Base-Mediated Allylic Defluorinative Functionalizations of β-CFH-1,3-enynes Enables the Construction of Terminal Monofluoroenynes.

The base-mediated allylic defluorinative functionalization of β-CFH-1,3-enynes with nucleophiles is described, affording terminal monofluoroalkenes bearing an alkynyl group in synthetically useful yields and / selectivities. Importantly, the resultant / mixture could be separated by flash chromatography in all cases; thus, stereoisomerically pure monofluoroenynes were obtained. Postsynthetic modifications of the synthesized monofluoroenynes were also accomplished to access diverse molecular structures.

Synthesis of Benzopyrone-Fused Hydrobenzo[,]indoles via Cascade Annulation of -Quinamines and 3-Formylchromones.

A 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU)-catalyzed cascade annulation reaction between -quinamines and 3-formylchromones was developed, affording a series of benzopyrone-fused hydrobenzo[,]indoles in moderate to high yields with excellent diastereoselectivity.

Base-Controlled Divergent Synthesis of Fluorine-Containing Benzo[4,5]imidazo[2,1-][1,3]thiazines from 2-Mercaptobenzimidazoles and β-CF-1,3-Enynes.

A base-controlled divergent cyclization between 2-mercaptobenzimidazoles and β-CF-1,3-enynes providing either trifluoromethylated or fluorinated benzo[4,5]imidazo[2,1-][1,3]thiazines has been developed. The β-CF-1,3-enyne, as a three-carbon synthon, underwent a 1,8-diazabicyclo[5.4.

Synthesis of CF-Substituted Alkylamines, 1,2-Bisazoles, and 1,4,5,6-Tetrahydro-1,2,4-triazines from Newly Designed Tetrazole-Activated Trifluoromethyl Alkenes.

A new class of Michael acceptor, tetrazolyl-trifluoromethyl alkenes, has been discovered. They readily undergo Michael-type addition instead of addition-elimination reaction with aliphatic amines and azoles to furnish β-trifluoromethyl alkylamines and CF-substituted 1,2-bisazole derivatives, respectively. Additionally, some of the products are capable of engaging in microwave-assisted intramolecular denitrogenative annulation, leading to the formation of CF-substituted 1,4,5,6-tetrahydro-1,2,4-triazines that are otherwise difficult to access by other methodologies.

Preclinical Evaluation of the Multiple Tyrosine Kinases Inhibitor Anlotinib in Leukemia Stem Cells.

Leukemia stem cells (LSCs) constitute the critical barrier to the cure of acute myeloid leukemia (AML) due to their chemoresistance and immune evasion property. Herein, the role of anlotinib, a multiple tyrosine kinase inhibitor, in killing LSCs and regulating chemoresistance and immune evasion was explored. Anlotinib treatment induced apoptosis of LSC-like cells as well as primary AML LSCs, while sparing the normal mononuclear cells in vitro.

-Trifluoropropylation of Azoles through -Vinylation and Sequential Hydrogenation.

Installing a fluoroalkyl group onto the nitrogen atom of azoles represents a potential strategy for lead optimization in medicinal chemistry. Herein, we describe a method for the -trifluoropropylation of azoles. This process is accomplished using a combination of regioselective -vinylation and sequential hydrogenation.

Catalytic divergent synthesis of imidazoles reaction condition-dependent [3 + 2] cyclization of TosMIC.

A base-catalyzed divergent synthesis of multisubstituted imidazoles through TosMIC-based [3 + 2] cyclization reaction has been developed. In the presence of ketenimines and BuONa, 1,4,5-trisubstituted imidazoles were obtained. Nonetheless, in the absence of ketenimines, 1,4-disubstituted imidazole was produced through cyclodimerization of TosMIC.

1,2-Dicarbofunctionalization of Trifluoromethyl Alkenes with Pyridinium Salts via a Cycloaddition/Visible-Light-Enabled Fragmentation Cascade.

Although trifluoromethyl alkenes have great synthetic potential, their 1,2-difunctionalization has been a challenge. In this Letter, we disclose the first 1,2-dicarbofunctionalization of trifluoromethyl alkenes with pyridinium salts via a cascade process involving a base-promoted [3 + 2] cycloaddition followed by a visible-light-mediated Norrish-type-II fragmentation. This protocol allows for the formation of pyridines bearing a trifluoromethyl-substituted quaternary center in moderate to excellent yields under mild conditions.

Stereoselective Access to Spirooxindoles and Bisoxindoles Through Organocatalyzed Asymmetric Divergent Transformations of Isatin-derived MBH Carbonates.

