ABSTRACT
A new generation of chroman/catechol hybrids bearing heterocyclic five-membered rings, such as 1,2,4-oxadiazole 1,3,4-oxadiazole, 1,2,3-triazole, tetrazole and isoxazole, were designed and synthesized. The activity of the new derivatives against oxidative stress induced neuronal damage, was evaluated using glutamate-challenged hippocampal HT22 cells. Compound 3 in which a 3,4-dimethoxyphenyl moiety, is directly attached to the 1,2,4-oxadiazole ring was the most active among the 2-substituted chroman analogues, with EC(50)=254+/-65nM. Concerning the 5-subtituted chroman analogues, isoxazole derivative 29 exhibited the strongest activity (EC(50)=245+/-38nM). However, 29 was cytotoxic at concentrations higher than 1microM, while the triazole analogue 24 (EC(50)=801+/-229nM), was non-toxic at all concentrations tested.
Subject(s)
Catechols/chemical synthesis , Chromans/chemical synthesis , Neurons/drug effects , Oxidative Stress/drug effects , Animals , Azoles/chemistry , Catechols/pharmacology , Cell Death/drug effects , Cell Line , Chromans/pharmacology , Dose-Response Relationship, Drug , Hippocampus/cytology , Mice , Structure-Activity RelationshipABSTRACT
beta-Thujaplicin (hinokitiol or 2-hydroxy-4-isopropyl-2,4,6-cycloheptatrien-1-one), a natural tropolone, shows numerous activities while its synthetic analogues were found to exhibit anticancer and anti-ischemic activity. However, the ability of tropolone derivatives to protect neuronal cells from oxidative stress-induced cell damage has not been studied so far. As an ongoing effort toward highly effective antioxidants with potential neuroprotective activity, we have synthesized 7-substituted derivatives of beta-thujaplicin and its methoxy analogue. The substituents were heterocycles (piperazine, morpholine) or heteroaromatics (triazoles, pyridine). Only the piperazine derivatives of beta-thujaplicin were able to protect HT22 hippocampal neurons from oxidative stress-induced cell death.
Subject(s)
Hippocampus/drug effects , Monoterpenes/chemical synthesis , Monoterpenes/pharmacology , Neurons/drug effects , Neuroprotective Agents , Tropolone/analogs & derivatives , Tropolone/chemical synthesis , Tropolone/pharmacology , Animals , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Antioxidants/chemical synthesis , Antioxidants/chemistry , Antioxidants/pharmacology , Cell Death , Cell Line , Hippocampus/cytology , Molecular Structure , Monoterpenes/chemistry , Neuroprotective Agents/chemical synthesis , Neuroprotective Agents/pharmacology , Tropolone/chemistryABSTRACT
Three series of chromans substituted at positions 2 or 5 by catechol derivatives were synthesized, and their activity against oxidative stress induced cellular damage was studied. Specifically, the ability of the new molecules to protect cultured cells from H(2)O(2)-induced DNA damage was evaluated using single cell gel electrophoresis (comet assay), while the neuroprotective activity of the new compounds against oxidative stress induced programmed cell death was studied using glutamate-challanged hippocampal HT22 cells. The majority of the new compounds are stronger neuroprotectants than quercetin. 5-Substituted chroman analogues such as the caffeic acid amides 12 and 16 and the dihydrostilbene analogue 24 were the most potent against both H(2)O(2)- and glutamate-induced damage in Jurkat T cells and HT22 cells, respectively.
Subject(s)
Antioxidants/chemical synthesis , Antioxidants/pharmacology , Catechols/chemistry , Chromans/chemical synthesis , Chromans/pharmacology , Oxidative Stress/drug effects , Antioxidants/chemistry , Cell Death/drug effects , Cell Line , Chromans/chemistry , DNA Damage , Drug Evaluation, Preclinical , Humans , Hydrogen Peroxide/pharmacology , Molecular Structure , Oxidative Stress/physiology , StereoisomerismABSTRACT
Novel hybrids of lipoic acid and trolox connected through triamine spacers as well as analogues in which the lipoic acid was attached at different positions of the chroman moiety of vitamin E through an amide bond, were synthesized and exhibited strong inhibition of the microsomal lipid peroxidation. Moreover, the new molecules, at 1 microM concentration, reduced reperfusion arrhythmias and MDA content on isolated rat heart preparations, with the 2- and 5-subtituted chromans possessing the better cardioprotective activity.
