Molecule recognition of nucleic acids, nucleosides, nucleotides, and their derivatives

<p>It has long been known that the efficiency of anticancer drugs is limited by the emergence of resistance due to the evolving repair of such DNA lesions in malignant cells. Therefore, development of pharmaceutical agents, which can interfere with the DNA repair pathways, may represent a novel approach to enhance the cytotoxic effects of chemotherapy by reducing drug resistance. Abasic sites (AP sites) are the key intermediates in the BER pathway and promising targets for BER inhibition. In chapter 2, we report the synthesis of two small molecules specifically targeting at AP sites and the evaluation of their activity in terms of interstrand crosslinking formation. Our results show no covalent adduct is induced, which is due to the weak DNA binding affinity. In chapter 3, we try to use TFOs to deliver the interstrand crosslinking moiety to the AP site in a sequence specific manner. Two modified phosphoramidites were synthesized and incorporated into the 5' end of TFOs. The activity was evaluated by using various biophysical and biochemical experiments. The work reported in chapter 4 is focused on the G-quadruplex structure formed in the guanine rich telomeric sequence. Many studies have shown G4 ligands can induce and stabilize G-quadruplex within telomere region and inhibit the activity of telomerase that is overexpressed in 80-90% of cancer cells. Our results indicate that phenanthroline based metal complexes, Ni(Phen) 2 , have strong binding affinity and selectivity towards G-quadruplex over duplex DNA. The effect of Ni(Phen) 2 on telomerase activity and cytotoxicity towards cancer cells was also investigated. Calixarenes containing DNA building units such as nucleotides, nucleosides, and nucleobases have recently aroused much interest because of their versatile applications. In chapter 5, we report the synthesis of calix[4]arenes ( 5.11-5.14 ) functionalized with a single nucleobase (thymine, adenine, guanine, or cytosine) at the upper rim via click chemistry. Their complexation with alkali metal ions was examined using MALDI-TOF mass spectrometry and their molecular interactions were determined using 1 H NMR. All calix[4]arene derivatives show good complexation with alkali metal ions with apparent selectivity. The results also reveal that nucleobase-calix[4]arenes are capable of self-association in CDC1 3 and calix[4]arenes bearing complementary nucleobases can bind to each other via base pairing.</p>

Name thesis:degree_name

Doctor of Philosophy (Ph.D.)

Level thesis:degree_level

Dissertation - Pacific Access Restricted

Discipline thesis:degree_discipline

Pharmaceutical and Chemical Sciences

Year dc:date.available

2013

Author dc:creator

• Liu, Wanbo

Contributors dc:contributor

• Liang Xue

• Organic chemistry
• Pharmacy sciences
• Pure sciences
• Health and environmental sciences
• Abasic sites
• Calixarenes
• G-quadruplexes
• Nucleosides
• Telomeres
• Chemicals and Drugs
• Chemistry
• Medical Pharmacology
• Medicinal-Pharmaceutical Chemistry
• Medicine and Health Sciences
• Pharmaceutical Preparations
• Pharmacy and Pharmaceutical Sciences
• Physical Sciences and Mathematics

Licence

• http://rightsstatements.org/vocab/InC/1.0/

Identifier

9781303533952

OAI identifier oai:identifier

oai:scholarlycommons.pacific.edu:uop_etds-1149