Synthesis and HPLC-ECD Study of Cytostatic Condensed O,N-Heterocycles Obtained from 3-Aminoflavanones

Biomolecules. 2020 Oct 20;10(10):1462. doi: 10.3390/biom10101462.


Racemic chiral O,N-heterocycles containing 2-arylchroman or 2-aryl-2H-chromene subunit condensed with morpholine, thiazole, or pyrrole moieties at the C-3-C-4 bond were synthesized with various substitution patterns of the aryl group by the cyclization of cis- or trans-3-aminoflavanone analogues. The 3-aminoflavanone precursors were obtained in a Neber rearrangement of oxime tosylates of flavanones, which provided the trans diastereomer as the major product and enabled the isolation of both the cis- and trans-diastereomers. The cis- and trans-aminoflavanones were utilized to prepare three diastereomers of 5-aryl-chromeno[4,3-b][1,4]oxazines. Antiproliferative activity of the condensed heterocycles and precursors was evaluated against A2780 and WM35 cancer cell lines. For a 3-(N-chloroacetylamino)-flavan-4-ol derivative, showing structural analogy with acyclic acid ceramidase inhibitors, 0.15 μM, 3.50 μM, and 6.06 μM IC50 values were measured against A2780, WM35, and HaCat cell lines, and apoptotic mechanism was confirmed. Low micromolar IC50 values down to 2.14 μM were identified for the thiazole- and pyrrole-condensed 2H-chromene derivatives. Enantiomers of the condensed heterocycles were separated by HPLC using chiral stationary phase, HPLC-ECD spectra were recorded and TDDFT-ECD calculations were performed to determine the absolute configuration and solution conformation. Characteristic ECD transitions of the separated enantiomers were correlated with the absolute configuration and effect of substitution pattern on the HPLC elution order was determined.

Keywords: 3-(N-chloroacetylamino)-flavan-4-ol; 3-aminoflavanones; HPLC-ECD; TDDFT-ECD calculations; antiproliferative activity; lamellarin analogues; neber rearrangement; pyrrole-condensed 2H-chromene; thiazole-condensed 2H-chromene.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Benzopyrans / chemical synthesis
  • Benzopyrans / chemistry
  • Benzopyrans / pharmacology
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Chromatography, High Pressure Liquid
  • Cytostatic Agents / chemistry
  • Female
  • Flavonoids / chemistry
  • Flavonoids / pharmacology
  • Heterocyclic Compounds / chemical synthesis
  • Heterocyclic Compounds / chemistry
  • Heterocyclic Compounds / pharmacology
  • Humans
  • Molecular Conformation / drug effects
  • Molecular Structure
  • Morpholines / chemistry
  • Morpholines / pharmacology
  • Ovarian Neoplasms / drug therapy*
  • Ovarian Neoplasms / pathology
  • Stereoisomerism


  • 3-aminoflavone
  • 5,7-dimethoxy-2-methyl-2H-benzopyran
  • Benzopyrans
  • Cytostatic Agents
  • Flavonoids
  • Heterocyclic Compounds
  • Morpholines
  • morpholine