ABSTRACT
BACKGROUND: NEO212 is a novel small-molecule anticancer agent that was generated by covalent conjugation of the natural monoterpene perillyl alcohol (POH) to the alkylating agent temozolomide (TMZ). It is undergoing preclinical development as a therapeutic for brain-localized malignancies. The aim of this study was to characterize metabolism and pharmacokinetic (PK) properties of NEO212 in preclinical models. METHODS: We used mass spectrometry (MS) and modified high-performance liquid chromatography to identify and quantitate NEO212 and its metabolites in cultured glioblastoma cells, in mouse plasma, brain, and excreta after oral gavage. RESULTS: Our methods allowed identification and quantitation of NEO212, POH, TMZ, as well as primary metabolites 5-aminoimidazole-4-carboxamide (AIC) and perillic acid (PA). Intracellular concentrations of TMZ were greater after treatment of U251TR cells with NEO212 than after treatment with TMZ. The half-life of NEO212 in mouse plasma was 94 min. In mice harboring syngeneic GL261 brain tumors, the amount of NEO212 was greater in the tumor-bearing hemisphere than in the contralateral normal hemisphere. The brain:plasma ratio of NEO212 was greater than that of TMZ. Excretion of unaltered NEO212 was through feces, whereas its AIC metabolite was excreted via urine. CONCLUSIONS: NEO212 preferentially concentrates in brain tumor tissue over normal brain tissue, and compared to TMZ has a higher brain:plasma ratio, altogether revealing favorable features to encourage its further development as a brain-targeted therapeutic. Its breakdown into well-characterized, long-lived metabolites, in particular AIC and PA, will provide useful equivalents for PK studies during further drug development and clinical trials with NEO212.
ABSTRACT
The 355 nm time-of-flight negative ion photoelectron spectra of (o-, m-, and p-chlorophenyl)nitrene radical anions are reported. Electron affinities are obtained from the photoelectron spectra, and are 1.79 +/- 0.05, 1.82 +/- 0.05, and 1.72 +/- 0.05 eV for the (o-, m-, and p-chlorophenyl)nitrenes, respectively. Singlet-triplet splittings are determined to be 14 +/- 2, 15 +/- 1, and 14 +/- 2 kcal/mol, respectively. The shapes of the photoelectron bands indicate resonance interactions in the singlet states for the ortho- and para-substituted isomers, which is attributed to quinoidal structures of the open-shell singlet states. Reanalysis of the photoelectron spectrum of phenylnitrene anion leads to a revised experimental singlet-triplet splitting of 14.8 kcal/mol in the unsubstituted phenylnitrene.
ABSTRACT
The open-shell benzoylnitrene radical anion, readily generated by electron ionization of benzoylazide, undergoes unique chemical reactivity with radical reagents and Lewis acids in the gas phase. Reaction with nitric oxide, NO, proceeds by loss of N2 and formation of benzoate ion. This novel reaction is also observed to occur with phenylnitrene anion, forming phenoxide. Similar reactivity was observed in the reaction between benzoylnitrene radical anion and NO2, forming benzoate ion and nitrous oxide. Electronic structure calculations indicate that the reaction has a high-energy barrier that is overcome by the energy released by bond formation. Benzoylnitrene radical anion also transfers oxygen anion to NO and NO2 as well as to CS2 and SO2. In contrast, phenylnitrene anion reacts with carbon disulfide by C+ or CS+ abstraction, forming S- or S2-. Electronic structure calculations indicate that benzoylnitrene in the ground state resembles a slightly polarized benzoate anion, but with a free radical localized on the nitrogen.
Subject(s)
Imines/chemistry , Anions/chemistry , Computer Simulation , Free Radicals/chemistry , Gases/chemistry , Imines/chemical synthesis , Models, Chemical , Molecular StructureABSTRACT
Benzoylnitrene radical anion, formed in high abundance by electron ionization of benzoylazide, is found to be a useful reagent for the formation of ionized reactive intermediates, such as diradicals and carbenes. The reactivity of the ion is similar to what is observed with atomic oxygen anion, occurring in many instances by H(2)(+) transfer. However, because benzoylnitrene radical anion is less basic than oxygen anion, it undergoes H(2)(+) transfer with substrates that react with oxygen anion by only proton transfer and therefore can be used to generate reactive ions not easily prepared by other methodologies.
ABSTRACT
The thermochemical properties of benzoylnitrene radical anion, C6H5CON-, were determined by using a combination of energy-resolved collision-induced dissociation (CID) and proton affinity bracketing. Benzoylnitrene radical anion dissociates upon CID to give NCO- and phenyl radical with a dissociation enthalpy of 0.85 +/- 0.09 eV, which is used to derive an enthalpy of formation of 33 +/- 9 kJ/mol for the nitrene radical anion. Bracketing studies with the anion indicate a proton affinity of 1453 +/- 10 kJ/mol, indicating that the acidity of benzamidyl radical, C6H5CONH, is between those of benzamide and benzoic acid. Combining the measurements gives an enthalpy of formation for benzamidyl radical of 110 +/- 14 kJ/mol and a homolytic N-H bond dissociation energy in benzamide of 429 +/- 14 kJ/mol. Additional thermochemical properties obtained include the electron affinity of benzamidyl radical, the hydrogen atom affinity of benzoylnitrene radical anion, and the oxygen anion affinity of benzonitrile.