An interesting β-isoquinidine catalyzed divergent reaction was developed to produce either spirocyclopentene oxindoles, spirocyclopentadiene oxindoles or bisoxindoles in a high enantioselective fashion. The utility of this protocol was demonstrated by the versatile transformations of the products. This work not only represents the first highly stereoselective intermolecular catalytic asymmetric allylic alkylation reaction between two isatin-derived MBH carbonate molecules but also constitutes a rare example of isatin-derived MBH carbonate-based enantioselective and α-regioselective [3+2] cycloaddition reactions.

QAP14 suppresses breast cancer stemness and metastasis via activation of dopamine D1 receptor.

Breast cancer is the second leading cause of cancer-related mortality in women, mainly due to metastasis, which is strongly associated with cancer stemness. Our previous studies showed that the eradication of cancer stem-like cells (CSCs) may be related to the activation of dopamine D1 receptor (D1DR). This study aimed to explicitly demonstrate the target-role of D1DR activation in antimetastatic therapy and to investigate the potential efficacy and the underlying D1DR-related mechanisms of QAP14, a new oral compound.

Catalytic Enantioselective Isocyanide-Based Reactions: Beyond Passerini and Ugi Multicomponent Reactions.

The development of catalytic enantioselective isocyanide-based reactions is currently of great interest because the resulting products are valuable in organic synthesis, pharmacological chemistry, and materials science. This review assembles and comprehensively summarizes the recent achievements in this rapidly growing area according to the reaction types. Special attention is paid to the advantages, limitations, possible mechanisms, and synthetic applications of each reaction.

Development and validation of a highly sensitive HPLC-MS/MS method for the QAP14, a novel potential anti-cancer agent, in rat plasma and its application to a pharmacokinetic study.

QAP14 is a novel anti-cancer compound exhibiting good efficacy and safety in preclinical study. To investigate its pharmacokinetic properties, a rapid and sensitive HPLC-MS/MS method was developed and validated to quantify the concentration of QAP14 in rat plasma. QAP14 was separated on ZORBAX Eclipse XDB-C8 column with a gradient elution.

Catalyst-free formal [4+1]/[4+2] cyclization cascade sequence of isocyanides with two molecules of acylketene formed in situ from thermal-induced Wolff rearrangement of 2-diazo-1,3-diketones.

An expedient and economic approach for constructing O,O,N-spiro compounds consisting of both a 1,3-oxazine and a furan ring through a catalyst-free formal [4+1]/[4+2] cycloaddition cascade sequence of isocyanides with two molecules of acylketene formed in situ through thermal-induced Wolff rearrangement of 2-diazo-1,3-diketones was developed. The reaction displayed good functional group tolerance and was compatible with different isocyanides and 2-diazo-1,3-diketones. Furthermore, preliminary asymmetric attempts of this reaction are made by utilizing optically pure isocyanides as inputs, and moderate diastereomeric induction was observed.

Diastereoselective Synthesis of 1,3-Diyne-Tethered Trifluoromethylcyclopropanes through a Sulfur Ylide Mediated Cyclopropanation/DBU-Mediated Epimerization Sequence.

A one-pot synthesis of 1,3-diyne-tethered trifluoromethylcyclopropanes starting from 2-CF-3,5-diyne-1-enes and sulfur ylides via a sulfur ylide mediated cyclopropanation and a DBU-mediated epimerization sequence is described in this work. This process is highly diastereoselective with broad substrate scope. Moreover, a series of synthetic transformations based on the diyne moieties were conducted smoothly, affording cyclopropanes featuring trifluoromethyl-substituted all-carbon quaternary centers.

Tandem Cross-Coupling/Spirocyclization/Mannich-Type Reactions of 3-(2-Isocyanoethyl)indoles with Diazo Compounds toward Polycyclic Spiroindolines.

Tandem reactions of Pd-catalyzed cross-coupling of 3-(2-isocyanoethyl)indoles with diazoacetates and subsequent spirocyclization/Mannich-type reaction have been developed to assemble polycyclic spiroindoline skeletons. Formation of spiroindolenines has been proven as the crucial step for the following Mannich-type cyclization reaction. Accordingly, a novel approach on chiral phosphoric acid catalyzed Mannich-type cyclization toward the formation of diastereomerically and enantiomerically enriched pentacyclic spiroindolines has been established.

N-arylpiperazine-containing compound (C2): An enhancer of sunitinib in the treatment of pancreatic cancer, involving D1DR activation.

