Synthesis of G-Analogs that Stabilize G-Quadruplexes to Inhibit Telomerase

University Of Puerto Rico Rio Piedras, San Juan PR

Investigators

Linked publications & trials

Abstract

In line with our long-term goal to develop novel small molecules for the treatment of cancer and other human diseases, we propose to establish the feasibility of using novel guanosine (dG) analogues to create stable G-quadruplexes. Our central hypothesis is that increasing the number of desolvated hydrogen (H) - bonds holding G-quadruplexes together will stabilize their secondary structure. The specific aims for this proposal are (1) to synthesize and characterize two families of dG-analogs having carefully positioned functional groups that increase potential H-bonding sites - relative to 2'-deoxyguanosine; (2a) to synthesize a series of DNA-oligonucleotides containing the dG-analogs from specific aim one; (2b) to determine the feasibility of in situ modification of oligonucleotides containing 8-acetyl-2'-deoxyguanosine; (3) to determine the stability of the DNA-quadruplex structures from the oligonucleotides prepared in specific aim two under conditions simulating the intracellular environment; (4) to test the nucleoside analogs from specific aim one against telomerase activity in vitro using malignant gliomas as model system. Our approach is innovative because it combines the concepts of stabilization of secondary DNA structure by increasing attractive interactions with in situ modification of a synthetic nucleoside. The importance of this work to biomedical research is related to the fact that G-quadruplexes have been identified as having an important role in telomere maintenance in most cancerous cells. The rationale for these studies is that G-quadruplexes of increased stability, will also have an increased activity in inhibiting telomerase activity. Our expectations are that, at the conclusion of this research, we will have a better understanding on the role of H-bonding in the stability of G-quadruplexes, the chemistry of in situ modifiable dG-analogs and would have identified novel inhibitors for telomerase activity. A better understanding of the structure and dynamics of G-quadruplexes will most likely yield to novel and better chemotherapies.