Pummerer-like Rearrangement Induced Cascade Reactions: Synthesis of Highly Functionalized Imidazoles.

Imidazoles are among the most important pharmacophores in medicinal chemistry. Herein we report a tandem protocol for the synthesis of highly substituted imidazoles through Pummerer-like rearrangement induced cascade reactions including two carbon-nitrogen bond formations, and concomitant aromatization under mild reaction conditions. This procedure gives imidazole derivatives bearing numerous functional groups and could be used for modifying natural products as well as pharmaceuticals.

The Effects of Angiosome Morphology on Choke Vessels and Flap Necrosis in a Rat Multiterritory Perforator Flap.

BACKGROUND: Although the angiosome concept has been proposed for a long time, very few studies have been done on its morphology. Our study investigated the effects of angiosome morphology on choke vessels and flap necrosis in a rat multiterritory perforator flap. METHODS: Seventy-two male Sprague-Dawley rats were randomly divided into 3 groups (n = 24/group). The flap contained the right iliolumbar, posterior intercostal, and thoracodorsal angiosomes (TDAVs), termed angiosomes I, II, and III, respectively. Only the posterior intercostal artery and iliolumbar vein were preserved in group 1, whereas only the posterior intercostal artery and vein were preserved in group 2, and only the posterior intercostal artery and thoracodorsal vein were preserved in group 3. Distances from angiosome II to angiosome I (II-I), angiosome II to angiosome III (II-III), angiosome I to the caudal side of the flap (I-caudal), and angiosome III to the cranial side of the flap (III-cranial) were measured. Arteriography, flap necrosis, average microvascular density, and vascular endothelial growth factor expression were evaluated. RESULTS: The II-I distance was significantly greater than that of II-III (3.853 ± 0.488 versus 3.274 ± 0.433 cm, P = 0.012), whereas the distance of I-caudal resembled that of III-cranial (1.062 ± 0.237 versus 0.979 ± 0.236 cm, P = 0.442). The iliolumbar and posterior intercostal angiosomes were multidirectional, whereas the TDAV was craniocaudal and unidirectional. Seven days after the operation, the choke arteries had transformed into true anastomotic arteries. Flap necrosis was lowest in group 3, followed by group 2, and highest in group 1 (10.5% ± 2.4% versus 18.3% ± 3.5% versus 25.5% ± 4.6%, P < 0.01), whereas group 3 showed the highest microvascular density and vascular endothelial growth factor expression, in contrast to groups 2 and 1, with the lowest. CONCLUSIONS: The choke vessel adjacent to the craniocaudal and unidirectional TDAV significantly blocked venous return. Increasing venous return may reduce the necrosis.

Cytotoxicity of 4 Wild Mushrooms in a Case of Yunnan Sudden Unexplained Death.

OBJECTIVES: To explore the cytotoxicity of four wild mushrooms involved in a case of Yunnan sudden unexplained death (YNSUD), to provide the experimental basis for prevention and treatment of YNSUD. METHODS: Four kinds of wild mushrooms that were eaten by family members in this YNSUD incident were collected and identified by expert identification and gene sequencing. Raw extracts from four wild mushrooms were extracted by ultrasonic extraction to intervene HEK293 cells, and the mushrooms with obvious cytotoxicity were screened by Cell Counting Kit-8 (CCK-8). The selected wild mushrooms were prepared into three kinds of extracts, which were raw, boiled, and boiled followed by enzymolysis. HEK293 cells were intervened with these three extracts at different concentrations. The cytotoxicity was detected by CCK-8 combined with lactate dehydrogenase (LDH) Assay Kit, and the morphological changes of HEK293 cells were observed under an inverted phase contrast microscope. RESULTS: Species identification indicated that the four wild mushrooms were Butyriboletus roseoflavus, Boletus edulis, Russula virescens and Amanita manginiana. Cytotoxicity was found only in Amanita manginiana. The raw extracts showed cytotoxicity at the mass concentration of 0.1 mg/mL, while the boiled extracts and the boiled followed by enzymolysis extracts showed obvious cytotoxicity at the mass concentration of 0.4 mg/mL and 0.7 mg/mL, respectively. In addition to the obvious decrease in the number of HEK293 cells, the number of synapses increased and the refraction of HEK293 cells was poor after the intervention of Amanita manginiana extracts. CONCLUSIONS: The extracts of Amanita manginiana involved in this YNSUD case has obvious cytotoxicity, and some of its toxicity can be reduced by boiled and enzymolysis, but cannot be completely detoxicated. Therefore, the consumption of Amanita manginiana is potentially dangerous, and it may be one of the causes of the YNSUD.

