Synthesis, Src kinase inhibitory and anticancer activities of 1-substituted 3-(N-alkyl-N-phenylamino)propane-2-ols

Deepti Sharma, Raman K. Sharma, Sumati Bhatia, Rakesh Tiwari, Deendayal Mandal, Jessica Lehmann, Keykavous Parang, Carl E. Olsen, Virinder S. Parmar, Ashok K. Prasad

Research output: Contribution to journalArticlepeer-review

Abstract

A series of 3-(N-alkyl-N-phenylamino)propan-2-ol derivatives were synthesized from epichlorohydrine in a multi-step strategy and were evaluated as Src kinase inhibitors. First, epoxy ring opening of epichlorohydrine was carried out in the presence of N-alkylanilines to yield 3-(N-alkyl-N-phenylamino)-1-chloro-propan-2-ol derivatives using Ca(OTf)2 as catalyst based on our previous studies [1]. Second, ring closure was performed under basic conditions to afford N-epoxymethyl N-alkylaniline derivatives. Finally, the epoxide ring opening with four different secondary amines and three nucleobases afforded the final products, i.e., a series of β-amino alcohols. All compounds were screened for their inhibitory activity against Src kinase and anticancer activity on human breast carcinoma cells, BT-20 cell line. Among all compounds, 3-N-methyl-N-phenylamino-1-(pyrrolidin-1-yl)propan-2-ol (13b) exhibited the highest inhibitory potency (IC50 = 66.1 μM) against Src kinase. Structure-activity relationship studies suggested that the incorporation of bulky groups at position 1 and N-substitution with groups larger than methyl moiety, reduced the inhibitory potency of the compound significantly. Compounds 3-(N-ethyl-N-phenylamino-)-1-(4-methylpiperazin-1-yl)propan-2-ol (14c) and 3-(N-ethyl-N-phenylamino)-1-(thymine-1-yl)propan-2-ol (17) were found to inhibit the growth of breast carcinoma cells by approximately 45-49% at concentration of 50 μM.

Original languageEnglish (US)
Pages (from-to)1164-1172
Number of pages9
JournalBiochimie
Volume92
Issue number9
DOIs
StatePublished - Sep 2010
Externally publishedYes

Keywords

  • β-Amino alcohol
  • Cancer
  • Cell proliferation
  • Epoxide
  • Src kinase

ASJC Scopus subject areas

  • Biochemistry

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