesis / Q000494:pharmacology; D001880:Boranes / Q000138:chemical synthesis* / Q000494:pharmacology*; D018492:Dopamine Antagonists / Q000138:chemical synthesis / Q000494:pharmacology; D006801:Humans; D000960:Hypolipidemic Agents / Q000138:chemical synthesis / Q000494:pharmacology; D015394:Molecular Structure; D010024:Osteoporosis / Q000188:drug therapy; D058919:Purinergic P2 Receptor Antagonists; D058472:Receptors, Purinergic P2Y1; D013997:Time Factors
D000894:Anti-Inflammatory Agents, Non-Steroidal; D000970:Antineoplastic Agents; D000998:Antiviral Agents; D001880:Boranes; D018492:Dopamine Antagonists; D000960:Hypolipidemic Agents; C546382:P2RY1 protein, human; C546383:P2ry1 protein, mouse; D058919:Purinergic P2 Receptor Antagonists; D058472:Receptors, Purinergic P2Y1