Nucleoside Analogues for Positron Emission Tomography Imaging and to Study Radiation Mediated Generation of Radicals from Azides
Doctor of Philosophy (PhD)
First Advisor's Name
Stanislaw F. Wnuk
First Advisor's Committee Title
Second Advisor's Name
Second Advisor's Committee Title
Third Advisor's Name
Third Advisor's Committee Title
Fourth Advisor's Name
M. Alejandro Barbieri
Fourth Advisor's Committee Title
Fifth Advisor's Name
Fifth Advisor's Committee Title
Nucleosides, Prodrugs, PET Imaging, 18-Fluorine, 68-Gallium, Nucleotides, Radicals, Azides
Date of Defense
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.
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.
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