BIOREDUCTIVE QUINAZOLINES: SYNTHESIS AND BIOLOGICAL EVALUATION FOR PET IMAGING DIAGNOSIS AND TUMOR HYPOXIA TREATMENT

Abstract

Hypoxia, observed in tumors, is characterized by a decrease in oxygen supply to a tissue or cell due to decreased blood supply, and its occurrence is associated with resistance to conventional methods of treatment, such as chemotherapy and radiotherapy. The use of bioreductive compounds (e.g. nitro-derivatives and hydroquinones) for the treatment and diagnosis of tumor hypoxia can be due to the existence of a difference reducting potential in hypoxic cells compared to normoxic cells. Currently, bioreductive prodrugs and radiopharmaceuticals labeled with 18F, which explore the existing features in the hypoxic microenvironment, still have limitations that encourage the search for new molecules. Thus, this paper aims to synthesize and evaluate the biological activity of new bioreductive compounds and/or 18F radiopharmaceuticals containing the privileged structure quinazoline, substituted at C-5, C-6 and C-8 positions with methoxyl groups, fluorine-ethyl and nitro-aromatic or heteroaromatic ring, respectively. The compounds will be synthesized from the 4,5-dimethoxy-anthranilic acid, using classical methods, to obtain the 8-chloro-quinazoline intermediate, which the chlorine will be substituted with a nitro aromatic group, such as 2-([4-nitrobenzyl]oxy) ethanamine, followed by selective deacetylation and addition of a fluoro-ethyl at C-6, via a standard ether reaction. The bioreductive compounds will be evaluated for cytotoxic effect against several tumor cell lines grown under hypoxia or normoxia. All compounds potentially useful for the diagnosis of hypoxia in tumors will initially obtained with cold fluorine (19F) and subsequently labeled with the radioactive isotope 18F and evaluated in vitro and in vivo (PET/CT). (AU)