Palladium(0) π-Lewis Base Catalysis: Concept and Development.

The development of a new catalytic strategy plays a vital role in modern organic chemistry since it permits bond formation in an unprecedented and more efficient manner. Although the application of preformed metal complexes as π-base-activated reagents have enabled diverse transformations elegantly, the concept and strategy by directly utilizing transition metals as efficient π-Lewis base catalysts remain underdeveloped, especially in the field of asymmetric catalysis. Here, we outline our perspective on the discovery of palladium(0) as an efficient π-Lewis base catalyst, which is capable of increasing the highest occupied molecular orbital (HOMO) energy of both electron-neutral and electron-deficient 1,3-dienes and 1,3-enynes upon flexible η2-complexes formed in situ and resultant π-backdonation. Thus, fruitful carbon-carbon-forming reactions with diverse electrophiles can be achieved enantioselectively in a vinylogous addition pattern, which is conceptually different from the classical oxidative cyclization mechanism. Emphasis will be given to the concept and mechanism elucidation, catalytic features, and reaction design together with perspective on the further development of this emerging field.

Facile construction of benzofulvene frameworks via a palladium-catalysed three-component reaction.

Here we report a three-component reaction of 2-formylarylboronic acids, N-sulfonyl amines and 1,3-enynes, proceeding through a cascade imine formation/Pd0-catalysed vinylogous addition/intramolecular Suzuki coupling/isomerization process. This protocol exhibited broad substrate scope and good functionality tolerance, and a spectrum of multifunctionalised benzofulvene derivatives were furnished in moderate to good yields and E/Z-selectivity.

Targeting cytohesin-1 suppresses acute myeloid leukemia progression and overcomes resistance to ABT-199.

Adhesion molecules play essential roles in the homeostatic regulation and malignant transformation of hematopoietic cells. The dysregulated expression of adhesion molecules in leukemic cells accelerates disease progression and the development of drug resistance. Thus, targeting adhesion molecules represents an attractive anti-leukemic therapeutic strategy. In this study, we investigated the prognostic role and functional significance of cytohesin-1 (CYTH1) in acute myeloid leukemia (AML). Analysis of AML patient data from the GEPIA and BloodSpot databases revealed that CYTH1 was significantly overexpressed in AML and independently correlated with prognosis. Functional assays using AML cell lines and an AML xenograft mouse model confirmed that CYTH1 depletion significantly inhibited the adhesion, migration, homing, and engraftment of leukemic cells, delaying disease progression and prolonging animal survival. The CYTH1 inhibitor SecinH3 exerted in vitro and in vivo anti-leukemic effects by disrupting leukemic adhesion and survival programs. In line with the CYTH1 knockdown results, targeting CYTH1 by SecinH3 suppressed integrin-associated adhesion signaling by reducing ITGB2 expression. SecinH3 treatment efficiently induced the apoptosis and inhibited the growth of a panel of AML cell lines (MOLM-13, MV4-11 and THP-1) with mixed-lineage leukemia gene rearrangement, partly by reducing the expression of the anti-apoptotic protein MCL1. Moreover, we showed that SecinH3 synergized with the BCL2-selective inhibitor ABT-199 (venetoclax) to inhibit the proliferation and promote the apoptosis of ABT-199-resistant leukemic cells. Taken together, our results not only shed light on the role of CYTH1 in cell-adhesion-mediated leukemogenesis but also propose a novel combination treatment strategy for AML.

Lethal pulmonary thromboembolism in mice induced by intravenous human umbilical cord mesenchymal stem cell-derived large extracellular vesicles in a dose- and tissue factor-dependent manner.