Enantioselective Total Synthesis of Spirotryprostatin A.

In this paper, we disclosed a novel enantioselective total synthesis of spirotryprostatin A (1) in 15 steps with a 7.4% total yield from commercially available 2-iodo-5-methoxyaniline and γ-butyrolactone. The key step features of this synthesis include the copper-catalyzed cascade reaction of o-iodoaniline derivatives with alkynone to introduce the quaternary carbon stereocenter and an aza-Michael tandem reaction to construct the spiro[pyrrolidine-3,3'-oxindole] moiety.

Synthesis of 1-pyrroline derivatives via cyclization of terminal alkynes with 2-azaallyls.

An efficient transition-metal-free cyclization reaction to prepare 1-pyrroline derivatives bearing various functional groups is described. In this method, a simple combination of a base and a solvent allows the cyclization reaction of terminal alkynes and 2-azaallyls to be carried out efficiently under mild and metal-free conditions. This cyclization reaction will provide an efficient method for the synthesis of medicinally relevant polysubstituted and multifunctionalized pyrrolines.

Lewis acid mediated cyclization: synthesis of 2 spirocyclohexylindolines.

Herein, we report the synthesis of 2-spirocyclohexylindolines based on a Lewis acid mediated cyclization. This diastereoselective procedure provides the target structures in a straightforward way via dual activation.

Total Synthesis of Dactylicapnosines A and B.

Dactylicapnosines A and B, two natural products from Dactylicapnos scandens, exhibited potent anti-inflammatory and analgesic activities both in vitro and in vivo. In this paper, we report our second-generation synthesis of dactylicapnosine A and the first total synthesis of dactylicapnosine B. Our synthetic route features acid-induced isomerization of o-quinone (16), Co-mediated regioselective ring contraction of p-quinone (8b), and oxidative methoxylation of enone (18). This modified sequence provides dactylicapnosine A in 14 steps with an overall yield of 12% from a known compound (14a) and also offers opportunities to synthesize dactylicapnosine-like analogues for biological investigations.

Targeting c-met receptor tyrosine kinase by the DNA aptamer SL1 as a potential novel therapeutic option for myeloma.

Hepatocyte growth factor (HGF)/c-met pathway activation has been implicated in the pathogenesis of multiple myeloma (MM), and blocking this pathway has been considered a rational therapeutic strategy for treating MM. Aptamers are single-stranded nucleic acid molecules that fold into complex 3D structures and bind to a variety of targets. Recently, it was reported that DNA aptamer SL1 exhibited high specificity and affinity for c-met and inhibited HGF/c-met signaling in SNU-5 cells. However, as the first c-met-targeted DNA aptamer to be identified, application of SL1 to myeloma treatment requires further investigation. Here, we explore the potential application of SL1 in MM. Our results indicated that c-met expression is gradually increased in MM patients and contributes to poor outcomes. SL1 selectively bound to c-met-positive MM cells but not to normal B cells and suppressed the growth, migration and adhesion of MM cells in vitro in a co-culture model performed with HS5 cells, wherein SL1 inhibited HGF-induced activation of c-met signaling. In vivo and ex vivo fluorescence imaging showed that SL1 accumulated in the c-met positive tumour areas. In addition, SL1 was active against CD138+ primary MM cells and displayed a synergistic inhibition effect with bortezomib. Collectively, our data suggested that SL1 could be beneficial as a c-met targeted antagonist in MM.

