Ditopic complexation of selenite anions or calcium cations by pirenoxine: an implication for anti-cataractogenesis.
This study investigated whether and how pirenoxine (PRX) interacts with selenite or calcium ions, as these two ions have been proven respectively a factor leading to the formation of lens cataract. UV, NMR, and isothermal titration calorimetry (ITC) analysis indicated that PRX could bind maximum up to six selenite anions and the binding site preference was concentration dependent with the peripheral binding first followed by the π-π interactions with the aromatic moiety; while for calcium cation interaction the 3-carboxylate and β-ketoimine functional groups were responsible for chelating calcium ions. The results obtained by MP2/6-31+G(d) molecular orbital calculations provided theoretical evidence in support of the π-π interactions between selenite and the PRX aromatic framework, and further analysis of the binding energies with the aromatic moiety indicates that these interactions take place most likely at the benzoquinone (ring I) π-system. The calcium binding preferences with PRX were also determined based on the stabilization energy obtained by B3LYP/6-31+G(d) calculations, showing the binding preferences were site 2 > site 1 > site 3 > ring II, consistent with the experimental data. The in vitro study of the reduction of selenite or calcium ions-induced lens turbidity by PRX with ditopic recognition properties was thus demonstrated. These results may provide a rationale for using PRX as an anti-cataract agent and warrant further biological studies.
Institute of Biological Chemistry, Academia Sinica, Taipei 115, Taiwan.
Jiahn-Haur
JH
Liao
Chien-Sheng
CS
Chen
Chao-Chien
CC
Hu
Wei-Ting
WT
Chen
Shao-Pin
SP
Wang
I-Lin
IL
Lin
Yi-Han
YH
Huang
Ming-Hsuan
MH
Tsai
Tzu-Hua
TH
Wu
Fu-Yung
FY
Huang
Shih-Hsiung
SH
Wu
D002118:Calcium / Q000009:adverse effects / Q000378:metabolism; D002386:Cataract / Q000139:chemically induced / Q000188:drug therapy / Q000378:metabolism; D056831:Coordination Complexes / Q000737:chemistry / Q000378:metabolism* / Q000627:therapeutic use; D006801:Humans; D007908:Lens, Crystalline / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D009682:Magnetic Resonance Spectroscopy; D008968:Molecular Conformation; D009391:Nephelometry and Turbidimetry; D010078:Oxazines / Q000737:chemistry / Q000378:metabolism* / Q000627:therapeutic use; D018038:Sodium Selenite / Q000009:adverse effects / Q000378:metabolism; D013816:Thermodynamics
D056831:Coordination Complexes; D010078:Oxazines; C004580:pirenoxine; D018038:Sodium Selenite; D002118:Calcium