Mesenchymal stem cell-derived extracellular vesicles (MSC-EVs) have obvious advantages over MSC therapy. But the strong procoagulant properties of MSC-EVs pose a potential risk of thromboembolism, an issue that remains insufficiently explored. In this study, we systematically investigated the procoagulant activity of large EVs derived from human umbilical cord MSCs (UC-EVs) both in vitro and in vivo. UC-EVs were isolated from cell culture supernatants. Mice were injected with UC-EVs (0.125, 0.25, 0.5, 1, 2, 4 µg/g body weight) in 100 µL PBS via the tail vein. Behavior and mortality were monitored for 30 min after injection. We showed that these UC-EVs activated coagulation in a dose- and tissue factor-dependent manner. UC-EVs-induced coagulation in vitro could be inhibited by addition of tissue factor pathway inhibitor. Notably, intravenous administration of high doses of the UC-EVs (1 µg/g body weight or higher) led to rapid mortality due to multiple thrombus formations in lung tissue, platelets, and fibrinogen depletion, and prolonged prothrombin and activated partial thromboplastin times. Importantly, we demonstrated that pulmonary thromboembolism induced by the UC-EVs could be prevented by either reducing the infusion rate or by pre-injection of heparin, a known anticoagulant. In conclusion, this study elucidates the procoagulant characteristics and mechanisms of large UC-EVs, details the associated coagulation risk during intravenous delivery, sets a safe upper limit for intravenous dose, and offers effective strategies to prevent such mortal risks when high doses of large UC-EVs are needed for optimal therapeutic effects, with implications for the development and application of large UC-EV-based as well as other MSC-EV-based therapies.

The vascular risk factors and vascular neuropathology in subjects with autopsy-confirmed dementia with Lewy bodies.

BACKGROUND: The frequency of vascular risk factors (VRFs) and the relationship between vascular pathology and cognitive function in neurodegenerative disease remains incompletely understood. OBJECTIVE: The purpose of this study was to describe the frequency of VRFs and vascular pathology and explore the relationship between vascular pathology and cognitive function in dementia with Lewy bodies (DLB). METHODS: This study included 363 autopsy-confirmed DLB and 753 Alzheimer's disease (AD) patients from the National Alzheimer's Coordinating Center (NACC) database. We used chi-squared test and analysis of variance to compare the VRFs and related factors in DLB and AD. Multinomial logistic regression and Spearman's correlation test were used to examine the relationship between vascular pathology and cognitive function. RESULTS: No significant differences of VRFs were identified between DLB and AD. Alzheimer's disease patients had higher rates of microinfarcts (23.5% vs. 16.3%, p = 0.005) and moderate to severe amyloid angiopathy (45.9% vs. 36.1%, p = 0.002). In DLB patients, only cerebral amyloid angiopathy (CAA) pathology was negatively correlated with memory domain (r = -0.263, p < 0.001) and language (r = -0.112,p = 0.034). The rates of APOE ε4 allele carriers (60.0% vs. 44.9%, p = 0.004) and CAA pathology (45.9% vs.23.4%, p < 0.001) were much higher in the group with an intermediate likelihood of DLB than in the group with a high likelihood. There was a negative correlation between CAA pathology and memory (logical memory) in the group with an intermediate likelihood of DLB. CONCLUSION: No difference of VRFs was identified between autopsy-confirmed DLB and AD. Cerebral amyloid angiopathy was shown to be an important pathology in DLB, which specifically correlated with memory and language. The groups with high and intermediate likelihood of DLB differed in terms of CAA pathology, and CAA pathology may play an important role in the development of DLB.

Association between marital status and cognitive impairment based on a cross-sectional study in China.

BACKGROUND: Marital status may have an impact on the elderly population's health, but few studies in China discussed about the association between marital status and cognitive impairment. OBJECTIVE: To investigate the relationship between marital status and cognitive impairment. To compare the influences of marital status on dementia between men and women. METHODS: This study was based on a representative national cross-sectional epidemiological survey in China. We randomly selected 13 provinces and municipalities and included 19,276 participants aged 65 years or older in our study. Data was collected by interviewing the participants about their sociodemographic characteristics, and neuropsychological testing was administered to the participants by neurologists. To analyze the association between marital status and cognitive impairment, multiple logistic regression was based on a series of models. RESULTS: Among the 19,276 subjects, about 77.2% were married, 1.6% were single, 21.2% were divorced/separated or widowed. The odds ratios (OR) of dementia were higher in single (OR: 2.13, CI: 1.53-2.97; p < 0.001), divorced/separated/widowed when they were ≤55 years old (OR: 1.75, CI: 1.30-2.35; p < 0.001), and divorced/separated/widowed when they were >55 years old (OR: 1.16, CI: 1.03-1.31; p < 0.001) participants than in married ones. Divorced/separated/widowed ≤55 men had about 2.75 times increase in dementia risk than married men. CONCLUSION: People with long-term divorced/separated/widowed status would be associated to cognitive impairment more than those with short-term divorced/separated/widowed status. Men may be affected by marriage disruption more than women in terms of increasing the risk of dementia.

