Syntheses of C-13 and C-14-labeled versions of the investigational proteasome inhibitor MLN9708.
J Labelled Comp Radiopharm
; 56(9-10): 464-70, 2013.
Article
em En
| MEDLINE
| ID: mdl-24285522
ABSTRACT
MLN9708 (ixazomib citrate) is an investigational, orally bioavailable proteasome inhibitor that is under development by Millennium in clinical studies in both hematologic and nonhematologic malignancies. The stable isotope-labeled MLN9708 was required for bio-analytical studies. [(13) C9 ]-MLN9708 (11) was synthesized in seven steps from the uniformly labeled [(13) C6 ]-1,4-dichlorobenzene (3) and [1-(13) C]-acetyl chloride. Because of the presence of two chlorine atoms and a boron atom, compound 6 was further reacted with [(13) C2 ]-glycine to provide an internal standard that is well separated from the parent compound during mass spectrometric analysis. The radiolabeled version was prepared to support metabolite profiling and whole body autoradiography studies in experimental animals. [(14) C]-MLN9708 (19) was synthesized in six steps from commercially available [(14) C]-barium carbonate. The key intermediate, [carboxyl-(14) C]-2,5-dichlorobenzoic acid (14), was prepared by selective lithiation of 1-bromo-2,5-dichlorobenzene (12) followed by carbonation with [(14) C]-barium carbonate. In preparation for a one-time human absorption, distribution, metabolism and excretion (ADME) study, the stability of [(14) C]-MLN9708 and its precursors were also evaluated.
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1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Compostos de Boro
/
Inibidores de Proteassoma
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Glicina
Idioma:
En
Ano de publicação:
2013
Tipo de documento:
Article