Selective hydroboration of dieneamines. Formation of hydroxyalkylphenothiazines as MDR modulators

• Published in: Bioorganic & medicinal chemistry Vol. 20; no. 14; pp. 4258 - 4270
• Main Authors: Takács, Daniella, Nagy, Ildikó, Bombicz, Petra, Egyed, Orsolya, Jemnitz, Katalin, Riedl, Zsuzsanna, Molnár, József, Amaral, Leonard, Hajós, György
• Format: Journal Article
• Language: English
• Published: Amsterdam Elsevier Ltd 15.07.2012; Elsevier
• Subjects: Amines - chemistry; Animals; ATP-Binding Cassette, Sub-Family B, Member 1 - antagonists & inhibitors; ATP-Binding Cassette, Sub-Family B, Member 1 - metabolism; Biological and medical sciences; Boranes - chemistry; Catalytic hydrogenation; Cells, Cultured; Crystallography, X-Ray; Dieneamine; dimethyl sulfide; Drug Resistance, Multiple - drug effects; Hepatocytes - drug effects; Hydroboration; hydrogenation; Male; Medical sciences; Molecular Conformation; Multidrug resistance; nuclear magnetic resonance spectroscopy; P-gp inhibition; Pharmacology. Drug treatments; phenothiazine; Phenothiazines - chemical synthesis; Phenothiazines - chemistry; Phenothiazines - pharmacology; Pyrimidines - chemistry; Rats; Rats, Wistar; salts; X-radiation; Hydroboration; Catalytic hydrogenation; Dieneamine; Multidrug resistance; P-gp inhibition; Drug combination; Catalytic reaction; Selectivity; Hydrogenation; Multiple resistance; Reversibility; Inhibition; Chemosensitizing agent
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/j.bmc.2012.05.065

N-dienylphenothiazines synthesized from tetrazolo[1,5-a]pyridinium salts by treatment with phenothiazine were subjected to catalytic hydrogenation to yield N-butylphenothiazines, whereas transformation of these dienes with borane dimethyl sulfide (BH3×Me2S) resulted in selective hydroboration of one double bond and full reduction of the other double bond to give 2-hydroxybutylphenothiazines. Position of the hydroxyl group was supported by NMR spectroscopy and verified by X-ray analysis. Comparison of MDR modulatory activity of the new derivatives revealed that the hydroxybutyl compounds are promising candidates for development of novel MDR inhibitors.