Tetraphenylethene Derivatives with Different Numbers of Positively Charged Side Arms have Different Multimeric G-Quadruplex Recognition Specificity.

Abstract

Some G-rich sequences in the human genome have the potential to fold into a multimeric G-quadruplex (G4) structure and the formation of telomeric multimeric G4 has been demonstrated. Searching for highly specific multimeric G4 ligands is important for structure probing and for study of the function of G-rich gene sequences, as well as for the design of novel anticancer drugs. We found different numbers of positively charged side-arm substituents confer tetraphenylethene (TPE) derivatives with different multimeric G4 recognition specificity. 1,2-Bis{4-[(trimethylammonium)butoxy]phenyl}-1,2-tetraphenylethene dibromide (DATPE), which contains two side arms and gives a fluorescence response to only multimeric G4, has a low level of cytotoxicity and little or no effect on multimeric G4 conformation or stability. These features make DATPE a promising fluorescent probe for detection of multimeric G4 specifically in biological samples or in vivo. 1,1,2,2-Tetrakis{4-[(trimethylammonium)butoxy]phenyl}tetraphenylethene tetrabromide (QATPE), which contains four side arms, has a lower level of specificity for multimeric G4 recognition compared to DATPE but its binding affinity to multimeric G4 is higher compared to other structural DNAs. Its high multimeric G4-binding affinity, excellent multimeric G4-stabilizing ability, and the promotion of parallel G4 formation make QATPE a good candidate for novel anticancer drugs targeting multimeric G4 specifically, especially telomeric multimeric G4. This work provides information that might aid the design of specific multimeric G4 probes and the development of novel anticancer drugs.