The transplantation of rapamycin-treated senescent human mesenchymal stem cells with enhanced proangiogenic activity promotes neovascularization and ischemic limb salvage in mice.

Few therapies can reverse the proangiogenic activity of senescent mesenchymal stromal/stem cells (MSCs). In this study, we investigated the effects of rapamycin on the proangiogenic ability of senescent human umbilical cord MSCs (UCMSCs). An in vitro replicative senescent cell model was established in cultured UCMSCs. We found that late passage (P25 or later) UCMSCs (LP-UCMSCs) exhibited impaired proangiogenic abilities. Treatment of P25 UCMSCs with rapamycin (900 nM) reversed the senescent phenotype and notably enhanced the proangiogenic activity of senescent UCMSCs. In a nude mouse model of hindlimb ischemia, intramuscular injection of rapamycin-treated P25 UCMSCs into the ischemic limb significantly promoted neovascularization and ischemic limb salvage. We further analyzed the changes in the expression of angiogenesis-associated genes in rapamycin-primed MSCs and found higher expression of several genes related to angiogenesis, such as VEGFR2 and CTGF/CCN2, in primed cells than in unprimed MSCs. Taken together, our data demonstrate that rapamycin is a potential drug to restore the proangiogenic activity of senescent MSCs, which is of importance in treating ischemic diseases and tissue engineering.

[Research progress on chemical constituents and biological activities of Sarcandra glabra].

Sarcandra glabra, a medicinal plant in family Chloranthaceae, has been taken as an important raw material for multiple Chinese patent drugs due to its diverse indications. Considering the diversified chemical constituents and rich biological activities of S. glabra, numerous phytochemical and pharmacodynamic investigations were conducted to explore the material basis for its medicinal use. It has been found that its main chemical constituents were sesquiterpenoids, sesquiterpenoid polymers, phenolic acids, coumarins, and flavonoids. As revealed by pharmacological research, it possesses multiple biological activities like anti-inflammation, anti-bacteria, anti-tumor, anti-oxidation, and neuroprotection. Some unreported novel structures, including polymers of lindenane sesquiterpenes and monoterpenes, sesquiterpene trimers, and adducts of flavonoids and monoterpenes, have been identified from S. glabra in recent years. Moreover, biological studies relating to its anti-tumor, anti-inflammatory, and anti-oxidant activities have been deepened. This paper reviewed the chemical constituents and bioactivities of S. glabra explored over the past ten years, so as to provide a scientific basis for further development and utilization of this plant.

Asymmetric Auto-Tandem Palladium Catalysis for 2,4-Dienyl Carbonates: Ligand-Controlled Divergent Synthesis.

Developing new asymmetric auto-tandem catalysis processes, especially in a divergent manner, is highly attractive but extremely challenging. Presented herein is a palladium-catalyzed auto-tandem reaction between 2,4-dienyl carbonates and o-TsNH arylimines or trifluoroacetophenones that proceeds through a consecutive N-allylation, vinylogous addition, π-σ-π isomerization, and another N-allylation sequence. Importantly, switchable diastereodivergent synthesis could be achieved by tuning the chiral bisphosphine ligands, which led to the construction of a broad spectrum of fused tetrahydroquinoline architectures with moderate to excellent enantioselectivity. Ligand control even enabled effective access to regiodivergent azetidine or chemodivergent ß-H elimination with fair enantioselectivity, further showing the versatility of the current auto-tandem catalysis.

