Michael Brunavs

Synthesis of 6/7-Halotetralones

Abstract The title compounds were prepared from halobromobenzenes via a palladium catalysed coupling followed by cyclisation.

Direct fluorination of the anthraquinone nucleus: scope and application to the synthesis of novel rhein analogues

Abstract Direct fluorination of the functionalised anthraquinone dimethyl rhein methyl ester with Selectfluor TM proceeds regioselectively, providing a concise approach to fluorinated compounds of potential medicinal interest. This represents a new use for Selectfluor TM which hitherto has only been used for fluorinating relatively activated compounds.

An Integrated Approach for Screening and Identification of Positive Allosteric Modulators of N-Methyl-D-Aspartate Receptors:

N-methyl-D-aspartate receptors (NMDARs) are ionotropic glutamate receptors that play an important role in synaptic plasticity and learning and memory formation. Malfunctioning of NMDARs, in particular the reduction in NMDAR activity, is thought to be implicated in major neurological disorders. NMDAR positive allosteric modulators (PAMs) represent potential therapeutic interventions for restoring normal NMDAR function. We report a novel screening approach for identification and characterization of NMDAR-PAMs. The approach combines high-throughput fluorescence imaging with automated electrophysiological recording of glutamate-evoked responses in HEK-293 cells expressing NR1/NR2A NMDAR subunits. Initial high-throughput screening (HTS) of a chemical library containing >810,000 compounds using a calcium flux assay in 1536-well plate format identified a total of 864 NMDAR-PAMs. Concentration response determination in both calcium flux and automated electrophysiological assays found several novel chemical series with EC50 values between 0.49 and 10 µM. A small subset (six series) was selected and analyzed for pharmacological properties, subtype selectivity, mode of action, and activity at native NMDARs. Our approach demonstrates the successful application of HTS functional assays that led to identification of NMDAR-PAMs providing the foundation for further medicinal chemistry work that may lead to novel therapies for treatment of cognitive impairment associated with Alzheimer’s disease and schizophrenia.

SYNTHESIS OF 6-TERT-BUTYL-2-ARYLPYRIDINES

Abstract The title compounds were prepared from aryl β-ketoesters in a simple two step procedure.

Synthesis of 4,5,8-trimethoxy-9,10-dioxo-9,10-dihydroanthracene-2-carboxylic acid, an analogue of rhein with improved systemic exposure in the guinea pig

N,N-Diethyl(2-methoxy-4-methyl)benzamide 4 has been lithiated and treated with 2,5-dimethoxybenz-aldehyde to give 3-(2′,5′-dimethoxyphenyl)-7-methoxy-5-methylisobenzofuran-1(3H)-one 5. Reduction and cyclisation gives 4,5,8-trimethoxy-2-methylanthracen-10-ol 7 which is oxidised to give 4,5,8-trimethoxy-2-methylanthraquinone 8. Demethylation gives the natural product helminthosporin 9, oxidation gives 4,5,8-trimethoxy-9,10-dioxo-9,10-dihydroanthracene-2-carboxylic acid an analogue of the osteoarthritis drug rhein. Alternatively, dimethylrhein methyl ester 12 may be iodinated and the iodine displaced with methoxide to provide a large-scale synthesis of 3. Plasma concentration data in the guinea pig were obtained for 3, diacetylrhein, dimethylrhein and 4,5-dimethyl-8-fluororhein after oral dosing.

Anthraquinones related to rhein inhibit glucose uptake into chondrocytes. A mechanism for anti-osteoarthritis drugs?

Abstract Rhein has been shown to inhibit the uptake of glucose into Ehrlich Ascites tumor cells. In this paper we show that a wide range of antrhaquinones related to rhein can also inhibit glucose uptake into chondrocytes, many significantly more than the parent molecule.

Investigating the Behavior of Published PAINS Alerts Using a Pharmaceutical Company Data Set

Biochemical assay interference is becoming increasingly recognized as a significant waste of resource in drug discovery, both in industry and academia. A seminal publication from Baell and Holloway raised the awareness of this issue, and they published a set of alerts to identify what they described as PAINS (pan-assay interference compounds). These alerts have been taken up by drug discovery groups, even though the original paper had a somewhat limited data set. Here, we have taken Lilly’s far larger internal data set to assess the PAINS alerts on four criteria: promiscuity (over six assay formats including AlphaScreen), compound stability, cytotoxicity, and presence of a high Hill slope as a surrogate for non-1:1 protein–ligand binding. It was found that only three of the alerts show pan-assay promiscuity, and the alerts appear to encode primarily AlphaScreen promiscuous molecules. Although not enriching for pan-assay promiscuity, many of the alerts do encode molecules that are unstable, show cytotoxicity, and increase the prevalence of high Hill slopes.