Previous studies showed that dopamine (DA) significantly reduces the frequency of cancer stem-like cells (CSC) and enhances the efficacy of sunitinib (SUN) in the treatment of breast cancer and non-small cell lung cancer (NSCLC). To overcome the shortcomings of DA in clinical practice, the purpose of this study was to investigate the efficacy as well as the underlying mechanism of an orally available, N-arylpiperazine-containing compound C2, in the treatment of pancreatic cancer when used alone or in combination with SUN. Our results showed that C2 and SUN exerted synergistic effects on inhibiting the growth of SW1990 and PANC-1 pancreatic cancer cells.

Synthesis of Multisubstituted 1-Naphthoic Acids via Ru-Catalyzed C-H Activation and Double-Alkyne Annulation under Air.

An efficient [2 + 2 + 2] benzannulation of phthalic acids/anhydrides with two alkynes was developed for synthesis of multisubstituted 1-naphthoic acids via Ru-catalyzed C-H activation. The reaction preceded well using atmospheric oxygen as the sole oxidant with high atom/step economies. Facilitated by the free carboxyl group, the products can be easily converted to diverse polycyclic molecules.

Silencing of HMGA2 reverses retardance of cell differentiation in human myeloid leukaemia.

Background: High-mobility group AT-hook 2 (HMGA2) may serve as an architectural transcription factor, and it can regulate a range of normal biological processes including proliferation and differentiation. Upregulation of HMGA2 expression is correlated to the undifferentiated phenotype of immature leukaemic cells. However, the underlying mechanism of HMGA2-dependent myeloid differentiation blockage in leukaemia is unknown.

Allogeneic hematopoietic stem cell transplantation improves the prognosis of p16-deleted adult patients with acute lymphoblastic leukemia.

Aim: The prognostic value of CDKN2A inactivation in adult patients with acute lymphoblastic leukemia (ALL) is still under debate, and the role of allogeneic hematopoietic stem cell transplantation (allo-HSCT) for adult ALL with p16 deletion remains to be evaluated.

Materials & Methods: This study analyzed the clinical implications of p16 deletion in adult ALL and investigated the efficacy of allo-HSCT in patients with p16 deletion.

Results: Deletion of p16 was identified in 38.

Systemic mastocytosis with recurrent anaphylactic shock and multiple organ dysfunction failure.

Background: Systemic mastocytosis (SM) is a rare neoplasm. The symptoms of this disease vary among patients. The authors describe a rare case of SM with recurrent anaphylactic shock and multiple organ dysfunction failure.

Cyclic thrombocytopenia related to menstrual cycle: a case report and literature review.

Cyclic thrombocytopenia (CTP) is rarely seen and characterized by periodic fluctuations in platelet counts. In some cases, it occurs in phase with menstrual cycle. A 40-year-old female, presented firstly on June 30, 2012, with a 40-day history of appearance of purpuric skin rash and bruising, was readmitted on Aug 14, when she noted bruise on her lips.

Systemic Epstein-Barr virus positive T-cell lymphoproliferative disease of childhood with hemophagocytic syndrome.

Epstein-Barr virus (EBV) associated lymphoproliferative disease (LPD) are commonly derived from B-cells, however, it is becoming more and more apparently that EBV can also infect T-lymphocytes. Systemic EBV positive T-cell LPD of childhood is rare and characterized by an extremely aggressive course and poor prognosis. Here, we report a 22-year-old female of systemic EBV positive TLPD with acute EBV infection and review the clinical features of this disorder.

Asymmetric addition of triethylaluminium to aromatic aldehydes catalyzed by titanium-(5,5'-biquinoline-6,6'-diol) complexes.

A novel convenient procedure for the resolution of 5,5'-biquinoline-6,6'-diol (BIQOL) was achieved by separating the corresponding diastereomeric mixture of (S)-(+)-camphorsulfonates on a semiprepared XDB-C8 column followed by hydrolysis. The efficient asymmetric addition of triethylaluminium to aromatic aldehydes catalyzed by Ti-(+)/(-)BIQOL complexes under mild conditions is described. The reactions led to the formation of 1-arylpropan-1-ol in up to 87.

shRNA-Mediated BAALC knockdown affects proliferation and apoptosis in human acute myeloid leukemia cells.

Brain and acute leukemia, cytoplasmic (BAALC) is a novel molecular marker indicating an inferior outcome in acute myeloid leukemia (AML) with normal cytogenetics. The biological function of BAALC is largely unknown. In this study, BAALC gene expression in an acute myeloid leukemia cell line KG1a was knocked down by a small hairpin RNA (shRNA).