Synthesis and pharmacological investigation of new N-hydroxyalkyl-2- aminophenothiazines exhibiting marked MDR inhibitory effect

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Abstract

Novel N-hydroxyalkyl-2-aminophenothiazines implying a tetrazole moiety at the alkyl chain have been synthesized by hydroboration-oxidation of dienes followed by Buchwald-Hartwig cross-coupling reaction. Also, some sulfoxide and sulfone derivatives have been prepared by selective oxidations. MDR inhibition studies on rat hepatocyte cell culture revealed that some derivatives exhibit marked biological efficacy exceeding that of the standard verapamil (e.g., 3h, 4h, 16). Selected derivatives were subjected to chemical resolution to provide both enantiomers which were shown of similar activity on P-gp interaction measurements. The new compounds exhibited no toxicity.

Original languageEnglish
Pages (from-to)3760-3779
Number of pages20
JournalBioorganic and Medicinal Chemistry
Volume21
Issue number13
DOIs
Publication statusPublished - Jul 1 2013

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sulfoxide
Sulfones
Cross Reactions
Verapamil
Hepatocytes
Cell Culture Techniques
Pharmacology
Derivatives
Oxidation
Enantiomers
Cell culture
Toxicity
Rats
1H-tetrazole

Keywords

  • Buchwald-Hartwig cross-coupling reaction
  • MDR inhibition
  • N-Hydroxyalkyl-2-aminophenothiazines
  • Resolution of racemate
  • Sulfoxide and sulfone derivatives

ASJC Scopus subject areas

  • Pharmaceutical Science
  • Drug Discovery
  • Organic Chemistry
  • Molecular Medicine
  • Molecular Biology
  • Clinical Biochemistry
  • Biochemistry
  • Medicine(all)

Cite this

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title = "Synthesis and pharmacological investigation of new N-hydroxyalkyl-2- aminophenothiazines exhibiting marked MDR inhibitory effect",
abstract = "Novel N-hydroxyalkyl-2-aminophenothiazines implying a tetrazole moiety at the alkyl chain have been synthesized by hydroboration-oxidation of dienes followed by Buchwald-Hartwig cross-coupling reaction. Also, some sulfoxide and sulfone derivatives have been prepared by selective oxidations. MDR inhibition studies on rat hepatocyte cell culture revealed that some derivatives exhibit marked biological efficacy exceeding that of the standard verapamil (e.g., 3h, 4h, 16). Selected derivatives were subjected to chemical resolution to provide both enantiomers which were shown of similar activity on P-gp interaction measurements. The new compounds exhibited no toxicity.",
keywords = "Buchwald-Hartwig cross-coupling reaction, MDR inhibition, N-Hydroxyalkyl-2-aminophenothiazines, Resolution of racemate, Sulfoxide and sulfone derivatives",
author = "Daniella Tak{\'a}cs and O. Egyed and L. Drahos and P. Szab{\'o} and K. Jemnitz and M{\'o}nika Szab{\'o} and Z. Veres and J. Visy and J. Moln{\'a}r and Z. Riedl and G. Haj{\'o}s",
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T1 - Synthesis and pharmacological investigation of new N-hydroxyalkyl-2- aminophenothiazines exhibiting marked MDR inhibitory effect

AU - Takács, Daniella

AU - Egyed, O.

AU - Drahos, L.

AU - Szabó, P.

AU - Jemnitz, K.

AU - Szabó, Mónika

AU - Veres, Z.

AU - Visy, J.

AU - Molnár, J.

AU - Riedl, Z.

AU - Hajós, G.

PY - 2013/7/1

Y1 - 2013/7/1

N2 - Novel N-hydroxyalkyl-2-aminophenothiazines implying a tetrazole moiety at the alkyl chain have been synthesized by hydroboration-oxidation of dienes followed by Buchwald-Hartwig cross-coupling reaction. Also, some sulfoxide and sulfone derivatives have been prepared by selective oxidations. MDR inhibition studies on rat hepatocyte cell culture revealed that some derivatives exhibit marked biological efficacy exceeding that of the standard verapamil (e.g., 3h, 4h, 16). Selected derivatives were subjected to chemical resolution to provide both enantiomers which were shown of similar activity on P-gp interaction measurements. The new compounds exhibited no toxicity.

AB - Novel N-hydroxyalkyl-2-aminophenothiazines implying a tetrazole moiety at the alkyl chain have been synthesized by hydroboration-oxidation of dienes followed by Buchwald-Hartwig cross-coupling reaction. Also, some sulfoxide and sulfone derivatives have been prepared by selective oxidations. MDR inhibition studies on rat hepatocyte cell culture revealed that some derivatives exhibit marked biological efficacy exceeding that of the standard verapamil (e.g., 3h, 4h, 16). Selected derivatives were subjected to chemical resolution to provide both enantiomers which were shown of similar activity on P-gp interaction measurements. The new compounds exhibited no toxicity.

KW - Buchwald-Hartwig cross-coupling reaction

KW - MDR inhibition

KW - N-Hydroxyalkyl-2-aminophenothiazines

KW - Resolution of racemate

KW - Sulfoxide and sulfone derivatives

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