Regulation of the physiological effects of peroxidovanadium(V) complexes by the electronic nature of ligands.
Although the physiological effects of peroxidovanadium(V) complexes (pVs) have been extensively investigated both in vitro and in vivo with regard to their pharmacological activity, such as insulin-mimetic and antitumor activities, the relationship between the chemical and pharmacological properties of pVs is still unclear. Rational drug design with pVs depends on a full understanding of this relationship. Toward this end, the current report evaluates the physiological effects of 13 pVs were evaluated bound to a variety of ligand. Six of these ligands are tripodal tetradentate ligands, one is a linear tetradentate ligand, one boasts two pendant groups, three are tridentate ligands, and two are alkoxido-bridging, dinucleating ligands. The cytotoxicities of these pVs could be classified into three groups: significantly toxic, moderately toxic, and non- or negligibly toxic. Further, IC50 values could be related with the LMCT transition energies of the peroxido group, particularly among complexes with similar ligands. This relation indicates that the electronic properties of the peroxido group affected the physiological activity of the pV complex. We also investigated the insulin-signaling intensity of each pV. Phosphorylation of protein kinase B and extracellular signal-regulated kinase 1/2, two major insulin-signaling proteins, was observed after treating cells with pV for 30 min. Phosphorylation was particularly remarkable for complexes that exhibited high cytotoxicity. The present results demonstrate that the toxicity and physiological effects of pVs can be controlled by selecting an appropriate ancillary ligand. These findings provide a guide for synthesis of new pVs that may be used as candidate therapeutic agents.
Advanced Nanosciences and Biosciences, Graduate School of Innovative Life Science, University of Toyama, 3190 Gofuku, Toyama 930-8555, Japan.
Hironori
H
Sugiyama
Seiichi
S
Matsugo
Hirofumi
H
Misu
Toshinari
T
Takamura
Shuichi
S
Kaneko
Youhei
Y
Kanatani
Mikako
M
Kaido
Chie
C
Mihara
Nilka
N
Abeywardana
Ayana
A
Sakai
Kyouhei
K
Sato
Yoshitaro
Y
Miyashita
Kan
K
Kanamori
D000818:Animals; D045744:Cell Line, Tumor; D056831:Coordination Complexes / Q000138:chemical synthesis* / Q000494:pharmacology; D003603:Cytotoxins / Q000138:chemical synthesis* / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004583:Electrons; D005786:Gene Expression Regulation / Q000187:drug effects; D007328:Insulin / Q000378:metabolism / Q000494:pharmacology; D008024:Ligands; D019950:Mitogen-Activated Protein Kinase 1 / Q000235:genetics / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000235:genetics / Q000378:metabolism; D010545:Peroxides / Q000138:chemical synthesis* / Q000494:pharmacology; D010766:Phosphorylation / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects; D013329:Structure-Activity Relationship; D017968:Vanadium Compounds / Q000138:chemical synthesis* / Q000494:pharmacology
D056831:Coordination Complexes; D003603:Cytotoxins; D007328:Insulin; D008024:Ligands; D010545:Peroxides; D017968:Vanadium Compounds; D051057:Proto-Oncogene Proteins c-akt; C535149:Mapk1 protein, rat; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3