title: Chemical synthesis of tetracyclic terpenes and evaluation of antagonistic activity on endothelin-A receptors and voltage-gated calcium channels.
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.
authors.affiliation: Department of Chemistry, Kansas State University, Manhattan, KS 66506, USA.
authors.forename: Jianyu
authors.initials: J
authors.lastname: Lu
authors.affiliation: Department of Chemistry, Kansas State University, Manhattan, KS 66506, USA.
authors.forename: Angelo
authors.initials: A
authors.lastname: Aguilar
authors.affiliation: AfaSci Research Laboratories, 522 Second Avenue, Redwood City, CA 94063, USA.
authors.forename: Bende
authors.initials: B
authors.lastname: Zou
authors.affiliation: Department of Chemistry, Kansas State University, Manhattan, KS 66506, USA.
authors.forename: Weier
authors.initials: W
authors.lastname: Bao
authors.affiliation: Department of Chemistry, Kansas State University, Manhattan, KS 66506, USA.
authors.forename: Serkan
authors.initials: S
authors.lastname: Koldas
authors.affiliation: Department of Chemistry, Kansas State University, Manhattan, KS 66506, USA.
authors.forename: Aibin
authors.initials: A
authors.lastname: Shi
authors.affiliation: Department of Chemistry, Kansas State University, Manhattan, KS 66506, USA.
authors.forename: John
authors.initials: J
authors.lastname: Desper
authors.affiliation: Department of Anatomy and Physiology, Kansas State University, Manhattan, KS 66506, USA.
authors.forename: Philine
authors.initials: P
authors.lastname: Wangemann
authors.affiliation: AfaSci Research Laboratories, 522 Second Avenue, Redwood City, CA 94063, USA.
authors.forename: Xinmin Simon
authors.initials: XS
authors.lastname: Xie
authors.affiliation: Department of Chemistry, Kansas State University, Manhattan, KS 66506, USA. Electronic address: duy@ksu.edu.
authors.forename: Duy H
authors.initials: DH
authors.lastname: Hua
mesh_terms: D015220:Calcium Channels / Q000737:chemistry*; D006976:Hypertension, Pulmonary / Q000628:therapy*; D015394:Molecular Structure; D044022:Receptor, Endothelin A / Q000737:chemistry*; D013729:Terpenes / Q000138:chemical synthesis* / Q000737:chemistry*
chemical_list: D015220:Calcium Channels; D044022:Receptor, Endothelin A; D013729:Terpenes
keywords: Antagonistic activity; Endothelin-1 (ET-1); Pulmonary hypertension; Tetracyclic terpenes; Vascular related diseases; Vasoconstriction; Voltage-activated Ca(2+) channels