Chemical synthesis of tetracyclic terpenes and evaluation of antagonistic activity on endothelin-A receptors and voltage-gated calcium channels

Bioorg Med Chem. 2015 Sep 1;23(17):5985-98. doi: 10.1016/j.bmc.2015.06.055. Epub 2015 Jun 27.

Abstract

A class of tetracyclic terpenes was synthesized and evaluated for antagonistic activity of endothelin-1 (ET-1) induced vasoconstriction and inhibitory activity of voltage-activated Ca(2+) channels. Three repeated Robinson annulation reactions were utilized to construct the tetracyclic molecules. A stereoselective reductive Robinson annulation was discovered for the formation of optically pure tricyclic terpenes. Stereoselective addition of cyanide to the hindered α-face of tetracyclic enone (-)-18 was found and subsequent transformation into the aldehyde function was affected by the formation of bicyclic hemiiminal (-)-4. Six selected synthetic tetracyclic terpenes show inhibitory activities in ET-1 induced vasoconstriction in the gerbil spiral modiolar artery with putative affinity constants ranging between 93 and 319 nM. Moreover, one compound, (-)-3, was evaluated further and found to inhibit voltage-activated Ca(2+) currents but not to affect Na(+) or K(+) currents in dorsal root ganglion cells under similar concentrations. These observations imply a dual mechanism of action. In conclusion, tetracyclic terpenes represent a new class of hit molecules for the discovery of new drugs for the treatment of pulmonary hypertension and vascular related diseases.

Keywords: Antagonistic activity; Endothelin-1 (ET-1); Pulmonary hypertension; Tetracyclic terpenes; Vascular related diseases; Vasoconstriction; Voltage-activated Ca(2+) channels.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Calcium Channels / chemistry*
  • Hypertension, Pulmonary / therapy*
  • Molecular Structure
  • Receptor, Endothelin A / chemistry*
  • Terpenes / chemical synthesis*
  • Terpenes / chemistry*

Substances

  • Calcium Channels
  • Receptor, Endothelin A
  • Terpenes