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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)
6.5 chemical sciences
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
  • 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

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