The posttranslational modification of chromatin through
acetylation
at selected histone lysine residues is governed by histone acetyltransferases
(HATs) and histone deacetylases (HDACs). The significance of this
subset of the epigenetic code is interrogated and interpreted by an
acetyllysine-specific protein–protein interaction with bromodomain
reader modules. Selective inhibition of the bromo and extra C-terminal
domain (BET) family of bromodomains with a small molecule is feasible,
and this may represent an opportunity for disease intervention through
the recently disclosed antiproliferative and anti-inflammatory properties
of such inhibitors. Herein, we describe the discovery and structure–activity
relationship (SAR) of a novel, small-molecule chemical probe for BET
family inhibition that was identified through the application of structure-based
fragment assessment and optimization techniques. This has yielded
a potent, selective compound with cell-based activity (PFI-1) that
may further add to the understanding of BET family function within
the bromodomains.
The use of flow photochemistry and its apparent superiority over batch has been reported by a number of groups in recent years. To rigorously determine whether flow does indeed have an advantage over batch, a broad range of synthetic photochemical transformations were optimized in both reactor modes and their yields and productivities compared. Surprisingly, yields were essentially identical in all comparative cases. Even more revealing was the observation that the productivity of flow reactors varied very little to that of their batch counterparts when the key reaction parameters were matched. Those with a single layer of fluorinated ethylene propylene (FEP) had an average productivity 20% lower than that of batch, whereas three-layer reactors were 20% more productive. Finally, the utility of flow chemistry was demonstrated in the scale-up of the ring-opening reaction of a potentially explosive [1.1.1] propellane with butane-2,3-dione.
Fused cyclobutenes, prepared by the photocycloaddition of propargyl alcohols to cyclic anhydride chromophores, undergo facile thermochemical ring opening to fused γ-lactones. The size of the fused ring profoundly influences the temperature that is required to facilitate the ring opening (from 50 °C to 180 °C) and the nature of the product that is formed. Our studies provide new insights into the mechanistic course of these reactions and have been extended to facilitate the preparation of lactams fused to medium-sized rings.
General rightsThis document is made available in accordance with publisher policies. Please cite only the published version using the reference above. Full terms of use are available: http://www.bristol.ac.uk/pure/about/ebr-terms 25 antiproliferative effects against a number of human cell lines. In 26 particular, the oxetane 2, which was formed from 7-epi-27 (+)-goniofufurone, had a cytotoxic potency greater than that of 28 the natural product and, with some cell lines, even greater
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