[3,3]-Sigmatropic Rearrangements of Naphthyl 1-Propargyl Ethers: para-Propargylation and Catalytic Asymmetric Dearomatization.

The para-Claisen rearrangement of aryl 1-propargyl ethers involves two-step [3,3]-sigmatropic rearrangements and dearomatization process, which has high activation barriers and is of challenge. Here we discovered thermal para-Claisen rearrangement of naphthyl 1-propargyl ethers, and it enabled the formation of formal para-C-H propargylation products upon rearomatization. Chirality transfer occurred if optically active propargyl ethers were employed, leading to the construction of aryl/propargyl-containing stereogenic centers. Moreover, catalytic asymmetric dearomatization of naphthyl 1-propargyl ethers with different substitution at para-position gave access to benzocyclohexenones bearing all-carbon quaternary stereocenters. The reaction was accelerated by a chiral N,N'-dioxide/Co(OTf)2 complex catalyst to achieve high yields (up to 98 %) and high enantioselectivities (up to 93 % ee). The DFT calculations and experimental results provided important clues to clarify the para-Claisen rearrangement process as well as the chiral induction and remote delivery.

Enantioselective Synthesis of Azetidines through [3 + 1]-Cycloaddition of Donor-Acceptor Aziridines with Isocyanides.

The enantioselective [3 + 1]-cycloaddition of racemic donor-acceptor (D-A) aziridines with isocyanides was first realized under mild reaction conditions using a chiral N,N'-dioxide/MgII complex as catalyst, providing a facile route to enantioenriched exo-imido azetidines with good to excellent yield (up to 99%) and enantioselectivity (up to 94% ee). An obvious chiral amplification effect was observed in this system, and an explanation was elucidated based on the experimental investigation and X-ray crystal structure of the enantiomerically pure catalyst.

Asymmetric Catalytic Epoxidation of Terminal Enones for the Synthesis of Triazole Antifungal Agents.

An enantioselective epoxidation of α-substituted vinyl ketones was realized to construct the key epoxide intermediates for the synthesis of various triazole antifungal agents. The reaction proceeded efficiently in high yields with good enantioselectivities by employing a chiral N,N'-dioxide/ScIII complex as the chiral catalyst and 35% aq. H2O2 as the oxidant. It enabled the facile transformation for optically active isavuconazole, efinaconazole, and other potential antifungal agents.

Synthesis and structure-activity relationship studies of LLY-507 analogues as SMYD2 inhibitors.

SET and MYND domain-containing protein 2 (SMYD2), a lysine methyltransferase, is reported to catalyze the methylation of lysine residues on histone and non-histone proteins. As a potential target for cancer therapy, there are several SMYD2 inhibitors are reported, LLY-507 as a cell-active inhibitor exhibits submicromolar potency against SMYD2 in several cancer cell lines. To know which structural fragment of LLY-507 is suitable for chemical modification, three sites are chosen for structure-activity relationship studies (SARs). Among our focused library, compounds 43 and 44 with amide link on site C showed reasonably improved potency indicating that modification on this fragment is more flexible and introduction of electrophilic warheads in this position might provide lysine-targeting covalent inhibitors for SMYD2.

Covalent Inhibitors Allosterically Block the Activation of Rho Family Proteins and Suppress Cancer Cell Invasion.

The Rho family GTPases are crucial drivers of tumor growth and metastasis. However, it is difficult to develop GTPases inhibitors due to a lack of well-characterized binding pockets for compounds. Here, through molecular dynamics simulation of the RhoA protein, a groove around cysteine 107 (Cys107) that is relatively well-conserved within the Rho family is discovered. Using a combined strategy, the novel inhibitor DC-Rhoin is discovered, which disrupts interaction of Rho proteins with guanine nucleotide exchange factors (GEFs) and guanine nucleotide dissociation inhibitors (GDIs). Crystallographic studies reveal that the covalent binding of DC-Rhoin to the Cys107 residue stabilizes and captures a novel allosteric pocket. Moreover, the derivative compound DC-Rhoin04 inhibits the migration and invasion of cancer cells, through targeting this allosteric pocket of RhoA. The study reveals a novel allosteric regulatory site within the Rho family, which can be exploited for anti-metastasis drug development, and also provides a novel strategy for inhibitor discovery toward "undruggable" protein targets.

Design, synthesis, and biological evaluation of tetrahydroquinolin derivatives as potent inhibitors of CBP bromodomain.

