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\u27-monophosphate to 5\u27-diphosphate by purine monophosphate kinase, and possible dephosphorylation of its respective 5\u27-monophosphate by 5\u27-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\u27-azido-3\u27-deoxythymidine (3\u27-AZT) or 5-azidomethyl-2\u27-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