Enantioselective Total Synthesis of (+)-Nocardioazine B.

In this paper, we report an enantioselective total synthesis of (+)-nocardioazine B, a prenylated hexahydropyrrolo[2,3- b]indole (HPI) alkaloid with a central 2,5-diketopiperazine (DKP) ring. The key step in our synthetic route is a copper-catalyzed sequential arylation-alkylation of o-haloanilide derivatives. Based on this transformation, the construction of C3 all-carbon quaternary stereocenters presented in the HPI systems was achieved with high yields and excellent diastereoselectivity.

Synthesis and anti-proliferative activity of allogibberic acid derivatives containing 1,2,3-triazole pharmacophore.

Sixty novel allogibberic acid derivatives containing 1,2,3-triazole pharmacophore were designed and synthesized. The key chemical processes include aromatization of the A ring in gibberellins, formation of allogibberic azides and its copper mediated Huisgen 1,3-dipolar cycloaddition with alkynes. A number of hybrids containing α,ß-unsaturated ketone moiety exhibited excellent in vitro cytotoxic activities. Some of the hybrids were more selective to MCF-7 and SW480 cell lines with IC50 values at least 8-fold more cytotoxic than cisplatin (DDP). The most potent compounds C43 and C45 are more cytotoxic than cisplatin (DDP) against all tested five tumor cell lines, with IC50 values of 0.25-1.72 µM. Mechanism of action studies indicated that allogibberic-triazole derivative C45 could induce the S phase cell cycle arrest and apoptosis in SMMC-7721 cell lines.

Charge Transport between Coupling Colloidal Perovskite Quantum Dots Assisted by Functional Conjugated Ligands.

Long alkyl-chain capping ligands are indispensable for preparing stable colloidal quantum dots. However, its insulating feature blocks efficient carrier transport among QDs, leading to inferior performance in light-emitting diodes (LEDs). The trade-off between conductivity and colloidal stability of QDs has now been overcome. Methylamine lead bromide (MAPbBr3 ) QDs with a conjugated alkyl-amine, 3-phenyl-2-propen-1-amine (PPA), as ligands were prepared. Owing to electron cloud overlapping and the delocalization effect of conjugated molecules, the conductivity and carrier mobility of PPA-QDs films increased almost 22 times over that of OA-QD films without compromising colloidal stability and photoluminescence. PPA-QDs LEDs exhibit a maximum current efficiency of 9.08 cd A-1 , which is 8 times of that of OA-QDs LEDs (1.14 cd A-1 ). This work provides critical solution for the poor conductivity of QDs in applications of energy-related devices.

DNA ligase III is critical for mtDNA integrity but not Xrcc1-mediated nuclear DNA repair.

DNA replication and repair in mammalian cells involves three distinct DNA ligases: ligase I (Lig1), ligase III (Lig3) and ligase IV (Lig4). Lig3 is considered a key ligase during base excision repair because its stability depends upon its nuclear binding partner Xrcc1, a critical factor for this DNA repair pathway. Lig3 is also present in the mitochondria, where its role in mitochondrial DNA (mtDNA) maintenance is independent of Xrcc1 (ref. 4). However, the biological role of Lig3 is unclear as inactivation of murine Lig3 results in early embryonic lethality. Here we report that Lig3 is essential for mtDNA integrity but dispensable for nuclear DNA repair. Inactivation of Lig3 in the mouse nervous system resulted in mtDNA loss leading to profound mitochondrial dysfunction, disruption of cellular homeostasis and incapacitating ataxia. Similarly, inactivation of Lig3 in cardiac muscle resulted in mitochondrial dysfunction and defective heart-pump function leading to heart failure. However, Lig3 inactivation did not result in nuclear DNA repair deficiency, indicating essential DNA repair functions of Xrcc1 can occur in the absence of Lig3. Instead, we found that Lig1 was critical for DNA repair, but acted in a cooperative manner with Lig3. Additionally, Lig3 deficiency did not recapitulate the hallmark features of neural Xrcc1 inactivation such as DNA damage-induced cerebellar interneuron loss, further underscoring functional separation of these DNA repair factors. Therefore, our data reveal that the critical biological role of Lig3 is to maintain mtDNA integrity and not Xrcc1-dependent DNA repair.

