Synthesis, Crystal Structure, Absolute Configuration and Antitumor Activity of the Enantiomers of 5-Bromo-2-chloro-N-(1-phenylethyl)pyridine-3-sulfonamide

Molecules. 2015 Nov 24;20(11):20926-38. doi: 10.3390/molecules201119740.

Abstract

Pyridinesulfonamide is an important fragment which has a wide range of applications in novel drugs. R- and S-isomers of 5-bromo-2-chloro-N-(1-phenylethyl)pyridine-3-sulfonamide have been synthesized, and the stereostructures have been researched. Single crystals of both compounds were obtained for X-ray analysis, and the absolute configurations (ACs) have been further confirmed by electronic circular dichroism (ECD), optical rotation (OR) and quantum chemical calculations. The crystal structures and calculated geometries were extremely similar, which permitted a comparison of the relative reliabilities of ACs obtained by ECD analyses and theoretical simulation. In addition, the effect of stereochemistry on the PI3Kα kinase and anticancer activity were investigated. Compounds 10a and 10b inhibit the activity of PI3Kα kinase with IC50 values of 1.08 and 2.69 μM, respectively. Furthermore, molecular docking was performed to analyze the binding modes of R- and S-isomers.

Keywords: DFT; ECD; PI3K; X-ray diffraction; absolute configuration; antitumor activity; enantiomer; pyridinesulfonamide.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents / chemical synthesis
  • Antineoplastic Agents / chemistry*
  • Antineoplastic Agents / pharmacology*
  • Enzyme Activation / drug effects
  • Hep G2 Cells
  • Humans
  • Hydrogen Bonding
  • Inhibitory Concentration 50
  • Minor Histocompatibility Antigens
  • Models, Molecular*
  • Molecular Conformation*
  • Phosphatidylinositol 3-Kinases / chemistry
  • Phosphoinositide-3 Kinase Inhibitors
  • Phosphotransferases (Alcohol Group Acceptor) / antagonists & inhibitors
  • Protein Binding
  • Sulfonamides / chemical synthesis
  • Sulfonamides / chemistry*
  • Sulfonamides / pharmacology*

Substances

  • Antineoplastic Agents
  • Minor Histocompatibility Antigens
  • Phosphoinositide-3 Kinase Inhibitors
  • Sulfonamides
  • Phosphotransferases (Alcohol Group Acceptor)
  • phosphatidylinositol phosphate 4-kinase