Synthesis and Nitrogen Centered Radical Studies of Azido Modified Nucleosides and Sesquiterpene Lactones

Authors

Yahaira D. ReyesFollow

Document Type

Dissertation

Degree

Doctor of Philosophy (PhD)

Major/Program

Chemistry

First Advisor's Name

Stanislaw F. Wnuk

First Advisor's Committee Title

Committee Chair

Second Advisor's Name

Kevin O'Shea

Second Advisor's Committee Title

Committee Member

Third Advisor's Name

Manuel Barbieri

Third Advisor's Committee Title

Committee Member

Fourth Advisor's Name

Joong Ho Moon

Fourth Advisor's Committee Title

Committee Member

Fifth Advisor's Name

John Berry

Fifth Advisor's Committee Title

Committee Member

Sixth Advisor's Name

Amitava Adhikary

Sixth Advisor's Committee Title

Committee Member

Keywords

Azido nucleosides, 6-azidouridine, 6-azidomethyluridine, uracil C6-lithiation, C6-alkylation, click reactions, azido sesquiterpene lactones, aminyl radicals, radiosensitizers, cellular proliferation, coronene

Date of Defense

10-13-2023

Abstract

Beyond their click chemistry, radiosensitization of azides such as 3'-azido-2,3'-dideoxythymidine (AZT) and 5-azidomethyl-2'-deoxyuridine (5-AmdU) is attributed to the formation of nitrogen-centered aminyl π-type radicals (RNH•), which play a crucial role to trigger cancerous cell apoptosis. Two classes of 6-azidomodified uracil nucleosides; one with azido group directly attached to uracil ring and second with azido group attached via a methylene linker were investigated. 6-Azido-2'-deoxyuridine (6-AdU) was prepared in 55% overall yield via lithiation-based regioselective C6-iodination of silyl protected 2'-deoxyuridine followed by treatment of sodium azide and TBAF deprotection. Direct lithiation-based regioselective C6-hydroxymethylation followed by mesylation/azidation sequence and deprotection provided 6-azidomethyluridine (6-AmU) and 6-azidomethyl-2'-deoxyuridine (6-AmdU). Strain-promoted click reactions of 6-AdU and 6-AmdU with symmetrically fused cyclopropyl cyclooctyne (OCT) provided fluorescent triazoles. NMR studies of 5 vs. 6-AmdU revealed that 6-AmdU exists primarily in the syn conformation in aqueous solution. Electron paramagnetic resonance (EPR) studies in the absence of oxygen at 77K led to site-specific formation of a direct iminyl radical from 6-azidouridine (6-AU) and an allylic carbon radical from 6-AmU. Chemistry and biological activity of azido modified sesquiterpene lactones (SLs) was also explored. Michael additions of trimethylsilylazide in the presence of acetic acid and catalytic triethylamine to the α-methylene-γ-lactone unit of parthenolide (PTL) or dehydroleucodine (DhL) provided 1st generation azido-SLs. Oxidation of the methyl group at the C14 position of PTL with SeO2 in the presence of tert-butyl hydroperoxide (TBHP) followed by sequential mesylation and azidation of the resulting hydroxymethyl group provided 2nd generation azido-PTL. ESR studies demonstrated that addition of radiation-mediated prehydrated electrons to 1st generation azido parthenolide (AzPTL) at 77 K, forms a neutral carbon-centered aminomethyl-PTL• radical via an intramolecular reaction of the undetected aminyl radical PTL-NH•. Conversely, radiation-produced electron addition to azido dehydroleucodine (AzDhL) generated the expected π-aminyl NCR DhL-NH• and α-azidoalkyl radical. Cellular proliferation assays (MCF-7, MDA-MB-231, and PANC-1) revealed a dose dependent response of these azides compared to their parent SLs; AzPTL and AzDhL further suppress proliferation following 2 Gy radiation.

Identifier

FIDC906025

Previously Published In

Cabrera, M., Reyes, Y., Ward, S., Alahmadi, M., Barbolovici, A., Kumar, A., Sevilla, M. D., Wnuk, S. F., Adhikary, A. 263rd ACS National Meeting & Exposition in San Diego, California 2022, Division of Physical Chemistry # 3649777.

Reyes, Y.; Mebel, A.; Wnuk, S. F. Nucleosides, Nucleotides, & Nucleic Acids 2023, DOI: 10.1080/15257770.15252023.12271023.

Adjei, D.; Reyes, Y.; Kumar, A.; Ward, S.; Denisov, S. A.; Alahmadi, M.; Sevilla, M. D.; Wnuk, S. F.; Mostafavi, M.; Adhikary, A. J. Phys. Chem. B 2023, 127, 1563-1571.

Reyes, Y.; Barbieri, M. A.; Pathak, R.; Ward, S.; Sevilla, M. D.; Adhikary, A.; Wnuk, S. F. 263rd ACS National Meeting & Exposition in San Diego, California 2022, Division of Medicinal Chemistry, #3647326 - Board #3642247.

He, C.; Kaiser, R. I.; Lu, W.; Ahmed, M.; Reyes, Y.; Wnuk, S. F.; Mebel, A. M. J. Am. Chem. Soc. 2023, 145, 3084-3091.

Goettl, S. J.; Tuli, L. B.; Turner, A. M.; Reyes, Y.; Howlader, A. H.; Wnuk, S. F.; Hemberger, P.; Mebel, A. M.; Kaiser, R. I. J. Am. Chem. Soc. 2023, 145, 15443-15455.

Creative Commons License

This work is licensed under a Creative Commons Attribution 4.0 License.

Recommended Citation

Reyes, Yahaira D., "Synthesis and Nitrogen Centered Radical Studies of Azido Modified Nucleosides and Sesquiterpene Lactones" (2023). FIU Electronic Theses and Dissertations. 5398.
https://digitalcommons.fiu.edu/etd/5398