[A new cembranoid diterpene from Olibanum].

Five compounds were isolated from the alcohol extract of Olibanum by MCI, silica gel, ODS, and Sephadex LH-20 column chromatographies and preparative high-performance liquid chromatography(HPLC). On the basis of spectral data and literature data, the compounds were identified as:(1S,3R,4S,7R,11S,12R)-1:12,4:7-diepoxisonane-8(19)-ene-3,11-diol(1), boscartin A(2),(+)-resinolin(3),(+)-5-hydroxy-3,4-dimethyl-5-pentylfuran-2(5H)-one(4), and acerogenin A(5). Compound 1 is a new compound, and compounds 3-5 were isolated from Olibanum for the first time. The structure of compound 1 was determined by spectroscopic analysis and single-crystal X-ray diffraction. Compounds 1 and 2 were tested for PC12 neurotoxicity, and the results showed that they were both safe compounds.

[A new sesquiterpene from Chloranthus henryi].

Eight sesquiterpenes were isolated and purified from the ethanol extract of Chloranthus henryi by column chromatographies over silica gel, ODS and Sephadex LH-20,and preparative HPLC. Their chemical structures were established by spectral data and physiochemical properties as(1S,6S,8S,10R)-8-ethoxy-10-methoxychlomultin C(1),tianmushanol(2),multistalide A(3),myrrhterpenoid N(4),1α,9α-dihydroxy-8,12-expoxy-eudesma-4,7,11-trien-6-one(5),4ß,10α-aromadendranediol(6),oplopanone(7),10α-hydroxycadinan-4-en-3-one(8). Among them, compound(1) was a new compound, and compounds 2-8 were isolated from Chloranthus henryi for the first time.

[Research progress on chemical constituents from Chloranthus plants and their biological activities].

The genus Chloranthus has 13 species and 5 varieties in China, which can be found in the southwest and northeast regions. Phytochemical studies on Chloranthus plants have reported a large amount of terpenoids, such as diterpenoids, sesquiterpenoids, and sesquiterpenoid dimers. Their anti-inflammation, anti-tumor, antifungal, antivirus, and neuroprotection activities have been confirmed by previous pharmacological research. Herein, research on the chemical constituents from Chloranthus plants and their biological activities over the five years was summarized to provide scientific basis for the further development and utilization of Chloranthus plants.

[Chemical constituents of sesquiterpenes from Chloranthus multistachys].

With repeated silica gel, octadecyl silica(ODS), and Sephadex LH-20 column chromatography, normal-phase and reverse-phase high performance liquid chromatography(HPLC), etc., a pair of new enantiomers and 5 known compounds were separated from the 95% ethanol extract of Chloranthus multistachys. These compounds were identified by the nuclear magnetic resonance spectroscopy(including 1 D-NMR and 2 D-NMR), single-crystal X-ray diffraction, circular dichroism(CD) spectroscopy, mass spectrometry(MS), and some other methods as(1R,4R,5R,8S,10R)-chloraeudolide H(1 a),(1S,4S,5S,8R,10S)-chloraeudolide H(1 b), hydroxyisogermafurenolide(2), 4α-hydroxy-5α,8ß(H)-eudesm-7(11)-en-8,12-olide(3), chloraniolide A(4), chlorantene D(5), 4α,8ß-dihydroxy-5α(H)-eudesm-7(11)-en-8,12-olide(6). Compounds 1 a and 1 b are a pair of new eudesmane-type sesquiterpene enantiomers, and compounds 2-4 were isolated from C. multistachys for the first time.

A Double Deprotonation Strategy for Cascade Annulations of Palladium-Trimethylenemethanes and Morita-Baylis-Hillman Carbonates to Construct Bicyclo[3.1.0]hexane Frameworks.