CREB-binding protein (CBP) is a large multi-domain protein containing a HAT domain catalyzing transacetylation and a bromodomain responsible for acetylated lysine recognition. CBPs could act as transcription co-activators to regulate gene expression and have been shown to play a significant role in the development and progression of many cancers. Herein, through in silico screening two hit compounds with tetrahydroquinolin methyl carbamate scaffold were discovered, among which DC-CPin7 showed an in vitro inhibitory activity with the TR-FRET IC50 value of 2.5 ± 0.3 µM. We obtained a high-resolution co-crystal structure of the CBP bromodomain in complex with DC-CPin7 to guide following structure-based rational drug design, which yielded over ten DC-CPin7 derivatives with much higher potency, among which DC-CPin711 showed approximately 40-fold potency compared with hit compound DC-CPin7 with an in vitro TR-FRET IC50 value of 63.3 ± 4.0 nM. Notably, DC-CPin711 showed over 150-fold selectivity against BRD4 bromodomains. Moreover, DC-CPin711 showed micromolar level of anti-leukemia proliferation through G1 phase cell cycle arrest and cell apoptosis. In summary, through a combination of computational and crystal-based structure optimization, DC-CPin711 showed potent in vitro inhibitory activities to CBP bromodomain with a decent selectivity towards BRD4 bromodomains and good cellular activity to leukemia cells, which could further be applied to related biological and translational studies as well as serve as a lead compound for future development of potent and selective CBP bromodomain inhibitors.

Discovery of novel CBP bromodomain inhibitors through TR-FRET-based high-throughput screening.

The cAMP-responsive element binding protein (CREB) binding protein (CBP) and adenoviral E1A-binding protein (P300) are two closely related multifunctional transcriptional coactivators. Both proteins contain a bromodomain (BrD) adjacent to the histone acetyl transferase (HAT) catalytic domain, which serves as a promising drug target for cancers and immune system disorders. Several potent and selective small-molecule inhibitors targeting CBP BrD have been reported, but thus far small-molecule inhibitors targeting BrD outside of the BrD and extraterminal domain (BET) family are especially lacking. Here, we established and optimized a TR-FRET-based high-throughput screening platform for the CBP BrD and acetylated H4 peptide. Through an HTS assay against an in-house chemical library containing 20 000 compounds, compound DC_CP20 was discovered as a novel CBP BrD inhibitor with an IC50 value of 744.3 nM. This compound bound to CBP BrD with a KD value of 4.01 µM in the surface plasmon resonance assay. Molecular modeling revealed that DC_CP20 occupied the Kac-binding region firmly through hydrogen bonding with the conserved residue N1168. At the celluslar level, DC_CP20 dose-dependently inhibited the proliferation of human leukemia MV4-11 cells with an IC50 value of 19.2 µM and markedly downregulated the expression of the c-Myc in the cells. Taken together, the discovery of CBP BrD inhibitor DC_CP20 provides a novel chemical scaffold for further medicinal chemistry optimization and a potential chemical probe for CBP-related biological function research. In addition, this inhibitor may serve as a promising therapeutic strategy for MLL leukemia by targeting CBP BrD protein.

Kinetic Resolution of Aziridines via Catalytic Asymmetric Ring-Opening Reaction with Mercaptobenzothiazoles.

A highly efficient kinetic resolution of racemic 2-acyl-3-aryl-N-tosylaziridines is achieved through a chiral Lewis acid promoted ring-opening reaction with 2-mercaptobenzothiazoles as the nucleophiles. The chiral N,N'-dioxide-lanthanum complex as catalyst and the 2-mercaptobenzothiazoles as active sulfur nucleophiles are the keys to the success of the reaction. A variety of enantioenriched ß-amino thioethers and aziridines are obtained in good yields with good ee values.

Discovery of alkoxy benzamide derivatives as novel BPTF bromodomain inhibitors via structure-based virtual screening.

Bromodomain PHD finger transcription factor (BPTF), a bromodomain-containing protein, plays a crucial role in the regulation of downstream gene expression through the specific recognition of lysine acetylation on bulk histones. The dysfunction of BPTF is closely involved with the development and progression of many human diseases, especially cancer. Therefore, BPTF bromodomain has become a promising drug target for epigenetic cancer therapy. However, unlike BET family inhibitors, few BPTF bromodomain inhibitors have been reported. In this study, by integrating docking-based virtual screening with biochemical analysis, we identified a novel selective BPTF bromodomain inhibitor DCB29 with the IC50 value of 13.2 ±â€¯1.6 µM by homogenous time-resolved fluorescence resonance energy transfer (HTRF) assays. The binding between DCB29 and BPTF was confirmed by NMR and SPR. Molecular docking disclosed that DCB29 occupied the pocket of acetylated H4 peptide substrate and provided detailed SAR explanations for its derivatives. Collectively, DCB29 presented great potential as a powerful tool for BPTF-related biological research and further medicinal chemistry optimization.