Evaluation of PNU-159682 antibody drug conjugates (ADCs).

PNU-159682 is a highly potent secondary metabolite of nemorubicin belonging to the anthracycline class of natural products. Due to its extremely high potency and only partially understood mechanism of action, it was deemed an interesting starting point for the development of a new suite of linker drugs for antibody drug conjugates (ADCs). Structure activity relationships were explored on the small molecule which led to six linker drugs being developed for conjugation to antibodies. Herein we describe the synthesis of novel PNU-159682 derivatives and the subsequent linker drugs as well as the corresponding biological evaluations of the small molecules and ADCs.

Dehydrogenation of icosahedral carborane anions via gas-phase collisional activation.

RATIONALE: The icosahedral carborane anion HCB11 H11-1 is well known for its exceptional stability in solution and the solid state, but the gas-phase properties of this molecule have not previously been explored. METHODS: Electrospray ionization ion trap mass spectrometry, collisional activation, and isotopic labelling were used to examine the formation and reaction pathways of covalent and noncovalent carborane clusters. RESULTS: Covalent attachment of an amino group to the C-vertex of HCB11 H11-1 dramatically alters its stability in the gas phase. Interestingly, covalently bound carborane dimers are produced during electrospray ionization. Subsequent collisional activation of these dimers leads to facile hydrogen losses (7 H2 molecules). The loss of H2 does not follow a stochastic pattern, but occurs preferentially by loss of 3 H2 , followed by loss of 2 H2 and then another 2 H2 molecules. CONCLUSIONS: This study provides insight into new possible modes of B-H activation and functionalization in carborane cages. Copyright © 2016 John Wiley & Sons, Ltd.

Identification of inherently antioxidant regions in proteins with radical-directed dissociation mass spectrometry.

Antioxidant peptides such as glutathione play critically important roles within cells by opposing the action of oxidative species. Similarly all proteins may, as a secondary function, potentially contribute to the antioxidant capacity of the cellular milieu, though this possibility has not been thoroughly explored previously. Herein it is demonstrated that, in addition to radical quenching solution-phase behavior, antioxidant peptides display an astonishing ability to sequester radicals in the gas phase. Compared to other peptides of similar sequence and size, radical antioxidant peptides exhibit very little radical-directed dissociation when subjected to collisional activation in the gas phase. Importantly, this property can be leveraged in highly sensitive and rapid mass spectrometry based experiments to identify antioxidant peptides. Examination of peptides derived from human serum albumin (HSA), which is a protein known to behave as an antioxidant, revealed three previously unknown peptide regions that exhibit antioxidant capacity. One of these peptides, VAHRFK, shows antioxidant capacity comparable to that of glutathione. It is likely that these peptide regions contribute to the overall antioxidant capacity of HSA. In comparison with previous methods, the present technique is significantly more sensitive and less time-consuming, which should enable more wide-scale examination of antioxidant peptides that are relevant to redox homeostasis, food chemistry, and disease.