Differential DNA damage signaling accounts for distinct neural apoptotic responses in ATLD and NBS.

The MRN complex (Mre11/RAD50/NBS1) and ATM (ataxia telangiectasia, mutated) are critical for the cellular response to DNA damage. ATM disruption causes ataxia telangiectasia (A-T), while MRN dysfunction can lead to A-T-like disease (ATLD) or Nijmegen breakage syndrome (NBS). Neuropathology is a hallmark of these diseases, whereby neurodegeneration occurs in A-T and ATLD while microcephaly characterizes NBS. To understand the contrasting neuropathology resulting from Mre11 or Nbs1 hypomorphic mutations, we analyzed neural tissue from Mre11(ATLD1/ATLD1) and Nbs1(DeltaB/DeltaB) mice after genotoxic stress. We found a pronounced resistance to DNA damage-induced apoptosis after ionizing radiation or DNA ligase IV (Lig4) loss in the Mre11(ATLD1/ATLD1) nervous system that was associated with defective Atm activation and phosphorylation of its substrates Chk2 and p53. Conversely, DNA damage-induced Atm phosphorylation was defective in Nbs1(DeltaB/DeltaB) neural tissue, although apoptosis occurred normally. We also conditionally disrupted Lig4 throughout the nervous system using Nestin-cre (Lig4(Nes-Cre)), and while viable, these mice showed pronounced microcephaly and a prominent age-related accumulation of DNA damage throughout the brain. Either Atm-/- or Mre11(ATLD1/ATLD1) genetic backgrounds, but not Nbs1(DeltaB/DeltaB), rescued Lig4(Nes-Cre) microcephaly. Thus, DNA damage signaling in the nervous system is different between ATLD and NBS and likely explains their respective neuropathology.

ATR maintains select progenitors during nervous system development.

The ATR (ATM (ataxia telangiectasia mutated) and rad3-related) checkpoint kinase is considered critical for signalling DNA replication stress and its dysfunction can lead to the neurodevelopmental disorder, ATR-Seckel syndrome. To understand how ATR functions during neurogenesis, we conditionally deleted Atr broadly throughout the murine nervous system, or in a restricted manner in the dorsal telencephalon. Unexpectedly, in both scenarios, Atr loss impacted neurogenesis relatively late during neural development involving only certain progenitor populations. Whereas the Atr-deficient embryonic cerebellar external germinal layer underwent p53- (and p16(Ink4a/Arf))-independent proliferation arrest, other brain regions suffered apoptosis that was partially p53 dependent. In contrast to other organs, in the nervous system, p53 loss did not worsen the outcome of Atr inactivation. Coincident inactivation of Atm also did not affect the phenotype after Atr deletion, supporting non-overlapping physiological roles for these related DNA damage-response kinases in the brain. Rather than an essential general role in preventing replication stress, our data indicate that ATR functions to monitor genomic integrity in a selective spatiotemporal manner during neurogenesis.

Transition-Metal-Free Oxyfluorination of Olefinic Amides for the Synthesis of Fluorinated Heterocycles.

A series of fluorinated 4H-3,1-benzoxazines and iminoisobenzofurans have been synthesized through the electrophilic fluorocyclization of olefinic amides. This methodology is highlighted by its mild conditions, wide substrate scope, and good functional group tolerance.

miR-34 is associated with poor prognosis of patients with gallbladder cancer through regulating telomere length in tumor stem cells.

