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.
| Ramírez-Camejo, Luis A; Maldonado-Morales, Génesis; Bayman, Paul (2017) Differential Microbial Diversity in Drosophila melanogaster: Are Fruit Flies Potential Vectors of Opportunistic Pathogens? Int J Microbiol 2017:8526385 |
| Morales-Rivera, Keyla F; Piñero Cruz, Dalice M; Prieto, Jose A (2017) Crystal structure of (-)-(S)-4-[(2S,3S,4S,Z)-3-hydroxy-4-methyl-hept-5-en-2-yl]-1,3-dioxolan-2-one. Acta Crystallogr E Crystallogr Commun 73:1070-1072 |
| García-Arriaga, Marilyn; Acosta-Santiago, Maxier; Cruz, Antony et al. (2017) Probing the Limits of Supramolecular G-Quadruplexes Using Atomistic Molecular Dynamics Simulations. Inorganica Chim Acta 468:209-222 |
| Huang, Qing; Quiñones, Edwin (2016) A spectroscopic method to determine the activity of the restriction endonuclease EcoRV that involves a single reaction. Anal Biochem 497:103-5 |
| Mège, Pascal; Schizas, Nikolaos V; Reyes, Joselyd García et al. (2015) Genetic seascape of the threatened Caribbean elkhorn coral, Acropora palmata, on the Puerto Rico Shelf. Mar Ecol (Berl) 36:195-209 |
| Morales-Rivera, Amarilys; Hernández-Burgos, Mayté M; Martínez-Rivera, Arlene et al. (2014) Anxiolytic effects of oxytocin in cue-induced cocaine seeking behavior in rats. Psychopharmacology (Berl) 231:4145-55 |
| Ramírez-Camejo, Luis A; Torres-Ocampo, Ana P; Agosto-Rivera, José L et al. (2014) An opportunistic human pathogen on the fly: strains of Aspergillus flavus vary in virulence in Drosophila melanogaster. Med Mycol 52:211-9 |
| Martínez-Rivera, Arlene; Rodríguez-Borrero, Enrique; Matías-Alemán, María et al. (2013) Metabotropic glutamate receptor 5 within nucleus accumbens shell modulates environment-elicited cocaine conditioning expression. Pharmacol Biochem Behav 110:154-60 |
| Galindo-Cardona, Alberto; Acevedo-Gonzalez, Jenny P; Rivera-Marchand, Bert et al. (2013) Genetic structure of the gentle Africanized honey bee population (gAHB) in Puerto Rico. BMC Genet 14:65 |
| Santiago-Rodriguez, Tasha M; Rivera, Jessica I; Coradin, Mariel et al. (2013) Antibiotic-resistance and virulence genes in Enterococcus isolated from tropical recreational waters. J Water Health 11:387-96 |
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