piperidines and benzothiazole

The phosphoinositide 3-kinase γ (PI3Kγ) has been verified to be a potential drug target for the treatments of various human physical disorders. Although received lots of attention, the development of PI3Kγ-selective inhibitors is still a challenging subject because of its unique protein structural features. Aiming to uncover the interaction mechanism between the selective inhibitors and PI3Kγ, a series of benzothiazole and thiazolopiperidine PI3Kγ isoform-selective inhibitors were studied with an integrated in silico strategy by combining molecular docking, molecular dynamic simulations, binding free energy calculations, and decomposition analysis. Firstly, three molecular docking models, including rigid receptor docking, induced fit docking (IFD), and quantum mechanical-polarized ligand docking, were respectively, built, and the IFD preliminarily predicted the docking poses of all studied inhibitors and roughly analyzed the binding mechanism. Secondly, four binding complexes with representative inhibitors were selected to perform molecular dynamic simulations and free energy calculations. The predicted binding energies were consistent with the experimental bioactivities and different binding patterns between potent and weak inhibitors were uncovered. Finally, through the Molecular Mechanics/Generalized Born Surface Area binding free energy decomposition, residue-inhibitor interactions spectra were obtained and several key residues contributing to favorable binding were highlighted, which provides valuable information for rational PI3Kγ inhibitor design and modification.

Topics: Benzothiazoles; Binding Sites; Catalytic Domain; Class Ib Phosphatidylinositol 3-Kinase; Enzyme Inhibitors; Humans; Ligands; Molecular Docking Simulation; Molecular Dynamics Simulation; Piperidines; Thermodynamics

The (Z)-hex-1,5-diyne-3-ene reactive core common to the enediyne antitumor antibiotics undergoes a Bergman cyclization after proper activation to afford reactive diradical intermediates that are responsible for initiating DNA cleavage. Direct modification of the enediyne core has been proposed as a method to permit cancer cell-specific triggering of the diradical-generating cyclization. For example, 3-aza-3-ene-1,5-diynes undergo an aza-Bergman cyclization to afford the fleeting 2,5-didehydropyridine diradicals. While protonation of these aza-enediynes can afford products of diradical trapping, the hydrolytic instability of the 3-aza-3-ene-1,5-diyne moiety prevents its use in pH-triggered DNA cleaving anticancer agents. Recently, more hydrolytically stable systems incorporating the 4-aza-3-ene-1,6-diyne moiety were developed. We report here studies of the 4-aza-3-ene-1,6-diyne-containing benzimidazolium salt AZB002 [1-methyl-2-(phenylethynyl)-3-(3-phenylprop-2-ynyl)-3H-benzimidazolium tetrafluoroborate] and two structurally related heterocycles that lack the aza-enediyne functionality, AZB016 [1,3-dimethyl-2-(phenylethynyl)-3H-benzimidazolium triflate] and AZB004 [3-methyl-2-(phenylethynyl)benzothiazolium triflate]. The interaction of these compounds with supercoiled DNA, a double-stranded DNA fragment, and a short DNA duplex oligonucleotide was investigated. There are three distinct DNA interactions exhibited by AZB002: a frank strand scission leading to the relaxation of supercoiled DNA and formation of at least two different DNA adducts, one of which leads to cytosine-specific cleavage after piperidine/heat treatment. In contrast, analogues lacking the aza-enediyne functionality either fail to interact with DNA (AZB016) or cleave DNA at guanine residues, presumably through alkylation of the N-7 position (AZB004). We also investigated the cytotoxicity of AZB002 and the related heterocyclic compounds AZB004 and AZB016 and find that only the DNA interactive compounds AZB002 and AZB004 display significant cytotoxicity. In particular, AZB002 is cytotoxic against a wide range of cancer cell lines.

Topics: Alkynes; Antineoplastic Agents; Aza Compounds; Benzimidazoles; Benzothiazoles; Cytosine; DNA Adducts; DNA, Superhelical; Growth Inhibitors; Heterocyclic Compounds, 2-Ring; Hot Temperature; Humans; Hydrogen-Ion Concentration; Hydrolysis; Piperidines; Thiazoles; Tumor Cells, Cultured; U937 Cells