ABSTRACT
Proteasome, a large multicatalytic proteinase complex that plays an important role in processing of proteins, has been shown to possess multiple catalytic activities. Among its various activities, the 'chymotrypsin-like' activity of proteasome has emerged as the focus of drug discovery efforts in cancer therapy. Herein we report chiral boronate derived novel, potent, selective and cell-permeable peptidomimetic inhibitors 6 and 7 that displayed activity against various rodent and human tumor cell lines (in vitro).
Subject(s)
Boronic Acids/chemistry , Nitro Compounds/chemistry , Protease Inhibitors/chemistry , Proteasome Inhibitors , Animals , Boronic Acids/pharmacology , Boronic Acids/therapeutic use , Cell Line, Tumor , Cell Proliferation/drug effects , Drug Screening Assays, Antitumor , Humans , Liver/enzymology , Mice , Neoplasms/drug therapy , Nitro Compounds/pharmacology , Nitro Compounds/therapeutic use , Protease Inhibitors/pharmacology , Protease Inhibitors/therapeutic use , Proteasome Endopeptidase Complex/metabolismABSTRACT
In search of a next generation molecule to modafinil, a novel wake promoting agent, we previously disclosed bi-phenyl derived racemate compound (±)-2 as a new generation of wake-promoting agent. Here we describe the profiles of the individual enantiomers (-)-2 and (+)-2, respectively.
Subject(s)
Biphenyl Compounds/chemical synthesis , Central Nervous System Stimulants/chemical synthesis , Wakefulness/drug effects , Animals , Area Under Curve , Biphenyl Compounds/pharmacokinetics , Biphenyl Compounds/pharmacology , Central Nervous System Stimulants/pharmacokinetics , Central Nervous System Stimulants/pharmacology , Cytochrome P-450 Enzyme Inhibitors , Cytochrome P-450 Enzyme System/metabolism , Electroencephalography , Injections, Intraperitoneal , Motor Activity/drug effects , Rats , Rats, Sprague-Dawley , Retinoic Acid 4-Hydroxylase , Sleep/drug effects , Stereoisomerism , Structure-Activity Relationship , Wakefulness/physiologyABSTRACT
In search of a next generation molecule to the novel wake promoting agent modafinil, a series of bi-phenyl derived wakefulness enhancing agents (in rat) was developed. From this work, compound 17 has been selected for additional studies.
