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We report the first highly diastereo- and enantioselective C–C bond-forming reaction of racemic α-branched ketones to construct tertiary alcohols with adjacent stereocenters. Accordingly, a highly ...

We report an unprecedented tandem Wittig/cyanosilylation/DA reaction/retro-cyanosilylation/isomerization sequence by using our designed bifunctional ethylene equivalent Me2(CH2CH)SiCN.

We present a novel highly stereoselective Rh-catalyzed cyclopropanation of diazothiooxindoles with a broad range of α-functionalized styrenes, enabling facile access of chiral spirocyclopropylthiooxindoles in high to excellent enantiomeric excess.

Checkpoint kinase 1 inhibitors (CHK1i) have shown impressive single-agent efficacy in treatment of certain tumors, as monotherapy or potentiators of chemotherapy in clinical trials, but the sensitive tumor types and downstream effectors to dictate the therapeutic responses to CHK1i remains unclear. In this study we first analyzed GDSC (Genomics of Drug Sensitivity in Cancer) and DepMap database and disclosed that hematologic malignancies (HMs) were relatively sensitive to CHK1i or CHK1 knockdown. This notion was confirmed by examining PY34, a new and potent in-house selective CHK1i, which exhibited potent anti-HM effect in vitro and in vivo, as single agent. We demonstrated that the downregulation of c-Myc and its signaling pathway was the common transcriptomic profiling response of sensitive HM cell lines to PY34, whereas overexpressing c-Myc could partially rescue the anticancer effect of PY34. Strikingly, we revealed the significant correlations between downregulation of c-Myc and cell sensitivity to PY34 in 17 HM cell lines and 39 patient-derived cell (PDC) samples. Thus, our results demonstrate that HMs are more sensitive to CHK1i than solid tumors, and c-Myc downregulation could represent the CHK1i efficacy in HMs.

Checkpoint kinase 1 (CHK1) is a central component in DNA damage response and has emerged as a target for antitumor therapeutics. Herein, we describe the design, synthesis, and biological evaluation of a novel series of potent diaminopyrimidine CHK1 inhibitors. The compounds exhibited moderate to potent CHK1 inhibition and could suppress the proliferation of malignant hematological cell lines. The optimized compound 13 had a CHK1 IC50 value of 7.73±0.74 nM, and MV-4-11 cells were sensitive to it (IC50 =0.035±0.007 μM). Furthermore, compound 13 was metabolically stable in mouse liver microsomes in vitro and displayed moderate oral bioavailability in vivo. Moreover, treatment of MV-4-11 cells with compound 13 for 2 h led to robust inhibition of CHK1 autophosphorylation on serine 296. Based on these biochemical results, we consider compound 13 to be a promising CHK1 inhibitor and potential anticancer therapeutic agent.

A bifunctional silyl reagent Me

Diffuse large B-cell lymphoma (DLBCL) is the most widespread type of non-Hodgkin lymphoma (NHL). As the most aggressive form of the DLBCL, the activated B-cell-like (ABC) subtype is often resistant to standard chemotherapies. Bruton’s tyrosine kinase (BTK) inhibitor ibrutinib provides a potential therapeutic approach for the DLBCL but fails to improve the outcome in the phase III trial. In the current study, we investigated the molecular mechanisms underlying ibrutinib resistance and explored new combination therapy with ibrutinib. We generated an ibrutinib-resistant ABC-DLBCL cell line (OCI-ly10-IR) through continuous exposure to ibrutinib. Transcriptome analysis of the parental and ibrutinib-resistant cell lines revealed that the ibrutinib-resistant cells had significantly lower expression of the unfolded protein response (UPR) marker genes. Overexpression of one UPR branch-XBP1s greatly potentiated ibrutinib-induced apoptosis in both sensitive and resistant cells. The UPR inhibitor tauroursodeoxycholic acid (TUDCA) partially reduced the apoptotic rate induced by the ibrutinib in sensitive cells. The UPR activator 2-deoxy-D-glucose (2-DG) in combination with the ibrutinib triggered even greater cell growth inhibition, apoptosis, and stronger calcium (Ca(2+)) flux inhibition than either of the agents alone. A combination treatment of ibrutinib (15 mg·kg(−1)·d(−1), po.) and 2-DG (500 mg/kg, po, b.i.d.) synergistically retarded tumor growth in NOD/SCID mice bearing OCI-ly10-IR xenograft. In addition, ibrutinib induced the UPR in the sensitive cell lines but not in the resistant cell lines of the DLBCL. There was also a combined synergistic effect in the primary resistant DLBCL cell lines. Overall, our results suggest that targeting the UPR could be a potential combination strategy to overcome ibrutinib resistance in the DLBCL.

α-Chiral nitriles are prevalent structural motifs in natural products, drugs, and pharmaceutically active compounds. In addition, because the cyano group can undergo various diversifying reactions,...

We report carbonyl-stabilized phosphorus ylides as general and efficient catalysts for the cyanosilylation of ketones. The N,N-diethylacetamide derived phosphorane is identified as an extremely eff...

We report that phosphorane can activate (salen)TiCl2 complex to achieve unprecedented excellent enantioselectivity and a broad substrate scope in the cyanation of nitroolefins. Our cyanating reagent Me2(CH2Cl)SiCN proves to be more active than TMSCN in this reaction, allowing 11 β-aliphatic nitrolefins and 12 β-CF3 nitroolefins (either β-aryl or aliphatic) to work well to give the corresponding tertiary or quaternary β-nitronitriles with high to excellent enantioselectivity.

