title: Syntheses of C-13 and C-14-labeled versions of the investigational proteasome inhibitor MLN9708.
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.
authors.affiliation: Department of Drug Metabolism and Pharmacokinetics, Millennium Pharmaceuticals, Inc., 40 Landsdowne Street, Cambridge, MA, 02139, USA.
authors.forename: Mihaela
authors.initials: M
authors.lastname: Plesescu
authors.forename: Eric L
authors.initials: EL
authors.lastname: Elliott
authors.forename: Yuexian
authors.initials: Y
authors.lastname: Li
authors.forename: Shimoga R
authors.initials: SR
authors.lastname: Prakash
mesh_terms: D001896:Boron Compounds / Q000138:chemical synthesis* / Q000737:chemistry*; D002247:Carbon Isotopes / Q000737:chemistry; D002250:Carbon Radioisotopes / Q000737:chemistry; D060326:Chemistry Techniques, Synthetic; D005998:Glycine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry; D007553:Isotope Labeling; D061988:Proteasome Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry*
chemical_list: D001896:Boron Compounds; D002247:Carbon Isotopes; D002250:Carbon Radioisotopes; D061988:Proteasome Inhibitors; C548400:ixazomib; D005998:Glycine
keywords: [13C9]-2,5-dichlorohippuric acid; [13C9]-MLN9708; [14C]-MLN9708; [carboxyl-14C]-2,5-dichlorobenzoic acid