8 research outputs found
Synthesis of inhibitors of the IKK-complex for the treatment of prostate cancer
This thesis was previously held under moratorium from 24 July 2012 until 24th July 2016
Manganese dioxide mediated one-pot synthesis of methyl 9H-pyrido[3,4-b]indole-1-carboxylate: Concise synthesis of alangiobussinine
The carboline ring system is an important pharmacophore found in a number of biologically important targets. Development of synthetic routes for the preparation of these compounds is important in order to prepare a range of analogues containing the carboline heterocyclic moiety. A manganese dioxide mediated one-pot method starting with an activated alcohol and consisting of alcohol oxidation, PictetâSpengler cyclisation, and oxidative aromatisation, offers a convenient process that allows access to β-carbolines. This one-pot process for the preparation of methyl 9H-pyrido[3,4-b]indole-1-carboxylate has subsequently been used as the key step in the synthesis of alangiobussinine and a closely related analogue
Diastereoselective Additions of Titanium Enolates from <i>N</i>âGlycolyl Thiazolidinethiones to Acetals
The stereochemical outcome of the Lewis acid-mediated <i>glycolate</i> addition of the titanium enolates from protected <i>N</i>-hydroxyacetyl-4-isopropyl-1,3-thiazolidine-2-thiones to
dimethyl and dibenzyl acetals depends on the hydroxyl protecting group.
Particularly, the pivaloyl protected glycolate derivative provides
the reluctant <i>anti</i> adducts in high yields and diastereomeric
ratios, which can be isolated and further converted in enantiomerically
pure form to β-methoxy or β-benzyloxy ι-pivaloyloxy
carbonyl fragments in a straightforward manner
Topographical Mapping of Isoform-Selectivity Determinants for JâChannel-Binding Inhibitors of Sphingosine Kinases 1 and 2
Sphingosine kinase
enzymes (SK1 and SK2) catalyze the conversion
of sphingosine into sphingosine 1-phosphate and play a key role in
lipid signaling and cellular responses. Mapping of isoform amino acid
sequence differences for SK2 onto the recently available crystal structures
of SK1 suggests that subtle structural differences exist in the foot
of the lipid-binding âJ-channelâ in SK2, the structure
of which has yet to be defined by structural biology techniques. We
have probed these isoform differences with a ligand series derived
from the potent SK1-selective inhibitor, PF-543. Here we show how
it is possible, even with relatively conservative changes in compound
structure, to systematically tune the activity profile of a ligand
from ca. 100-fold SK1-selective inhibition, through equipotent SK1/SK2
inhibition, to reversed 100-fold SK2 selectivity, with retention of
nanomolar potency