ABSTRACT
The availability of several bioorthogonal reactions that can proceed selectively and efficiently under physiologically relevant conditions has garnered the interest of biochemists and organic chemists alike. Bioorthogonal cleavage reactions represent the latest innovation in click chemistry. Here, we employed the Staudinger ligation reaction to release radioactivity from immunoconjugates, improving target-to-background ratios. In this proof-of-concept study, model systems, including the anti-HER2 antibody trastuzumab, radioisotope I-131, and a newly synthesized bifunctional phosphine, were used. Staudinger ligation occurred when biocompatible N-glycosyl azides reacted with this radiolabeled immunoconjugate, leading to cleavage of the radioactive label from the molecule. We demonstrated this click cleavage in vitro and in vivo. Biodistribution studies in tumor models showed that radioactivity was eliminated from the bloodstream, thereby improving tumor-to-blood ratios. SPECT imaging revealed that tumors could be visualized with enhanced clarity. Our simple approach represents a novel application of bioorthogonal click chemistry in the development of antibody-based theranostics.
ABSTRACT
New manganese(II) complexes of substituted pyridino pentaaza macrocyclic ligands were prepared. The amino-, carboxy-, or other functional groups were placed in the vicinity of the axial position of the metal complex. Their SOD-like activity was determined by cytochrome c assay and compared with one another. The activities of pyridine analogs (12a-b and 13) and m-substituted analogs (12c and 12j) were similar and significantly better than that of the standard compound M-40403. The most potent compound was an o-aminobenzoyl derivative 12i, while the o-carboxybenzoyl analog 12d was the lowest active compound.
Subject(s)
Aza Compounds/chemistry , Macrocyclic Compounds/chemistry , Manganese/chemistry , Pyridines/chemistry , Superoxide Dismutase/metabolism , Cytochromes c/metabolism , Superoxide Dismutase/chemistryABSTRACT
The synthesis and antioxidant activity of oligo(ethylene glycol)-modified manganese salen complexes are reported. Their SOD activities were similar and 2- to 3-fold more potent than the standard compound EUK-134. Their catalase-like activity was lower than that of EUK-134 in the initial conversion rate; however, some analogs exhibited a better catalytic turnover number.
Subject(s)
Antioxidants/chemistry , Ethylene Glycol/chemistry , Manganese/chemistry , Catalase , Catalysis , Chemistry, Pharmaceutical/methods , Drug Design , Edetic Acid/chemistry , Hydrogen Peroxide/chemistry , Hydrogen-Ion Concentration , Inhibitory Concentration 50 , Models, Chemical , Oxygen/chemistry , Peroxidase/chemistry , Time FactorsABSTRACT
Pyrroloquinoline quinone (PQQ) was covalently attached to a gold electrode surface via the self-assembled monolayers of aminoalkanethiols (NH2)(CH2)nSH) with different alkyl chain lengths (n=2, 6, 8, and 11). The voltammetric behaviors of PQQ-SAMs both at full and at partial monolayers were examined. It was found that the redox response of PQQ became more reversible with increasing dilution by alkanethiols owing to the less lateral interaction between PQQ heads. Voltammograms were transformed from quasi-reversibility to irreversibility as the alkyl chain spacer became longer. The electron tunneling barrier constant (beta) and distance dependence of the long range electron-transfer parameters have been studied in acidic solution using cyclic voltammetry. A logarithmic dependence of the heterogeneous electron-transfer rate constant on the alkyl chain length was found for full and partial PQQ monolayers. The beta value was close to 1.0 per CH2 unit regardless of dilution effect.