Synthesis, Biological Evaluation, and Modeling of Dimeric PPI Analogues as Novel DNA Minor Groove Binders

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

doi:10.3390/molecules13051179

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 IC50 values below 10 μM 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.

Highlights

DNA minor groove binders (MGBs) are a novel family of anti-tumor agents and some of them have entered clinical trials
X-ray crystallographic and NMR studies on complexes of Hoechst 33258 with ATcontaining oligonucleotides have shown that the drug fits the minor groove snugly, with the planar benzimidazole groups oriented parallel to the direction of the groove and each inner-facing nitrogen atom hydrogen bonding in a bifurcated manner to a pair of adjacent hydrogen-bond donors on the edge of the AT base pairs [3]
Dimeric pump inhibitor (PPI) analogues were synthesized as a novel type of DNA minor groove binders

Summary

Introduction

DNA minor groove binders (MGBs) are a novel family of anti-tumor agents and some of them have entered clinical trials. A series of head-to-head linked bis-benzimidazoles was reported as new sequence-selective DNA-binding agents [4]. Preliminary pharmacologic tests showed that these symmetrical bis-benzimidazoles were cytotoxic at the μM level, with activity significantly greater than that shown by Hoechst 33258 in a group of ovarian carcinoma cell lines. Antiproliferative evalutation in tumor cell lines showed that 2,2’-di-[[(3,5-dimethyl4-methoxy)pyrid-2-yl]methylenethio]-5,5’-bis-1H,1’H-benzimidazole (2, Figure 1) effectively inhibited SKOV-3 cell proliferation with an IC50 value of 2.95 μM, which is more effective than that of Hoechst 33258.

Results

Conclusion