4 research outputs found
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A Computational and Experimental Investigation of the Origin of Selectivity in the Chiral Phosphoric Acid Catalyzed Enantioselective Minisci Reaction.
The Minisci reaction is one of the most valuable methods for directly functionalizing basic heteroarenes to form carbon-carbon bonds. Use of prochiral, heteroatom-substituted radicals results in stereocenters being formed adjacent to the heteroaromatic system, generating motifs which are valuable in medicinal chemistry and chiral ligand design. Recently a highly enantioselective and regioselective protocol for the Minisci reaction was developed, using chiral phosphoric acid catalysis. However, the precise mechanism by which this process operated and the origin of selectivity remained unclear, making it challenging to develop the reaction more generally. Herein we report further experimental mechanistic studies which feed into detailed DFT calculations that probe the precise nature of the stereochemistry-determining step. Computational and experimental evidence together support Curtin-Hammett control in this reaction, with initial radical addition being quick and reversible, and enantioselectivity being achieved in the subsequent slower, irreversible deprotonation. A detailed survey via DFT calculations assessed a number of different possibilities for selectivity-determining deprotonation of the radical cation intermediate. Computations point to a clear preference for an initially unexpected mode of internal deprotonation enacted by the amide group, which is a crucial structural feature of the radical precursor, with the assistance of the associated chiral phosphate. This unconventional stereodetermining step underpins the high enantioselectivities and regioselectivities observed. The mechanistic model was further validated by applying it to a test set of substrates possessing varied structural features.EPSRC
GSSK
ERC
Leverhulme Trust
Isaac Newton Trus
Isolation of Hox Cluster Genes from Insects Reveals an Accelerated Sequence Evolution Rate
Among gene families it is the Hox genes and among metazoan animals it is the insects (Hexapoda) that have attracted particular attention for studying the evolution of development. Surprisingly though, no Hox genes have been isolated from 26 out of 35 insect orders yet, and the existing sequences derive mainly from only two orders (61% from Hymenoptera and 22% from Diptera). We have designed insect specific primers and isolated 37 new partial homeobox sequences of Hox cluster genes (lab, pb, Hox3, ftz, Antp, Scr, abd-a, Abd-B, Dfd, and Ubx) from six insect orders, which are crucial to insect phylogenetics. These new gene sequences provide a first step towards comparative Hox gene studies in insects. Furthermore, comparative distance analyses of homeobox sequences reveal a correlation between gene divergence rate and species radiation success with insects showing the highest rate of homeobox sequence evolution
Pranlukast is a novel small molecule activator of the two-pore domain potassium channel TREK2
TREK2 (KCNK10, K2P10.1) is a two-pore domain potassium (K2P) channel and a potential target for the treatment of pain. Like the majority of the K2P superfamily, there is currently a lack of useful pharmacological tools to study TREK2. Here we present a strategy for identifying novel TREK2 activators. A cell-based thallium flux assay was developed and used to screen a library of drug-like molecules, from which we identified the CysLT1 antagonist Pranlukast as a novel activator of TREK2. This compound was selective for TREK2 versus TREK1 and showed no activity at TRAAK. Pranlukast was also screened against other members of the K2P superfamily. Several close analogues of Pranlukast and other CysLT1 antagonists were also tested for their ability to activate K2P channels. Consistent with previous work, structure activity relationships showed that subtle structural changes to these analogues completely attenuated the activation of TREK2, whereas for TREK1, analogues moved from activators to inhibitors. Pranlukast's activity was also confirmed using whole-cell patch clamp electrophysiology. Studies using mutant forms of TREK2 suggest Pranlukast does not bind in the K2P modulator pocket or the BL-1249 binding site. Pranlukast therefore represents a novel tool by which to study the mechanism of TREK2 activation
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DFT calculation Data From the Computational and Experimental Investigation of the Origin of Selectivity in the Chiral Phosphoric Acid-Catalyzed Enantioselective Minisci Reaction
This dataset contains Gaussian DFT output files of the key ground-states
and transition state DFT optimized structures.
The data is organised in one archive containing 95 separate folders. The hierarchical folder structure follows the convention of ‘substrate’/’mechanistic step’/ ’intermediate or TS stereochemistry’/’activation mode (if applicable)’.
The substrate, mechanistic step and activation mode naming conventions
follow that in the associated paper. Thus, ‘Subst3_QuinValine\II-III_TS\
RS\INT_sol’ folder contains the computational data of the substrate 3
R,S-INT deprotonation solvent transition states. Each of these lower level
folders contain at least the output of a frequency calculation at
B3LYP/6-31g** level with or without SMD(1,4-dioxane) solvent model (*_freq.out
files), as well as at least one single point calculation at a higher level,
usually at M06-2X/def2-TZVP/SMD(1,4-dioxane) or M06-2X/def2-TZVPD/
SMD(1,4-dioxane) level (*_sp.out files). All optimized geometries are also
provided as *.sdf files for even better usability.
All of the files can be opened in any text editor. Gaussian output structures
can be viewed and the frequency modes visualised in GausView, Avogadro, jmol
and in most other molecular viewers/editors. *.sdf files can be viewed in
essentially all 3D molecular editors and viewers.We are grateful to the EPSRC and GlaxoSmithKline for PhD studentships (to R.S.J.P. and B.W.H.), the Royal Society for a University Research Fellowship (to R.J.P.), the Leverhulme Trust (RPG-2018-081) and the European Research Council (Starting Grant 757381, NonCovRegioSiteCat). We also thank Leverhulme Trust (ECF-2017-255) and Isaac Newton Trust (17.08(d)) for Early Career Fellowship (to K.E.). The computational work has been performed using resources provided by the Cambridge Tier-2 system operated by the University of Cambridge Research Computing Service (http://www.hpc.cam.ac.uk) funded by EPSRC Tier-2 capital grant EP/P020259/1