Chemical synthesis of tetracyclic terpenes and evaluation of antagonistic activity on endothelin-A receptors and voltage-gated calcium channels. Issue 17 (1st September 2015)

• Record Type: Journal Article
• Authors: Lu, Jianyu; Aguilar, Angelo; Zou, Bende; Bao, Weier; Koldas, Serkan; Shi, Aibin; Desper, John; Wangemann, Philine; Xie, Xinmin Simon; Hua, Duy H.
• Is Part Of: Bioorganic & medicinal chemistry. Volume 23:Issue 17(2015)
• Page Start: 5985
• Page End: 5998
• Publication Date: 2015-09-01
• Subjects: 2D NOESY two-dimensional nuclear Overhauser effect spectroscopy -- Dibal-H diisobutylaluminum hydride -- DRG dorsal root ganglion -- ee enantiomeric excess -- ET-1 endothelin-1 -- ETA endothelin A receptors -- EGTA ethylene glycol tetraacetic acid -- EC50 median effective concentration -- EVK ethyl vinyl ketone -- HEPES 4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid -- HVA high-voltage-activated -- Ki inhibitory constant -- K-Selectride potassium tri-sec-butylborohydride -- LDA lithium diisopropylamide -- LVA low-voltage-activated -- MA myriceric acid A -- MgATP magnesium adenosine 5′-triphosphate -- MgGTP magnesium guanidine triphosphate -- ORTEP Oak Ridge thermal ellipsoid plot -- SEM standard error of the mean -- TBSCl t-butyldimethylsilyl chloride -- TTX Tetrodotoxin; Antagonistic activity -- Endothelin-1 (ET-1) -- Pulmonary hypertension -- Tetracyclic terpenes -- Vascular related diseases -- Vasoconstriction -- Voltage-activated Ca2+ channels; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; Biochemistry -- Periodicals; Chemistry, Clinical -- Periodicals; Chemistry, Organic -- Periodicals; Chimie bio-organique -- Périodiques; Chimie pharmaceutique -- Périodiques; 615.19
• DOI: 10.1016/j.bmc.2015.06.055
• Languages: English
• ISSNs: 0968-0896

Abstract

Graphical abstract: 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.