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

In-situ generation of 2-Iodoxybenzoic Acid (IBX) in the presence of Tetraphenylphosphonium monoperoxysulfate (TPPP) for the conversion of primary alcohols into the corresponding aldehydes

Primary alcohols are oxidized to the corresponding aldehydes by tetraphenylphosphonium monoperoxysulfate (TPPP) in the presence of catalytic 2-iodobenzoic acid. Over-oxidation to carboxylic acids is not observed, in contrast to the use of catalytic 2-iodobenzoic acid with Oxone as reoxidant

A highly selective synthesis of the indolo[2,3-a]quinolizine ring system and application to natural product synthesis

We present a facile and highly stereoselective approach to the indolo[2,3-a]quinolizine ring system from a readily available, non-racemic chiral template. We demonstrate the potential for application of this methodology to natural product synthesis through conversion of the template to some representative indole alkaloids with high enantiomeric purity in both enantiomeric series

Facile asymmetric construction of a functionalized dodecahydrobenz[a]indolo[3,2-h]quinolizine template

We report a highly diastereoselective approach for the synthesis of a functionalized dodecahydrobenz[a]indolo[3,2-h]quinolizine ring system that is present as the heterocyclic core of the manadomanzamine alkaloids. We have achieved complete control over the relative and absolute stereochemistries at the three contiguous stereocentres at ring positions 1, 10 and 24 in only two linear synthetic steps. The introduction of useful functionality to the heterocyclic skeleton is significant as this may allow for future derivatization, and application of this route in an asymmetric synthesis of the manadomanzamine natural products

Enantioselective Total Synthesis of (+)-Scuteflorin A Using Organocatalytic Asymmetric Epoxidation

We report the first enantioselective total synthesis of (+)-scuteflorin A in 14% overall yield, employing a chiral iminium salt to effect an organocatalytic asymmetric epoxidation of xanthyletin in >99% ee as the key step

Enantioselective Total Synthesis of (+)-Scuteflorin A Using Organocatalytic Asymmetric Epoxidation

We report the first enantioselective total synthesis of (+)-scuteflorin A in 14% overall yield, employing a chiral iminium salt to effect an organocatalytic asymmetric epoxidation of xanthyletin in >99% ee as the key step

Kinetic Resolution in Asymmetric Epoxidation using Iminium Salt Catalysis

The first reported examples of kinetic resolution in epoxidation reactions using iminium salt catalysis are described, providing up to 99% ee in the epoxidation of racemic <i>cis</i>-chromenes

Asymmetric Epoxidation Using Iminium Salt Organocatalysts Featuring Dynamically Controlled Atropoisomerism

Introduction of a pseudoaxial substituent at a stereogenic center adjacent to the nitrogen atom in binaphthyl- and biphenyl-derived azepinium salt organocatalysts affords improved enantioselectivities and yields in the epoxidation of unfunctionalized alkenes. In the biphenyl-derived catalysts, the atropoisomerism at the biphenyl axis is controlled by the interaction of this substituent with the chiral substituent at nitrogen

Asymmetric Epoxidation Using Iminium Salt Organocatalysts Featuring Dynamically Controlled Atropoisomerism

Introduction of a pseudoaxial substituent at a stereogenic center adjacent to the nitrogen atom in binaphthyl- and biphenyl-derived azepinium salt organocatalysts affords improved enantioselectivities and yields in the epoxidation of unfunctionalized alkenes. In the biphenyl-derived catalysts, the atropoisomerism at the biphenyl axis is controlled by the interaction of this substituent with the chiral substituent at nitrogen