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Synthesis of 5-fluoro-2'-deoxyuridine phosphoramidates with potential anticancer activity
Marta Lewandowska
Abstract
The subject of presented dissertation was the synthesis of a series of novel 4-chloroaryloxy phosphoramidate diesters of 5-fluoro-2’-deoxyuridine and examination of obtained compounds for their cytotoxic activity in several human cancer cell lines. The selection of protecting groups on 5’-phosphorus atom was made based on literature data concerning pronucleotides with antiviral activity and experience of our research group. 4-Chlorophenyloxy substituent was chosen, because it undergo hydrolysis more easily than phenyloxy one due to the inductive effect of halogen atom. The series of phosphoramidate diesters of FdU and its analogues was synthesized using modified phosphorylation of Chattopadhyaya and Reese. For the phosphorylation of 5-fluoro nucleosides was used 4-chlorophenyl phosphoroditriazolide, which was prepared by the reaction of 4-chlorophenyl phosphorodichloridate with 1,2,4-triazole in the presence of triethylamine in acetonitrile. Reaction of 4-chlorophenyl phosphoroditriazolide with analogues of 5-fluoro-2’-deoxyuridine in the presence of pyridine led to the key intermediate, which after treatment with appropriate amine gave products. All new compounds were characterized by spectroscopic methods. The cytotoxic activity of the new 5’-monophosphates was determined in human cancer cell lines: nasopharyngeal, cervical carcinoma, breast, osteosarcoma carcinoma and one with enzyme thymidine kinase deficient (TK-) using the sulforhodamine B (SRB) assay.- Record ID
- UAM5fcdb8297be246be9200eeeb754c2db8
- Diploma type
- Doctor of Philosophy
- Author
- Title in Polish
- Synteza nowych pochodnych 5'-amidofosforanów 5-fluoro-2'-deoksyurydyny o potencjalnej aktywności przeciwnowotworowej
- Title in English
- Synthesis of 5-fluoro-2'-deoxyuridine phosphoramidates with potential anticancer activity
- Language
- pol (pl) Polish
- Certifying Unit
- Wydział Chemii [nowa struktura organizacyjna] (SNŚ/WC)
- Scientific discipline (2.0)
- Status
- Finished
- Year of creation
- 2019
- Defense Date
- 04-09-2015
- Title date
- 04-09-2015
- Supervisor
- URL
- http://hdl.handle.net/10593/13852 Opening in a new tab
- Keywords in English
- Phosphoramidates, ,phosphorylation,cytotoxic activity,human cancer cell lines HeLa, KB and MCF-7
- Abstract in English
- The subject of presented dissertation was the synthesis of a series of novel 4-chloroaryloxy phosphoramidate diesters of 5-fluoro-2’-deoxyuridine and examination of obtained compounds for their cytotoxic activity in several human cancer cell lines. The selection of protecting groups on 5’-phosphorus atom was made based on literature data concerning pronucleotides with antiviral activity and experience of our research group. 4-Chlorophenyloxy substituent was chosen, because it undergo hydrolysis more easily than phenyloxy one due to the inductive effect of halogen atom. The series of phosphoramidate diesters of FdU and its analogues was synthesized using modified phosphorylation of Chattopadhyaya and Reese. For the phosphorylation of 5-fluoro nucleosides was used 4-chlorophenyl phosphoroditriazolide, which was prepared by the reaction of 4-chlorophenyl phosphorodichloridate with 1,2,4-triazole in the presence of triethylamine in acetonitrile. Reaction of 4-chlorophenyl phosphoroditriazolide with analogues of 5-fluoro-2’-deoxyuridine in the presence of pyridine led to the key intermediate, which after treatment with appropriate amine gave products. All new compounds were characterized by spectroscopic methods. The cytotoxic activity of the new 5’-monophosphates was determined in human cancer cell lines: nasopharyngeal, cervical carcinoma, breast, osteosarcoma carcinoma and one with enzyme thymidine kinase deficient (TK-) using the sulforhodamine B (SRB) assay.
- Thesis file
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- File: 1
- Praca doktorska ML.pdf
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- Uniform Resource Identifier
- https://researchportal.amu.edu.pl/info/phd/UAM5fcdb8297be246be9200eeeb754c2db8/
- URN
urn:amu-prod:UAM5fcdb8297be246be9200eeeb754c2db8