Observations and numerical simulations have shown that outflows generally exist in the accretion process. We revisit the thermal equilibrium solutions of black hole accretion flows by including the role of outflows. Our study focuses on the comparison of the cooling rate of outflows with that of advection. Our results show that, except for the inner region, outflows can dominate over advection in a wide range of the flow, which is in good agreement with previous numerical simulations. We argue that an advection-dominated inner region together with an outflow-dominated outer region should be a general radial distribution for both super-Eddington accretion flows and optically thin flows with low accretion rates., Comment: 9 pages, 4 figures, accepted for publication in ApJ

We report that phosphorane can activate (salen)TiCl

Herein, we design and synthesize an array of benzofuro[3,2-c]quinolines starting from 3-(2-methoxyphenyl)quinolin-4(1H)ones via a sequential chlorination/demethylation, intramolecular cyclization pathway. This sequential transformation was efficient, conducted under metal-free and mild reaction conditions, and yielded corresponding benzofuro[3,2-c]quinolines in high yields. In vitro biological evaluation indicated that such type of compounds showed excellent antileukemia activity and selectivity, and therefore may offer a promising hit compound for developing antileukemia compounds.

The convergent synthesis of two biologically significant classes of trisubstituted hexahydroimidazo[1,2-a]pyridine and 1,4-diazepane derivatives from readily available aromatic aldehydes, ketones, and ethane-1,2-diamine is reported. This protocol is promoted by the highly effective l-phenylalanine triflate catalyst through intermolecular annulation, and tolerates a variety of functional groups with excellent yields.

An Alice-Bob Kadomtsev-Petviashivili (ABKP) equation with shifted-parity ( P ^ s x parity with a shift for the space variable x) and delayed time reversal ( T ^ d , time reversal with a delay) symmetries is investigated. The multi-soliton solutions with three arbitrary even or odd functions are found from the P ^ s x T ^ d symmetry reductions of a coupled local KP system. The result shows that for the ABKP equation with P ^ s x T ^ d nonlocality, the odd numbers of solitons are prohibited. The solitons of the ABKP must be paired. For the ABKPII equation, there exists a critical value of wave numbers for the existence of paired solitons. For the ABKPI equation, there are two types of “breather” excitations. A lump solution of the ABKPI may possess four, five or six leaves.

The first catalytic asymmetric thioacetalization of salicylaldehyde and dithiol is reported.

We report here the first catalytic asymmetric thioacetalization of salicylaldehyde and dithiol. Chiral phosphoric acid STRIPC5is identified as a powerful catalyst for this reaction to afford various chiral dithioacetals in high to excellent yields and enantioselectivities under mild conditions.

Functionally graded piezoelectric ceramics (FGM) plates are attractive due to their ability to broaden the frequency bandwidth of the ultrasonic transducers. A resistivity gradient La-doped Lead Zirconate Titanate/Al-doped Zinc Oxide (La-PZT/Al-ZnO) piezoelectric ceramics plate was developed using a powder metallurgical process. Grading of the piezoelectric modulus across the plate was experimentally confirmed by the electrical impedance analysis and its gradient distribution was characterized using the profile-technique. The distribution of Zn2+ ions in the PZT region was examined using EPMA, XRD and SEM/EDX, respectively. Analysis results show that the gradient distributions of structural and electrical properties inside the FGM plate are mainly caused by the diffusion and aggregation of Zn2+ ions in the PZT layer. The functionally graded piezoelectric ceramics plate presented here will be useful for broadening the frequency bandwidth of piezoelectric transducers.

Perovskite Neodymium-modified Bi4Ti3O12 (BNdT) thin films were prepared on Pt/TiO2/SiO2/Si substrates by the pulsed laser deposition (PLD) technique, and their structures and ferroelectric properties were investigated. The remnant polarization was increased with Nd-modification. The remanent polarization (2Pr) and coercive field (2Ec) of BNdT thin films are 78 μC/cm2 and 619 kV/cm, respectively. The good fatigue behavior of BNdT films has been obtained. The reduction of remanent polarization of +Pr and -Pr is smaller than 25 % after 1010 switching cycles. The effect of substrate temperature and laser repetition frequency on the structure and ferroelectric properties is remarkable.© (2004) COPYRIGHT SPIE--The International Society for Optical Engineering. Downloading of the abstract is permitted for personal use only.

6at.% Al-doped Ba0.6Sr0.4TiO3 (BSTA) thin films were grown on Ir∕MgO-buffered Si(001) substrates by in situ pulsed-laser deposition techniques. All-epitaxial growth of BSTA∕Ir∕MgO∕Si(001) heterostructures with layer-by-layer mode was evidenced by in situ reflection high-energy electron-diffraction observation and x-ray diffraction. The epitaxy relationship was determined as: BSTA⟨100⟩‖Ir⟨100⟩MgO⟨100⟩‖Si⟨100⟩ (in-plane) and BSTA(001)‖Ir(001)MgO(001)‖Si(001) (out-of-plane). The BSTA thin films exhibit an extremely smooth surface with a roughness of RMS=0.89nm. The largely reduced leakage current for BSTA thin films, which was dominated by the Schottky emission mechanism, might be attributed to combination effects of the crystal-structure-perfection and acceptor Al doping. Moreover, the BSTA thin films show good dielectric properties at low-frequency regime.