miR-34a has been identified as a tumor suppressor in several tumors, but its involvement in gallbladder cancer (GBC) has not been reported. In this study, the miR-34a level and telomere length were measured in 77 gallbladder adenocarcinomas and 36 peritumoral tissues by real-time PCR. Forced miR-34a expression was established by an adenovirus carrying a miR-34a expression cassette. The colony-forming ability of isolated CD44+CD133+ GBC tumor stem-like cells was measured by matrigel colony assay. The xenograft tumor models were established by inoculating nude mice with CD44+CD133+cells. Results showed that significantly lower miR-34a expression and longer telomere length were observed in gallbladder adenocarcinoma tissues, which correlated with poor prognosis of GBC patients. Forced overexpression of miR-34a inhibited the colony-forming ability of CD44+CD133+ GBC tumor stem-like cells in vitro and xenograft tumor growth in vivo. Injection of Ad-miR-34a downregulated PNUTS expression and reduced telomere length in xenograft GBC tumor cells. In conclusion, miR-34a is a tumor suppressor in gallbladder cancer. Both low miR-34a expression and long telomere length are markers for poor prognosis of patients with gallbladder adenocarcinoma. Our study also suggests that the miR-34a gene could be a target for targeting therapy of GBC.

Design, synthesis and aromatase inhibitory activities of novel indole-imidazole derivatives.

A series of novel indole-imidazole derivatives have been prepared and evaluated in vitro on the aromatase inhibitory activities. The results suggested that proton or a small electron-withdrawing group at para-position of the phenyl ring would enhance the inhibitory activities and any bulky group should be avoided in order to keep a relative small volume for this kind of molecules.

Local atomic structure studies of Zr55Cu35Al10 alloy around Tg.

As a result of examining the structure of Zr55Cu35Al10 alloy around the glass transition temperature (Tg) using the classical molecular dynamics simulations, it was proven that the atomic bonds in the interconnecting zones (i-zones) became loose with the small amount of energy absorption, and it became free volumes easily when the temperature approached Tg. Instead of i-zones, when clusters were largely separated by free volume networks, the solid amorphous structure was converted into supercooled liquid state, resulting in a sharp strength reduce and the great plasticity change from a limited plastic deformation to superplasticity.

Photoinduced Borylation of the Inert C(sp3)-O Bond of Alkyl Heteroaryl Ethers.

A photoinduced reductive Calkyl-O borylation of alkyl heteroaryl ethers with very negative reduction potential in the presence of 4-dimethylaminopyridine (DMAP) and bis(catecholato)diborane(B2cat2) was developed. Despite the high reducing power, various substrates with liable functional groups were well-tolerated as well as ethers derived from natural products and medicinal-relevant compounds. Mechanistic investigation implied that an intra-single electron transfer process in an electron donor-acceptor complex formed from ethers with the adduct of B2cat2 and DMAP should be involved.

Characteristics, health risks, and premature mortality attributable to ambient air pollutants in four functional areas in Jining, China.

Air pollution is one of the leading causes for global deaths and understanding pollutant emission sources is key to successful mitigation policies. Air quality data in the urban, suburban, industrial, and rural areas (UA, SA, IA, and RA) of Jining, Shandong Province in China, were collected to compare the characteristics and associated health risks. The average concentrations of PM2.5, PM10, SO2, NO2, and CO show differences of -3.87, -16.67, -19.24, -15.74, and -8.37% between 2017 and 2018. On the contrary, O3 concentrations increased by 4.50%. The four functional areas exhibited the same seasonal variations and diurnal patterns in air pollutants, with the highest exposure excess risks (ERs) resulting from O3. More frequent ER days occurred within the 25-30°C, but much larger ERs are found within the 0-5°C temperature range, attributed to higher O3 pollution in summer and more severe PM pollution in winter. The premature deaths attributable to six air pollutants can be calculated in 2017 and 2018, respectively. Investigations on the potential source show that the ER of O3 (r of 0.86) had the tightest association with the total ER. The bivariate polar plots indicated that the highest health-based air quality index (HAQI) in IA influences the HAQI in UA and SA by pollution transport, and thus can be regarded as the major pollutant emission source in Jining. The above results indicate that urgent measures should be taken to reduce O3 pollution taking into account the characteristics of the prevalent ozone formation regime, especially in IA in Jining.