Synthesis and activity of a novel Autotaxin inhibitor-Icodextrin conjugate

© Copyright 2018 American Chemical Society. Autotaxin is an extracellular phospholipase D that catalyses the hydrolysis of lysophosphatidyl choline (LPC) to generate the bioactive lipid lysophosphatidic acid (LPA). Autotaxin has been implicated in many pathological processes relevant to cancer. Intraperitoneal administration of an autotaxin inhibitor may benefit patients with ovarian cancer, however low molecular mass compounds are known to be rapidly cleared from the peritoneal cavity. Icodextrin is a polymer that is already in clinical use because it is slowly eliminated from the peritoneal cavity. Herein we report conjugation of the autotaxin inhibitor HA-155 to icodextrin. The conjugate inhibits autotaxin activity (IC50 = 0.86 ± 0.13 μg mL-1) and reduces cell migration. Conjugation of the inhibitor increased its solubility, decreased its membrane permeability and improved its intraperitoneal retention in mice. These observations demonstrate the first application of icodextrin as a covalently-bonded drug delivery platform with potential use in the treatment of ovarian cancer

Fluorine–Fluorine Interactions in the Solid State: An Experimental and Theoretical Study

The solid state structures of three compounds that contain a perfluorinated chain, CF₃(CF₂)₅CH₂CH(CH₃)CO₂H, CF₃(CF₂)₅(CH₂)₄(CF₂)₅CF₃ and {CF₃(CF₂)₅CH₂CH₂}₃PO have been compared and a number of C–F···F–C and C–F···H–C interactions that are closer than the sum of the van der Waals radii have been identified. These interactions have been probed by a comprehensive computational chemistry investigation and the stabilizing energy between dimeric fragments was found to be 0.26–29.64 kcal/mol, depending on the type of interaction. An Atoms-in-Molecules (AIM) study has confirmed that specific C–F···F–C interactions are indeed present, and are not due simply to crystal packing. The weakly stabilizing nature of these interactions has been utilized in the physisorption of a selected number of compounds containing long chain perfluorinated ponytails onto a perfluorinated self-assembled monolayer, which has been characterized by IRRAS (Infrared Reflection Absorption Spectroscopy)

Fluorine–Fluorine Interactions in the Solid State: An Experimental and Theoretical Study

The solid state structures of three compounds that contain a perfluorinated chain, CF₃(CF₂)₅CH₂CH(CH₃)CO₂H, CF₃(CF₂)₅(CH₂)₄(CF₂)₅CF₃ and {CF₃(CF₂)₅CH₂CH₂}₃PO have been compared and a number of C–F···F–C and C–F···H–C interactions that are closer than the sum of the van der Waals radii have been identified. These interactions have been probed by a comprehensive computational chemistry investigation and the stabilizing energy between dimeric fragments was found to be 0.26–29.64 kcal/mol, depending on the type of interaction. An Atoms-in-Molecules (AIM) study has confirmed that specific C–F···F–C interactions are indeed present, and are not due simply to crystal packing. The weakly stabilizing nature of these interactions has been utilized in the physisorption of a selected number of compounds containing long chain perfluorinated ponytails onto a perfluorinated self-assembled monolayer, which has been characterized by IRRAS (Infrared Reflection Absorption Spectroscopy)

Fluorine–Fluorine Interactions in the Solid State: An Experimental and Theoretical Study

The solid state structures of three compounds that contain a perfluorinated chain, CF₃(CF₂)₅CH₂CH(CH₃)CO₂H, CF₃(CF₂)₅(CH₂)₄(CF₂)₅CF₃ and {CF₃(CF₂)₅CH₂CH₂}₃PO have been compared and a number of C–F···F–C and C–F···H–C interactions that are closer than the sum of the van der Waals radii have been identified. These interactions have been probed by a comprehensive computational chemistry investigation and the stabilizing energy between dimeric fragments was found to be 0.26–29.64 kcal/mol, depending on the type of interaction. An Atoms-in-Molecules (AIM) study has confirmed that specific C–F···F–C interactions are indeed present, and are not due simply to crystal packing. The weakly stabilizing nature of these interactions has been utilized in the physisorption of a selected number of compounds containing long chain perfluorinated ponytails onto a perfluorinated self-assembled monolayer, which has been characterized by IRRAS (Infrared Reflection Absorption Spectroscopy)

Chirality Driven Metallic versus Semiconducting Behavior in a Complete Series of Radical Cation Salts Based on Dimethyl-Ethylenedithio-Tetrathiafulvalene (DM-EDT-TTF)

Enantiopure (<i>S</i>,<i>S</i>) and (<i>R</i>,<i>R</i>) dimethyl-ethylenedithio-tetrathiafulvalene (DM-EDT-TTF) <b>1</b> donors are synthesized by cross coupling followed by decarboxylation reactions. In the solid state the methyl groups are arranged in axial positions within sofa-type conformation for the six-membered rings. Crystalline radical cation salts formulated as [(<i>S</i>,<i>S</i>)-<b>1</b>]₂PF₆, [(<i>R</i>,<i>R</i>)-<b>1</b>]₂PF₆, and [(<i>rac</i>)-<b>1</b>]₂PF₆ are obtained by electrocrystallization. When the experiment is conducted with enantioenriched mixtures both enantiopure and racemic phases are obtained. The monoclinic enantiopure salts, containing four independent donors in the unit cell, show semiconducting behavior supported by band structure calculations of extended Hückel type. The racemic salt contains only one independent donor in the mixed valence oxidation state +0.5. Under ambient pressure the racemic material is metallic down to 120 K, while an applied pressure of 11.5 kbar completely suppresses the metal–insulator transition. Band structure calculations yield an open Fermi surface, typical for a pseudo-one-dimensional metal, with unperfected nesting, thus ruling out the possibility of charge or spin density modulations to be at the origin of the transition. Raman spectroscopy measurements, in agreement with structural analysis at 100 K, show no indication of low-temperature charge ordering in the racemic material at ambient pressure, thus suggesting Mott-type charge localization for the observed metal–insulator transition