A phase 0 analysis of ixazomib in patients with glioblastoma.

Improving overall survival in recurrent glioblastoma remains a challenge, and drugs acting by unique mechanisms are urgently required. Ixazomib is an orally-administered proteasome inhibitor used in combination with lenalidomide and dexamethasone to treat patients with multiple myeloma who have received at least one prior therapy. However, ixazomib's ability to reach brain tumors has not been studied during its development. The aim of the present study (ClinicalTrials.gov, NCT02630030) was to establish and quantify ixazomib's presence in glioblastoma. The present study investigated 3 patients with recurrent glioblastoma after administration of oral ixazomib citrate (MLN 9708) at a fixed 4.0 mg dose within a 3-hpreoperative window. A total of 2 blood samples were taken from each patient at the time of incision, tumor sampling and closure. Brain tumor samples were collected during tumor resection. These samples were then used to measure the plasma and brain tumor tissue concentration of the biologically-active form of ixazomib (MLN 2238). Patient 1 had plasma concentrations of ixazomib averaging 26.2, 21.8 and 15.3 ng/ml at incision, tumor sampling and closure, respectively. The brain tumor tissue concentration was 7.88 ng/g. Patient 2 had the same interval and brain tumor tissue measurements of 19.0, 18.0 and 8.93 ng/ml, and 2.03 ng/g. Patient 3 had plasma concentration interval measurements of 25.6, 36.2 and 28.7 ng/ml. Multiple brain tumor tissue samples were taken in patient 3, with an average tissue ixazomib concentration of 3.37 ng/g. Ixazomib was found at plasma concentrations commensurate with its previously established pharmacokinetic profile without clinically relevant drug-related adverse events. Ixazomib reaches glioblastoma tissues at measurable concentrations at the time of tumor resection, confirming target tissue delivery. This justifies the phase I study of ixazomib in recurrent glioblastoma currently in development.

Stereochemistry of imine reduction by a hydroxycyclopentadienyl ruthenium hydride.

The stereochemistry of hydrogen transfer from [2,5-Ph(2)-3,4-Tol(2)(eta(5)-C(4)COD)]Ru(CO)(2)D to N-aryl imines to give amine complexes was shown to be mostly trans stereospecific. Stereospecific hydrogen transfer is proposed to generate an amine and a coordinatively unsaturated ruthenium intermediate in close proximity. Coordination of the amine is proposed to occur faster than lone pair inversion of the amine. In contrast, hydrogen transfer to N-alkyl imines is stereorandom. It is proposed that stereochemistry is lost in part due to the reversibility of the hydrogen transfer being faster than amine coordination.

Reduction of imines by hydroxycyclopentadienyl ruthenium hydride: intramolecular trapping evidence for hydride and proton transfer outside the coordination sphere of the metal.

Reduction of imines by [2,5-Ph2-3,4-Tol2(eta(5)-C4COH)]Ru(CO)2H (2) produces kinetically stable ruthenium amine complexes. Reduction of an imine by 2 in the presence of an external amine trap gives only the complex of the newly generated amine. Reaction of 2 with H2N-p-C6H4N=CHPh (11), which contains an intramolecular amine trap, gave a 1:1 mixture of [2,5-Ph2-3,4-Tol2(eta(4)-C4CO)](CO)2RuNH(CH2Ph)(C6H4-p-NH2) (8), formed by coordination of the newly generated amine to the ruthenium center, and [2,5-Ph2-3,4-Tol2(eta(4)-C4CO)](CO)2RuNH2C6H4-p-NHCH2Ph (9), formed by coordination of the amine already present in the substrate. These results require transfer of hydrogen to the imine outside the coordination sphere of the metal to give a coordinatively unsaturated intermediate that can be trapped inside the initial solvent cage. Amine diffusion from the solvent cage must be much slower than coordination to the metal center. Mechanisms requiring prior coordination of the substrate to ruthenium would have led only to 8 and can be eliminated.