ABSTRACT
Using a simple amino amide ligand, ruthenium-catalyzed one-pot alkylation of primary and secondary amines with simple alcohols was carried out under a wide range of conditions. Using the alcohol as solvent, alkylation was achieved under mild conditions, even as low as room temperature. Reactions occurred with high conversion and selectivity in many cases. Reactions can also be carried out at high temperatures in organic solvent with high selectivity using stoichiometric amounts of the alcohol.
Subject(s)
Alcohols/chemistry , Amines/chemistry , Hydrogen/chemistry , Ruthenium/chemistry , Alkylation , Catalysis , Ligands , Molecular Structure , Solvents/chemistryABSTRACT
The development of new small molecule-based therapeutic drugs requires accurate quantification of drug bioavailability, biological activity and treatment efficacy. Rapidly measuring these endpoints is often hampered by the lack of efficient assay platforms with high sensitivity and specificity. Using an in vivo model system, we report a simple and sensitive liquid chromatography-tandem mass spectrometry assay to quantify the bioavailability of a recently developed novel cyclin-dependent kinase inhibitor VMY-1-103, a purvalanol B-based analog whose biological activity is enhanced via dansylation. We developed a rapid organic phase extraction technique and validated wide and functional VMY-1-103 distribution in various mouse tissues, consistent with its enhanced potency previously observed in a variety of human cancer cell lines. More importantly, in vivo MRI and single voxel proton MR-Spectroscopy further established that VMY-1-103 inhibited disease progression and affected key metabolites in a mouse model of hedgehog-driven medulloblastoma.
Subject(s)
Adenine/analogs & derivatives , Antineoplastic Agents/pharmacology , Cerebellar Neoplasms/drug therapy , Cyclin-Dependent Kinases/antagonists & inhibitors , Dansyl Compounds/pharmacology , Medulloblastoma/drug therapy , Protein Kinase Inhibitors/pharmacology , Adenine/chemistry , Adenine/pharmacokinetics , Adenine/pharmacology , Animals , Antineoplastic Agents/pharmacokinetics , Biological Availability , Cell Cycle/drug effects , Cerebellar Neoplasms/genetics , Cerebellar Neoplasms/metabolism , Chromatography, Liquid , Cyclin-Dependent Kinases/genetics , Cyclin-Dependent Kinases/metabolism , Dansyl Compounds/pharmacokinetics , Humans , Magnetic Resonance Imaging , Medulloblastoma/genetics , Medulloblastoma/metabolism , Mice , Protein Kinase Inhibitors/pharmacokinetics , Tandem Mass SpectrometryABSTRACT
The structure of Gd-DTPA-polylysine, Gd-DOTA-polylysine, Gd-SCN-Bz-DOTA-polylysine, and Gd-DTPA-poly(glu:lys) was investigated with circular dichroism, gel permeation chromatography, low angle light scattering, and proton longitudinal relaxivity. Molecular modeling calculations were performed and predicted helical secondary structure for charged Gd-chelator residues, i.e., Gd-DTPA, when the DTPA conjugation levels reached 90% and higher. This helical secondary structure was observed with circular dichroism. The conformational transition from coiled to extended linear was observed also by gel permeation chromatography and by proton relaxivity measurements. The helical secondary structure was not observed when the chelator was changed to DOTA. The residue charge interactions were eliminated in this case since the Gd-DOTA complex had no net charge. For this construct, the gel permeation and relaxivity measurements indicated a coiled conformation. An extended linear conformation was regained when the chelator complex was changed to Gd-SCN-Bz-DOTA, which had a net negative charge. The functional aspects of these structures were investigated by MR imaging of an animal tumor model. The linear extended polymer constructs gave 10-fold higher tumor signals then the coiled-collapsed constructs, indicating a much higher degree of trans-endothelial transport in the tumors.
