Selective hydroboration of dieneamines. Formation of hydroxyalkylphenothiazines as MDR modulators

Bioorg Med Chem. 2012 Jul 15;20(14):4258-70. doi: 10.1016/j.bmc.2012.05.065. Epub 2012 Jun 5.

Abstract

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 (BH(3) × Me(2)S) 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.

MeSH terms

  • ATP Binding Cassette Transporter, Subfamily B, Member 1 / antagonists & inhibitors
  • ATP Binding Cassette Transporter, Subfamily B, Member 1 / metabolism
  • Amines / chemistry*
  • Animals
  • Boranes / chemistry
  • Cells, Cultured
  • Crystallography, X-Ray
  • Drug Resistance, Multiple / drug effects
  • Hepatocytes / drug effects
  • Male
  • Molecular Conformation
  • Phenothiazines / chemical synthesis
  • Phenothiazines / chemistry*
  • Phenothiazines / pharmacology
  • Pyrimidines / chemistry
  • Rats
  • Rats, Wistar

Substances

  • ATP Binding Cassette Transporter, Subfamily B, Member 1
  • Amines
  • Boranes
  • Phenothiazines
  • Pyrimidines
  • tetrazolo(1,5-a)pyrimidine
  • phenothiazine