Synthesis, biological evaluation, and modeling of dimeric PPI analogues as novel DNA minor groove binders.
A series of symmetrical dimeric proton pump inhibitor (PPI) analogues, designed as novel type DNA minor groove binders, was synthesized and evaluated for anti-tumor activity. Some of these new compounds showed IC(50) values below 10 microM in an in vitro anti-tumor test. A molecular modeling study was performed to confirm the sequence selectivity of these compounds towards AT base pairs in DNA. Two effective compounds were selected and docked into the minor groove of DNA. The snug binding may be responsible for their cytotoxic and anti-tumor effects.
Key Lab of New Drug Design and Discovery of Liaoning Province, School of Pharmaceutical Engineering, Shenyang Pharmaceutical University, Shenyang 110016, P. R. China.
Yan-Hui
YH
Yang
Qing-He
QH
Wang
Han
H
Nie
Hong
H
Chen
Mao-Sheng
MS
Cheng
D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D045744:Cell Line, Tumor; D004247:DNA / Q000737:chemistry*; D019281:Dimerization; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D008958:Models, Molecular; D009690:Nucleic Acid Conformation; D011485:Protein Binding / Q000187:drug effects; D054328:Proton Pump Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*
D000970:Antineoplastic Agents; D054328:Proton Pump Inhibitors; D004247:DNA