Here we report that the chemoselective activation of Tsuji's 2-(cyanomethyl)allyl carbonates to generate the palladium-trimethylenemethane 1,3-dipoles via a deprotonation strategy can be realized in the presence of Morita-Baylis-Hillman carbonates from substantial activated ketones. The following SN 2'-addition enables the formation of new 1,3-dipole species having an activated alkene moiety through a second deprotonation process, which then undergo cascade [1+2]/[3+2] annulations to furnish complex bicyclic [3.1.0]hexane frameworks having three contiguous quaternary stereogenic centers with good to excellent enantioselectivity. Moreover, by using benzoyl aldehyde-derived substrates, a [1+4]/[3+2] annulation sequence is similarly developed to produce fused cyclopenta[b]furan architectures.

Transformations of Modified Morita-Baylis-Hillman Adducts from Isatins Catalyzed by Lewis Bases.

The development of synthetic protocols to access architectures with broad structural and functional diversity from readily available starting materials is very attractive in both organic and medicinal chemistry fields. Toward this objective, the multifunctional isatin-derived Morita-Baylis-Hillman (MBH) adducts provide opportunities to construct a variety of complex scaffolds containing a "privileged" oxindole motif through several catalytic pathways. By forming the ammonium or phosphonium salts with Lewis bases, isatin-derived MBH adducts can undergo allylic substitutions with a range of nucleophiles, usually in a SN 2'-SN 2' pattern. Besides, assisted by Brønsted bases, the corresponding onium salts can be converted into the allylic ylide intermediates, which can undergo various annulation reactions or even 1,3-difunctionalizations. Moreover, recent cooperative catalysis of Lewis bases and transition metal complexes further puts forward the application of isatin-derived MBH adducts. This tutorial review covers the significant transformations of isatin-derived MBH adducts, mostly in an asymmetric version, catalyzed by various Lewis bases over the past decade.

Pseudo-Stereodivergent Synthesis of Enantioenriched Tetrasubstituted Alkenes by Cascade 1,3-Oxo-Allylation/Cope Rearrangement.

The catalytic diastereodivergent construction of stereoisomers having two or more stereogenic centers has been extensively studied. In contrast, the switchable introduction of another stereogenic element, that is, Z/E configuration involving a polysubstituted alkene group, into the optically active stereoisomers, has not been recognized yet. Disclosed here is the pseudo-stereodivergent synthesis of highly enantioenriched tetrasubstituted alkene architectures from isatin-based Morita-Baylis-Hillman carbonates and allylic derivatives, under the cooperative catalysis of a tertiary amine and a chiral iridium complex. The success of the switchable construction of the tetrasubstituted alkene motif relies on the diastereodivergent 1,3-oxo-allylation reaction between N-allylic ylides and chiral π-allyliridium complex intermediates by ligand and substrate control, followed by the stereoselective concerted 3,3-Cope rearrangement process.

Auto-Tandem Cooperative Catalysis Using Phosphine/Palladium: Reaction of Morita-Baylis-Hillman Carbonates and Allylic Alcohols.

Auto-tandem catalysis (ATC), in which a single catalyst promotes two or more mechanistically different reactions in a cascade pattern, provides a powerful strategy to prepare complex products from simple starting materials. Reported here is an unprecedented auto-tandem cooperative catalysis (ATCC) for Morita-Baylis-Hillman carbonates from isatins and allylic carbonates using a simple Pd(PPh3 )4 precursor. Dissociated phosphine generates phosphorus ylides and the Pd leads to π-allylpalladium complexes, and they undergo a γ-regioselective allylic-allylic alkylation reaction. Importantly, a cascade intramolecular Heck-type coupling proceeds to finally furnish spirooxindoles incorporating a 4-methylene-2-cyclopentene motif. Experimental results indicate that both Pd and phosphine play crucial roles in the catalytic Heck reaction. In addition, the asymmetric versions with either a chiral phosphine or chiral auxiliary are explored, and moderate results are obtained.

Cooperative Tertiary Amine/Chiral Iridium Complex Catalyzed Asymmetric [4+3] and [3+3] Annulation Reactions.

