Chemical synthesis of tetracyclic terpenes and evaluation of antagonistic activity on endothelin-A receptors and voltage-gated calcium channels.
Bioorg Med Chem
; 23(17): 5985-98, 2015 Sep 01.
Article
in En
| MEDLINE
| ID: mdl-26190460
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.
Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Terpenes
/
Calcium Channels
/
Receptor, Endothelin A
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Hypertension, Pulmonary
Language:
En
Journal:
Bioorg Med Chem
Journal subject:
BIOQUIMICA
/
QUIMICA
Year:
2015
Document type:
Article
Affiliation country:
Estados Unidos