Mark B. Schilling

The Discovery of I-Bet726 (Gsk1324726A), a Potent Tetrahydroquinoline Apoa1 Up-Regulator and Selective Bet Bromodomain Inhibitor.

Through their function as epigenetic readers of the histone code, the BET family of bromodomain-containing proteins regulate expression of multiple genes of therapeutic relevance, including those involved in tumor cell growth and inflammation. BET bromodomain inhibitors have profound antiproliferative and anti-inflammatory effects which translate into efficacy in oncology and inflammation models, and the first compounds have now progressed into clinical trials. The exciting biology of the BETs has led to great interest in the discovery of novel inhibitor classes. Here we describe the identification of a novel tetrahydroquinoline series through up-regulation of apolipoprotein A1 and the optimization into potent compounds active in murine models of septic shock and neuroblastoma. At the molecular level, these effects are produced by inhibition of BET bromodomains. X-ray crystallography reveals the interactions explaining the structure-activity relationships of binding. The resulting lead molecule, I-BET726, represents a new, potent, and selective class of tetrahydroquinoline-based BET inhibitors.

Tributylgermanium hydride as a replacement for tributyltin hydride in radical reactions

Tributylgermanium hydride (Bu(3)GeH) can be used as an alternative to tributyltin hydride (Bu(3)SnH) as a radical generating reagent with a wide range of radical substrates. Tributylgermanium hydride has several practical advantages over tributyltin hydride, e.g. low toxicity, good stability and much easier work-up of reactions. The reagent can be easily prepared in good yield and stored indefinitely. Suitable substrates include iodides, bromides, activated chlorides, phenyl selenides, tert-nitroalkanes, thiocarbonylimidazolides and Barton esters. Alkyl, vinyl and aryl radicals can be generated in radical reactions including reduction and cyclisation processes. Common radical initiators such as ACCN and triethylborane can be used. The slower rate of hydrogen abstraction by carbon-centred radicals from Bu(3)GeH as compared to Bu(3)SnH facilitates improved cyclisation yields. Polarity reversal catalysis (PRC) with phenylthiol can be used in reactions which generate stable radical intermediates which will not abstract hydrogen from Bu(3)GeH.

Improved procedures for the preparation of (+) - (1R, 2S, 4R)-4-amino-2-hydroxy-1-hydroxymethyl cyclopentane

Abstract Two methods for the stereospecific synthesis of the title compound are described. These short and efficient syntheses provide rapid access to this key intermediate in the construction of 2′-Deoxy Carbocyclic Nucleosides.

Novel syntheses of the amino-1,2,4-triazine GW356194: identification of a synthesis amenable to scale up

Abstract New syntheses of the amino-1,2,4-triazine, GW356194 have been developed to improve on existing methodology. The use of different amidrazones in cyclisations with α-keto and α-amido carbonyl compounds as the key step for the synthesis of the 1,2,4-triazine core was evaluated and the results are presented here.

Regiochemical observations on the lithiation of 1,2,4-trichlorobenzene and reaction with DMF and oxamide electrophiles in THF

Unusual regiochemistry is observed in the products arising from the reaction of lithiated 1,2,4-trichlorobenzene with N,N-dimethylformamide and tetraalkyloxamides.

Dihydroisoquinolinium salts: catalysts for asymmetric epoxidation

A range of dihydroisoquinolinium salts has been prepared and tested as asymmetric epoxidation catalysts in an investigation of the reaction mechanism and the factors affecting enantioselectivity in this process.