Asymmetric reactions merging organocatalysis and metal catalysis significantly broaden the scope of organic synthesis. Nevertheless, the accomplishment of stereoselective annulations combining two types of dipole species, independently generated from the activations of organocatalysts and metal complexes, still remains as a challenging task. Now, Morita-Baylis-Hillman carbonates from isatins and carbamate-functionalized allyl carbonates could be chemoselectively activated by achiral Lewis basic tertiary amines and chiral iridium complexes. The zwitterionic allylic ylides and 1,4-π-allyliridium dipoles formed in situ are assembled in a highly stereoselective [4+3] annulation pattern. Similar cooperative catalytic strategy could be applied for the reactions of Morita-Baylis-Hillman carbonates and vinyl aziridines, furnishing an asymmetric [3+3] annulation reaction also with excellent stereocontrol.

BCR-ABL1-positive microvesicles malignantly transform human bone marrow mesenchymal stem cells in vitro.

The intercellular communication between leukemia cells and bone marrow mesenchymal stem cells (BM-MSCs) plays more important role in chronic myeloid leukemia (CML) than we previously understood. Recently, we found that microvesicles released from human leukemia cell line K562 (K562-MVs) containing BCR-ABL1 mRNA malignantly transformed normal hematopoietic transplants. Here, we investigated whether K562-MVs contribute to the transformation of human bone marrow mesenchymal stem cells (BM-MSCs). We showed that K562-MVs could be integrated into co-cultured normal BM-MSCs and dose-dependently enhanced the proliferation of BM-MSCs. Meanwhile, K562-MVs (400 ng/mL) significantly increased the expression of BCR-ABL1 in these BM-MSCs, accompanied by the enhanced secretion of TGF-ß1. These BM-MSCs in turn could trigger the TGF-ß1-dependent proliferation of K562 cells. Moreover, we confirmed the presence of BCR-ABL1 in circulating MVs from 11 CML patients. Compared to the normal BM-MSCs, the BM-MSCs from CML patients more effectively increased the BCR-ABL1 expression and TGF-ß1 secretion in K562 cells as well as the proliferation of K562 cells. Our findings enrich the mechanisms involved in the interaction between leukemia cells and BM-MSCs and provide novel ways to monitor minimal residual disease and worthwhile approaches to treat CML.

Serum deprivation elevates the levels of microvesicles with different size distributions and selectively enriched proteins in human myeloma cells in vitro.

AIM: To investigate the effects of serum deprivation (SD) on microvesicles (MVs) secreted from human myeloma cells and the implications for disease progression. METHODS: RPMI 8226, U266, and KM3 human myeloma cells were incubated in medium containing 10% (non-SD) or 1% fetal bovine serum (SD) and MVs were isolated. The levels and size distribution of MVs were analyzed with flow cytometry. The protein profiles of MVs were studied using 2D SDS-PAGE, MALDI-TOF-MS, and Western blotting. NF-κB activation was analyzed using EMSA. Angiogenesis was examined in Eahy926 endothelial cells. RESULTS: Exposure of RPMI 8226 cells to SD for 24 h did not alter the number of apoptotic cells. However, SD increased the number of MVs from RPMI 8226, U266, and KM3 cells to 2.5-, 4.3-, and 3.8-fold, respectively. The size distribution of SD MVs was also significantly different from that of non-SD MVs. Three proteins ZNF224, SARM, and COBL in SD MVs were found to be up-regulated, which were involved in cell cycle regulation, signal transduction and metabolism, respectively. Co-culture of SD MVs and RPMI 8226 cells increased NF-κB activation in the target RPMI 8226 cells. Furthermore, SD MVs from RPMI 8226 cells significantly increased the microtubule formation capacity of Eahy926 endothelial cells compared with non-SD MVs. CONCLUSION: SD elevates the levels of microvesicles with different size distribution and selectively enriched proteins in human myeloma cells in vitro. The selectively enriched proteins, especially ZNF224, may play key roles in regulation of myeloma cells, allowing better adaptation to SD.