title: Curcumin analogues inhibit phosphodiesterase-5 and dilate rat pulmonary arteries.
abstract: OBJECTIVE
  Phosphodiesterase (PDE)-5 inhibitors are useful as vasodilators for the treatment of pulmonary arterial hypertension. We aimed to study curcumin analogues for PDE5 inhibitory activity and vasorelaxation of rat pulmonary arteries.
  
  
  METHODS
  Three natural curcuminoids (1-3) and six synthetic analogues (4-9) were tested for PDE5 and PDE6 inhibitory activities using enzymatic radioassay. Their vasorelaxation was measured using freshly isolated segments of rat pulmonary artery and aorta.
  
  
  RESULTS
  Curcuminoids (1-3) mildly inhibited PDE5 (half maximal inhibitory concentration (IC50 ) = 18 µm): the metamethoxyl of curcumin was important for PDE5 inhibition. But hydroxyl rearrangements, removing both methoxyls and one ketomethylene, yielded the potent 7 and 9 (IC50  = 4 µm) (compared with sildenafil, IC50  = 0.03 µm). Only 1, 3 and 4 were PDE5 selective over PDE6. Triazole-carboxylic addition provided water-solubility while preserving potency. All analogues possessed concentration-dependent vasorelaxant activity on pulmonary arteries (40% of maximal effective concentration (EC40 ) = 29-90 µm, maximum response = 60-90% at 300 µm), while compounds (1-8) were weakly acting in aorta (maximum response <40%). Only demethoxycurcumin (2) and analogues 5, 8, 9 had endothelium-dependent actions. Sildenafil was highly potent (EC40  = 0.04 µm) and highly endothelium dependent in pulmonary artery but weak on intact aorta (EC40  = 1.8 µm). Activity profiles suggest actions through additional cell pathways for promoting vasorelaxation.
  
  
  CONCLUSIONS
  Curcumin analogues are potential leads for developing efficacious and selective PDE5 inhibitors and other pathologies of pulmonary hypertension.
authors.affiliation: Department of Pharmaceutical Chemistry and Pharmacognosy, Faculty of Pharmaceutical Sciences and Center of Excellence for Innovation in Chemistry, Naresuan University, Phitsanulok, Thailand.
authors.forename: Oraya
authors.initials: O
authors.lastname: Kruangtip
authors.forename: Krongkarn
authors.initials: K
authors.lastname: Chootip
authors.forename: Prapapan
authors.initials: P
authors.lastname: Temkitthawon
authors.forename: Kanokwan
authors.initials: K
authors.lastname: Changwichit
authors.forename: Thipphawan
authors.initials: T
authors.lastname: Chuprajob
authors.forename: Chatchawan
authors.initials: C
authors.lastname: Changtam
authors.forename: Apichart
authors.initials: A
authors.lastname: Suksamrarn
authors.forename: Nantaka
authors.initials: N
authors.lastname: Khorana
authors.forename: C Norman
authors.initials: CN
authors.lastname: Scholfield
authors.forename: Kornkanok
authors.initials: K
authors.lastname: Ingkaninan
mesh_terms: D000818:Animals; D003474:Curcumin / Q000031:analogs & derivatives*; D004305:Dose-Response Relationship, Drug; D004730:Endothelium, Vascular / Q000378:metabolism; D058986:Phosphodiesterase 5 Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D011651:Pulmonary Artery / Q000187:drug effects*; D051381:Rats; D013329:Structure-Activity Relationship; D014664:Vasodilation / Q000187:drug effects; D014665:Vasodilator Agents / Q000494:pharmacology*
chemical_list: D058986:Phosphodiesterase 5 Inhibitors; D014665:Vasodilator Agents; D003474:Curcumin
keywords: curcumin analogues; phosphodiesterase-5; pulmonary artery; pulmonary artery hypertension