ABSTRACT
A series of ethers of orvinol and isoorvinol has been prepared and evaluated in opioid receptor binding and in vitro functional assays. The most striking finding was the very large difference in kappa-opioid receptor activity between the diastereomeric ethyl ethers: 46-fold in binding, 150-fold in GPI, and 900-fold in the [(35)S]GTPgammaS assay in favor of the (R)-diastereomer. Additionally in the (R)-series there was a 700-fold increase in kappa-agonist potency in the [(35)S]GTPgammaS assay when OEt was replaced by OBn. The data can be explained in a triple binding site model: an H-bonding site, a lipophilic site, and an inhibitory site with which the 20-Me group in the (S)-ethers may interact. It appears that kappa-agonist binding of the orvinols avoids the inhibitory site in the intramolecular H-bonded conformation.
Subject(s)
Analgesics, Opioid/pharmacology , Hydroxamic Acids/chemical synthesis , Narcotics/pharmacology , Analgesics, Opioid/chemistry , Animals , Binding, Competitive/drug effects , CHO Cells , Cell Membrane/drug effects , Cell Membrane/metabolism , Cricetinae , Guanosine 5'-O-(3-Thiotriphosphate)/pharmacology , Guinea Pigs , Humans , Hydroxamic Acids/pharmacology , In Vitro Techniques , Magnetic Resonance Spectroscopy , Narcotics/chemical synthesis , Narcotics/chemistry , Spectrophotometry, Infrared , StereoisomerismABSTRACT
A series of cyclopropyl indolequinones based on structures 5-7 was designed and synthesized to probe the structural features essential for bioreductive cytotoxicity. Ring opening of the cyclopropane ring under radical conditions was demonstrated to be mechanistically feasible, and related to the involvement of such one-electron processes in the cytotoxicity of cyclopropyl indolequinones under hypoxic conditions.
Subject(s)
Antineoplastic Agents/chemical synthesis , Cyclopropanes/chemical synthesis , Indoles/chemical synthesis , Quinones/chemical synthesis , Animals , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Cell Death , Cell Hypoxia , Cell Line , Cricetinae , Crystallography, X-Ray , Mitomycin/chemistry , Mitomycin/pharmacology , Mitomycins , Molecular Structure , Oxidation-Reduction , Prodrugs , Structure-Activity RelationshipABSTRACT
The synthesis of the indolequinones 8 and 9 starting from methyl 4-(benzyloxy)-5-methoxy-indole-2-carboxylate (10) is described. The methoxy group in the indolequinones 1, 2, 4, 5, and 7-9 can be displaced by various nitrogen nucleophiles (ammonia, 2-methoxyethylamine, aziridine, 2-methylaziridine, pyrrolidine) in 22-88% yield. The resulting amino-substituted quinones, together with their methoxy precursors, were studied by cyclic voltammetry to determine their reduction potentials, which, in DMF solution, lie in the range -1.355 to -1.597 V (vs ferrocene). The cytotoxicity of the compounds towards aerobic and hypoxic mammalian cells was also determined; in general, under aerobic conditions, the cyclopropamitosenes are more toxic than the corresponding pyrrolo[1,2-a]indolequinones, which are in turn more toxic than the simple 1,2-dimethylindolequinones, with many of the compounds in each series showing greater toxicity toward hypoxic cells.
