Nucleoside Analogues for Positron Emission Tomography Imaging and to Study Radiation Mediated Generation of Radicals from Azides

Authors

Maria E. de Cabrera, Florida International UniversityFollow

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

Raphael Raptis

Second Advisor's Committee Title

Committee member

Third Advisor's Name

Kathleen Rein

Third Advisor's Committee Title

Committee member

Fourth Advisor's Name

M. Alejandro Barbieri

Fourth Advisor's Committee Title

Committee member

Fifth Advisor's Name

Jose Almirall

Fifth Advisor's Committee Title

Committee member

Keywords

Nucleosides, Prodrugs, PET Imaging, 18-Fluorine, 68-Gallium, Nucleotides, Radicals, Azides

Date of Defense

6-27-2019

Abstract

Gemcitabine is a potent anticancer cytidine analogue used to treat solid tumors. Its efficacy is diminished by rapid deamination to a toxic uridine derivative by cytidine deaminase. To overcome this limitation and add radioactive nuclei (¹⁸F or ⁶⁸Ga) for PET imaging, I synthesized two 4-N­-alkylgemcitabine analogues i) bearing β-keto tosylate moiety for subsequent ¹⁸F-fluorination and ii) having SCN-Bn-NOTA chelator to complex ⁶⁸Ga. The first was synthesized by replacement of tosylamide in 4-N­-tosylgemcitabine with 1-amino-10-undecene, followed by elaboration of terminal alkene through dihydroxylation, regioselective tosylation and oxidation. Subsequent fluorination using KF in presence of 18-Crown-6 at 75°C for 1 hr gave 4-N­-alkylgemcitabine fluoromethyl ketone. The second was synthesized by analogous replacement of tosylamide with N-Boc-1,3-propanediamine, followed by deprotection with TFA. The reactive terminal amine was condensed with SCN-Bn-NOTA, giving 4-N­-alkylgemcitabine-SCN-Bn-NOTA ligand, which efficiently complexed Ga or ⁶⁸Ga for in vivo PET studies in rats.

Clofarabine is a highly effective chemotherapeutic adenosine analogue used for treatment of acute lymphoblastic leukemia. Clofarabine undergoes rate limiting phosphorylation from its 5'-monophosphate to 5'-diphosphate by purine monophosphate kinase, and possible dephosphorylation of its respective 5'-monophosphate by 5'-nucleotidases. Synthesis of clofarabine diphosphate prodrugs, and potentially their ¹⁸F-radiolabeled analogues, were undertaken to overcome these limitations. Successful synthesis of model adenosine diphosphate prodrug, by coupling adenosine monophosphate with bis(benzoyloxybenzyl) phosphoramidite in presence of 5-phenyl-1-H­-tetrazole activator was achieved.

The aminyl radical generated from azide moiety in 3'-azido-3'-deoxythymidine (3'-AZT) or 5-azidomethyl-2'-deoxyuridine (AmdU), upon addition of radiation-produced electrons, is thought to be the source of their radiosensitizing effects. Herein, I report synthesis of azido-modified purine and pyrimidine analogues for EPR study of formation of reactive aminyl radical in guanine, adenine and cytidine bases. The EPR studies of electron addition to 2-azidoguanosine (i.e. 2-azidoinsoine), protected 4-azidocytidine and 4-tetrazolocytidine analogues clearly establish that the position of the azide in base moiety dictates reactivity. The azide directly attached to nucleobases at ortho/para position to ring nitrogens produce stable RN₃•^- that does not rapidly convert to aminyl radical, except in the excited state. Hence, these did not display much radiosensitizing effects in in vivo biological studies in MDA-MB-231, MCF7 and U87 cell lines.

Identifier

FIDC007805

ORCID

https://orcid.org/0000-0002-1185-5931

Recommended Citation

de Cabrera, Maria E., "Nucleoside Analogues for Positron Emission Tomography Imaging and to Study Radiation Mediated Generation of Radicals from Azides" (2019). FIU Electronic Theses and Dissertations. 4229.
https://digitalcommons.fiu.edu/etd/4229