The p300/CBP‐associated factor (PCAF) and related GCN5 bromodomain‐containing lysine acetyl transferases are members of subfamily I of the bromodomain phylogenetic tree. Iterative cycles of rational inhibitor design and biophysical characterization led to the discovery of the triazolopthalazine‐based L‐45 (dubbed L‐Moses) as the first potent, selective, and cell‐active PCAF bromodomain (Brd) inhibitor. Synthesis from readily available (1R,2S)‐(−)‐norephedrine furnished L‐45 in enantiopure form. L‐45 was shown to disrupt PCAF‐Brd histone H3.3 interaction in cells using a nanoBRET assay, and a co‐crystal structure of L‐45 with the homologous Brd PfGCN5 from Plasmodium falciparum rationalizes the high selectivity for PCAF and GCN5 bromodomains. Compound L‐45 shows no observable cytotoxicity in peripheral blood mononuclear cells (PBMC), good cell‐permeability, and metabolic stability in human and mouse liver microsomes, supporting its potential for in vivo use.
The diastereo‐ and enantioselective diboration of spirocyclobutenes provides a platform for the rapid preparation of a wide variety of chiral spirocyclic building blocks. The chemoselective functionalization of the carbon‐boron bond in the products, including a stereospecific sp3‐sp2 Suzuki–Miyaura cross‐coupling reaction, provides a powerful tool to control the directionality and the nature of the exit vectors in the spirocyclic framework.
Herein, we report a catalytic and stereospecific method for the preparation of enantioenriched a-hydroxy cyclopropylboronates with control in four contiguous stereocenters. The reaction involves the borylation of readily available allylic epoxides using an inexpensive Cu(I) salt and a commercially available phosphine ligand. High diastereocontrol is achieved and different diastereomers can be selectively prepared. Functionalization of the carbon-boron bond provides access to different enantiomerically enriched trisubstituted cyclopropanes from a common intermediate.
We present a strategy for the synthesis
of spirocyclic cyclobutanes
with modulable exit vectors based on the regioselective monoborylation
of spirocyclobutenes. Using an inexpensive copper salt and a commercially
available bidentate phosphine, a broad variety of borylated spirocycles
have been prepared with complete regiocontrol. The boryl moiety provides
a synthetic handled for further functionalization, allowing access
to a wide array of spirocyclic building blocks from a common intermediate.
The p300/CBP-associated factor (PCAF) and related GCN5 bromodomain-containing lysine acetyl transferases are members of subfamily Io ft he bromodomain phylogenetic tree.I terative cycles of rational inhibitor design and biophysical characterization led to the discovery of the triazolopthalazine-based L-45 (dubbed L-Moses)a st he first potent, selective,a nd cell-active PCAF bromodomain (Brd) inhibitor.S ynthesis from readily available (1R,2S)-(À)-norephedrine furnished L-45 in enantiopure form. L-45 was shown to disrupt PCAF-Brd histone H3.3 interaction in cells using an anoBRET assay,a nd ac o-crystal structure of L-45 with the homologous BrdP fGCN5 from Plasmodium falciparum rationalizes the high selectivity for PCAF and GCN5 bromodomains.C ompound L-45 shows no observable cytotoxicity in peripheral blood mononuclear cells (PBMC), good cell-permeability,and metabolic stability in human and mouse liver microsomes,supporting its potential for in vivo use.Bromodomains proteins (Brds) bind to acetylated lysines (KAc) through the Brd acetyllysine-binding site.M isregulation of these proteins is linked to the onset and progression of multiple disease states,s uch as cancer.[1] Significant efforts have been made recently to interrogate the role of these targets through the development of chemical probes and inhibitors.[2] Considerable work has focused on the BET family (Brd sub-family II), [3] however non-BET [4] Brds are increasingly receiving the attention of small molecule intervention efforts,w ith the disclosure of more than 10 new chemical probes/inhibitors in 2016. [5] Thep 300/CBP-associated factor,P CAF( KAT2B), is amulti-domain protein containing asingle Brd, an N-terminal domain, and ah istone acetyltransferase (HAT) domain. Known to associate with CBP [6] and p300 [6b] during transcription, misregulation of PCAF has been linked to cancer, [7] HIV infection, [7a, 8] and neuroinflammation. [7a, 9] Despite predictions of high druggability [10] and links with inflammatory disease, [7a, 11] the role of PCAF and, more specifically,c ontributions of the Brd in such disease states are poorly understood. Thedevelopment of asmall molecule modulator of PCAF Brd would provide au seful tool for interrogating this potential therapeutic target and allow for dissociation of the roles of the Brd and enzymatic domains in disease.Initial reports of PCAF Brd inhibitors were focused on disrupting interactions between the HIV-1 peptide TAT-1a nd PCAF Brd.[
Starting from trifluoroacetaldehyde ethyl hemiacetal, chiral amines and suitable aldehydes, diastereomerically pure fluorinated synor anti-g-amino alcohols can be obtained by a friendly one-pot solventfree L-proline catalysed Mannich-type reaction only by changing the temperature.Scheme 2 L-Proline methyl ester catalysed Mannich-type reaction.This journal is
Starting from C‐CF3‐substituted aldimines, trifluoromethyl β‐lactams were obtained as only products in the reaction with some α‐bromo esters in the presence of activated zinc dust. Different solvents, molar ratios, and temperature were tested to determine the best reaction conditions that led only to desired cyclic compounds. The influence of another ester group on the aldimine chain and the reaction diastereoselectivity were also considered.
L-α-amino esters were considered valuable chiral starting materials in the condensation reaction with trifluoroacetaldehyde (fluoral) ethyl hemiacetal to obtain new functionalized trifluoromethyl aldimines. Starting from these latter compounds, isovaleraldehyde was used in proline-catalyzed Mannich-type addition reactions to give trifluoromethyl syn- or anti-γ-amino alcohols bearing the L-α-amino ester function, simply by changing the reaction temperature.
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