Synthesis, biological evaluation, and modeling of dimeric PPI analogues as novel DNA minor groove binders

Yan-Hui Yang; Qing-He Wang; Han Nie; Hong Chen; Mao-Sheng Cheng

doi:10.3390/molecules13051179

Synthesis, biological evaluation, and modeling of dimeric PPI analogues as novel DNA minor groove binders

Molecules. 2008 May 20;13(5):1179-88. doi: 10.3390/molecules13051179.

Authors

Yan-Hui Yang¹, Qing-He Wang, Han Nie, Hong Chen, Mao-Sheng Cheng

Affiliation

¹ Key Lab of New Drug Design and Discovery of Liaoning Province, School of Pharmaceutical Engineering, Shenyang Pharmaceutical University, Shenyang 110016, P. R. China.

Abstract

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.

MeSH terms

Antineoplastic Agents / chemical synthesis
Antineoplastic Agents / chemistry
Antineoplastic Agents / pharmacology
Cell Line, Tumor
DNA / chemistry*
Dimerization
Drug Screening Assays, Antitumor
Humans
Models, Molecular*
Nucleic Acid Conformation*
Protein Binding / drug effects
Proton Pump Inhibitors / chemical synthesis*
Proton Pump Inhibitors / chemistry
Proton Pump Inhibitors / pharmacology*

Substances

Antineoplastic Agents
Proton Pump Inhibitors
DNA