Biological activity and molecular docking studies of some new quinolines as potent anticancer agents.

The objective of this study is to investigate the antiproliferative and cytotoxic properties and the action mechanism of substituted quinoline and tetrahydroquinolines 3, 4, 5, 7, and 8 against rat glioblastoma (C6), human cervical cancer (HeLa), human adenocarcinoma (HT29) cancer cell lines by BrdU Cell Proliferation ELISA, Lactate Dehydrogenase, DNA laddering and Topoisomerase I assays. The results of the study showed that 6,8-dibromotetrahydroquinoline 3 possess in vitro antiproliferative activity against C6, HeLa, and HT29 cell lines while morpholine/piperazine substituted quinoline 7 and 8 showed selective antiproliferative activity on C6 cell line with IC50 values 47.5 and 46.3 µg/mL, respectively. Moreover, 6,8-dibromoTHQ 3 caused DNA fragmentation while it did not inhibit the Topoisomerase I (Topo I) enzyme. On the other hand, compound 8 did not cause DNA laddering while 8 inhibited the Topo I enzyme. According to these results, 6,8-dibromoTHQ 3 stimulates apoptosis on the C6 cell line while 6,8-dibromo-3-morhonilylquinoline (8) inhibits the Topo I enzyme to cause antiproliferative activity.

ONIOM calculations on serotonin degradation by monoamine oxidase B: insight into the oxidation mechanism and covalent reversible inhibition.

Monoamine oxidase (MAO) is an enzyme which catalyzes the oxidation of neurotransmitter amines and regulates their level. There are two forms of the enzyme with 70% similarity, known as MAO-A and MAO-B. MAO inhibitors are used in the treatment of neurological disorders such as depression, Parkinson's and Alzheimer's diseases. Therefore, understanding the chemical steps of MAO catalyzed amine oxidation is crucial for rational drug design. However, despite many experimental studies and recent computational efforts in the literature, the amine oxidation mechanism by MAO enzymes is still controversial. The polar nucleophilic mechanism and hydride transfer mechanisms are under debate in recent QM/MM studies. In this study, the serotonin oxidation mechanism by MAO was explored via the ONIOM (QM : QM) methodology at the M06-2X/6-31+G(d,p):PM6 level. A modified MAO mechanism involving a covalent reversible inhibition step via formation of flavin N5 ylide was proposed. This mechanism can be used to modulate the potency and reversibility of novel mechanism-based covalent inhibitors by intelligent modifications of the structure of the inhibitors. NBO donor-acceptor analysis confirms that the rate-determining αC-H cleavage step is a hybrid of hydride and proton transfer where hydride transfer dominates over the proton transfer. The functional role of covalent FAD was also investigated by calculating the activation energy of noncovalent FAD models where a 22 fold decrease in the rate of catalysis was predicted. Geometrical features imply that the function of the covalent bond in FAD might be to maintain the correct geometry and conformation for a more efficient catalysis.

A comparative computational investigation on the proton and hydride transfer mechanisms of monoamine oxidase using model molecules.

Monoamine oxidase (MAO) enzymes regulate the level of neurotransmitters by catalyzing the oxidation of various amine neurotransmitters, such as serotonin, dopamine and norepinephrine. Therefore, they are the important targets for drugs used in the treatment of depression, Parkinson, Alzeimer and other neurodegenerative disorders. Elucidation of MAO-catalyzed amine oxidation will provide new insights into the design of more effective drugs. Various amine oxidation mechanisms have been proposed for MAO so far, such as single electron transfer mechanism, polar nucleophilic mechanism and hydride mechanism. Since amine oxidation reaction of MAO takes place between cofactor flavin and the amine substrate, we focus on the small model structures mimicking flavin and amine substrates so that three model structures were employed. Reactants, transition states and products of the polar nucleophilic (proton transfer), the water-assisted proton transfer and the hydride transfer mechanisms were fully optimized employing various semi-empirical, ab initio and new generation density functional theory (DFT) methods. Activation energy barriers related to these mechanisms revealed that hydride transfer mechanism is more feasible.