ABSTRACT
Etoposide is effective as an anti-tumour drug by inhibiting eukaryotic DNA topoisomerase II via establishing a covalent complex with DNA. Unfortunately, its wide therapeutic application is often hindered by multidrug resistance (MDR), low water solubility and toxicity. In our previous study, new derivatives of benzoxazoles, benzimidazoles and related fused heterocyclic compounds, which exhibited significant eukaryotic DNA topoisomerase II inhibitory activity, were synthesized and exhibited better inhibitory activity compared with the drug etoposide itself. To expose the binding interactions between the eukaryotic topoisomerase II and the active heterocyclic compounds, docking studies were performed, using the software Discovery Studio 2.1, based on the crystal structure of the Topo IIA-bound G-segment DNA (PDB ID: 2RGR). The research was conducted on a selected set of 31 fused heterocyclic compounds with variation in structure and activity. The structural analyses indicate coordinate and hydrogen bonding interactions, van der Waals interactions and hydrophobic interactions between ligands and the protein, as Topo IIA-bound G-segment DNA are responsible for the preference of inhibition and potency. Collectively, the results demonstrate that the compounds 1a, 1c, 3b, 3c, 3e and 4a are significant anti-tumour drug candidates that should be further studied.
Subject(s)
DNA Topoisomerases, Type II/chemistry , Heterocyclic Compounds/chemistry , Models, Molecular , Topoisomerase II Inhibitors/chemistry , DNA Topoisomerases, Type II/metabolism , Etoposide/chemistry , Etoposide/pharmacology , Heterocyclic Compounds/pharmacology , Humans , Ligands , Structure-Activity Relationship , Topoisomerase II Inhibitors/pharmacologyABSTRACT
The mechanisms of aluminum (Al) neurotoxicity is of increasing interest. Al compounds are known to produce neurological and behavioral abnormalities in some mammalian species. The present study was designed to determine the effects of Al chloride on the skilled motor performance in mice on the rota-rod treadmill. Al chloride, depending on the duration of treatment, produced an impairment of the motor coordination ability in mice.
Subject(s)
Aluminum/toxicity , Psychomotor Performance/drug effects , Animals , Depression, Chemical , Male , Mice , Postural Balance/drug effectsABSTRACT
A centrally acting antitussive agent dextromethorphan (DM) was tested to determine its possible interaction with naloxone in rats responding under a fixed-interval schedule of positive reinforcement. A sugar sweetened milk reward was used as a positive reinforcer. Under the same experimental conditions the effects of morphine alone and in combination with naloxone were also determined. Low dose DM (10 mg/kg) produced a slight increase, while higher doses (20-40 mg/kg) produced dose-dependent decreases in response rate. Morphine (0.3, 1.0 and 3.0 mg/kg) produced dose-dependent decreases in response rate. When doses of naloxone (0.1-1.0 mg/kg) were administered after the injection of DM the rate-decreasing effects of DM were potentiated even after the rate-increasing dose of naloxone (0.1 mg/kg) was used. When a dose of naloxone (0.1 mg/kg) was administered after the injection of morphine the rate-decreasing effects of morphine were markedly antagonized, i.e., the morphine dose-response curve was shifted to the right. The observed potentiation of DM disruption by naloxone on fixed-interval performance in rats is consistent with findings showing that naloxone potentiates the disruptive behavioral effects of a number of drugs that are psychotomimetic in man.
