Design, Synthesis, and Characterization of Phenanthroline-neomycin Conjugates as G4 Ligands

Authors

Mandeep Singh, University of the PacificFollow
Siwen Wang, University of the PacificFollow
Liang Xue, University of the PacificFollow

Poster Number

4a

Lead Author Affiliation

Chemical synthesis and Drug Design (PCSP)

Lead Author Status

Doctoral Student

Second Author Affiliation

Chemical synthesis and Drug Design (PCSP)

Second Author Status

Doctoral Student

Third Author Affiliation

Department of Chemistry

Third Author Status

Faculty

Introduction/Abstract

G-quadruplexes are polymorphic, dynamic four stranded non-canonical DNA structures formed by stacking of G-tetrads in the presence of metal ions. There are over more than 370,000 putative G-quadruplex forming sequences in the human genome. This number is further broadened by considering the bulges in the G-quadruplexes. Most studied sequences are human telomeric DNA, G-quadruplex forming sequences in the promoter regions of proto-oncogenes like c-KIT, c-MYC, and RET, etc.

Purpose

The idea is to selectively target and stabilize the G-quadruplexes with small molecules, as these structures are frequently associated with genetic instability and strand breaks. Cell death can be potentiated in cells deficient in DNA damage repair genes

Method

The compounds have been successfully characterized with analytical techniques like ¹H NMR, ¹H-¹H COSY, ¹D-TOSCY, HRMS. The binding affinity of the synthesized conjugates was ascertained with CD-melting studies and G4 FID assay. The inhibition of telomerase activity was determined with ³²P TRAP assay.

Results

The designed compounds have dual recognition mode in which phenanthroline end stacking ability is coupled with neomycin groove binding ability. There is a remarkable synergistic effect observed on stabilization of G-quadruplex by conjugating two moieties with different binding modes.

Significance

This strategy has great potential in cancer therapy. Due to the multi-drug resistance in cancer cells, we need new mode/strategies to induce cancer cell death. G-quadruplex stabilization with small molecules is one of the very promising approaches. The genetic instability and double-strand breaks induced by stabilizing the G-quadruplex has been used successfully in combinatorial therapy in which G-quadruplex stabilizers are used in combination with DNA damage repair inhibitors to induce cancer cells death.

Location

DeRosa University Center

Format

Poster Presentation

Poster Session

Afternoon 1pm-3pm