Artigo De: orcid, cienciavitae

A quinazoline-derivative DOTA-type gallium(III) complex for targeting epidermal growth factor receptors: Synthesis, characterisation and biological studies

Journal of Biological Inorganic Chemistry

Maria Paula Cordeiro Crespo Cabral Campello Aboim de Barros; António Paulo; Campello, Maria Paula Cabral2008Springer

Informações chave

Autores:

Maria Paula Cordeiro Crespo Cabral Campello Aboim de Barros (Maria Paula Cordeiro Crespo Cabral Campello Aboim de Barros); António Paulo (António Manuel Rocha Paulo); Eva Toth; Fouskova, Petra; Garcia, Raquel; Santos, Isabel; Paulo, António; Gano, Lurdes (Maria de Lurdes Barrela Patrício Gano); Toth, Eva; Campello, Maria Paula Cabral

Publicado em

13/11/2008

Resumo

The novel DOTA-like chelator 1,4,7,10-tetraazacyclododecane-1-{4-[(3-chloro-4-fluorophenyl)amino] quinazoline-6-yl}propionamide-4,7,10-triacetic acid (H3L) was synthesised by alkylation of 1,4,7,10-tetraazacyclododecane-1,4,7-tris(t-butyl acetate) with N-{4-[(3-chloro-4-fluorophenyl)amino]quinazoline-6-yl}-3-bromopropionamide, followed by hydrolysis of the ester groups with trifluoracetic acid. H3L has been fully characterised by multinuclear NMR spectroscopy, mass spectrometry and high-performance liquid chromatography (HPLC). Five protonation constants, log KHi, of H3L were determined by potentiometry and UV–vis spectrophotometry and the values found are 10.47, 9.18, 5.24, 4.00 and 2.23. These methods, complemented with variable-pH 71Ga NMR studies, allowed us to ascertain the stability constant of the Ga(III) complex of L. GaL has a remarkably high thermodynamic stability constant (log KML = 24.5). The radioactive complex 67GaL was prepared in high yield and high radiochemical purity. Its HPLC chromatogram is identical to that obtained for the GaL complex prepared at the macroscopic level. At pH 7.4, 67GaL has an overall neutral charge, is highly hydrophilic (log D = -1.02 ± 0.03) and presents high in vitro stability in physiological media and in the presence of an excess of diethylenetriaminepentaethanoic acid . In vitro studies indicated that H3L and GaL do not inhibit the cell growth of epidermal growth factor receptor expressing cell lines, such as A431 cervical carcinoma cells, a result which agrees with the very low cell internalisation found for 67GaL in the same cell line. Biodistribution studies in mice indicated high in vivo stability for 67GaL, a high total excretion rate and a relatively slow blood clearance, in full accordance with its hydrophilic character and the relatively important protein binding.

Detalhes da publicação

Autores da comunidade :

Versão da publicação

AO - Versão original do autor

Editora

Springer

Título do contentor da publicação

Journal of Biological Inorganic Chemistry

Primeira página ou número de artigo

261

Última página

271

Volume

14

Fascículo

2

Domínio Científico (FOS)

health-sciences - Ciências de Saúde

Palavras-chave

  • Epidermal Growth Factor Receptor
  • Gallium
  • DOTA Derivatives
  • Tyrosine kinase inhibitors

Idioma da publicação (código ISO)

eng - Inglês

Identificador alternativo (URI)

http://www.scopus.com/inward/record.url?eid=2-s2.0-58949100316&partnerID=MN8TOARS

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