Expanding the scope of the successive ring expansion strategy for macrocycle and medium-sized ring synthesis: unreactive and reactive lactams.

New methods are described that expand the scope of the Successive Ring Expansion (SuRE) with respect to synthetically challenging lactams. A protocol has been developed for use with 'unreactive' lactams, enabling SuRE reactions to be performed on subsrates that fail under previously established conditions. Ring expansion is also demonstarted on 'reactive' lactams derived from iminosugars for the first time. The new SuRE methods were used to prepare a diverse array of medium-sized and macrocyclic lactams and lactones, which were evaluted in an anti-bacterial assay against E. coli BW25113WT.

Ring Expansion Strategies for the Synthesis of Medium Sized Ring and Macrocyclic Sulfonamides.

Two new ring expansion strategies are reported for the synthesis of medium sized ring and macrocyclic sulfonamides. Both methods can be performed without using classical protecting groups, with the key ring expansion step initiated by nitro reduction and amine conjugate addition respectively. Each method can be used to make diversely functionalised cyclic sulfonamides in good to excellent yields, in a range of ring sizes. The ring size dependency of the synthetic reactions is in good agreement with the outcomes modelled by Density Functional Theory calculations.

Access to Phosphine-Containing Quinazolinones Enabled by Photo-Induced Radical Phosphorylation/Cyclization of Unactivated Alkenes.

A mild and facile photo-induced cascade radical addition/cyclization of unactivated alkenes has been reported, through which a variety of biologically valuable phosphine-containing quinazolinones could be obtained in moderate to good yields. The protocol was characterized by mild conditions, broad substrate scope, and high atomic economy.

Berberine and folic acid co-modified pH-sensitive cascade-targeted PTX-liposomes coated with Tween 80 for treating glioma.

Chemotherapy is a conventional treatment for glioma, but its efficacy is greatly limited due to low blood-brain barrier (BBB) permeability and lack of specificity. Herein, intelligent and tumor microenvironment (TME)-responsive folic acid (FA) derivatives and mitochondria-targeting berberine (BBR) derivatives co-modified liposome coated with Tween 80 loading paclitaxel (PTX-Tween 80-BBR + FA-Lip) was constructed. Specifically speaking, liposomes modified by FA can be effectively target ed to glioma cells. BBR, due to its delocalized positive electricity and lipophilicity, can be attracted by mitochondrial membrane potential and concentrate on mitochondria to achieve mitochondrial targeting and induce cell apoptosis. By simultaneously modifying the liposome with FA and BBR to deliver drugs, leads to a good therapeutic effect of glioma through FA-based glioma targeting and BBR-based mitochondrial targeting. In addition, the surface of the liposome was coated with Tween 80 to further improve BBB penetration. All results exhibited that PTX-Tween 80-BBR + FA-Lip can observably improve the chemotherapy therapeutic efficacy through the highly specific tumor targeting and mitochondrial targeting, which can provide new ideas and methods for the targeted therapy of glioma.

Optimization of empty container allocation for inland freight stations considering stochastic demand.

In the post-COVID-19 epidemic era (PCEE), the supply of empty containers will face stronger uncertainty. Estimating the amount of self-owned and leased empty containers that need to be allocated to each inland freight station in a specific area becomes a critical issue for liner companies in PCEE. However, owing to the high degree of unpredictability of the demand and the limited flexibility of empty container relocation, the abovementioned issue has not been fully addressed. This paper provides a model for empty container allocation without knowing the probability distribution function of empty container demand in advance. The abovementioned model can jointly optimize the quantities of self-owned empty containers and leased containers allocated to each inland freight station. To solve the model, a largest-debt-first policy is adopted to simplify the complicated model, and a differential evolutionary (DE) algorithm is developed to solve the simplified model. Compared with some commonly used algorithms, DE has advantages considering the ability to explore the optimal solution. In addition, the utility of the largest-debt-first policy proposed in this paper is compared with that of the traditional method. Experimental results show that in the case of high demand fluctuations, the proposed policy is better in controlling the operational and management costs. Overall, the theory and method proposed in this paper can effectively help the carrier set a reasonable regional empty container stock level and determine the number of self-owned and leased empty containers.

Divergent Construction of Diverse Scaffolds through Catalyst-Controlled C-H Activation Cascades of Quinazolinones and Cyclopropenones.

A transition-metal-catalyzed C-H activation cascade strategy to rapidly construct diverse quinazolinone derivatives in a one-pot manner is reported. The catalysts play an important role in the different transformations. Additionally, the procedure is scalable, proceeds with high efficiency and good chemo-/regio-selectivity, and tolerates a range of functional groups.

Influence of transportation network on transmission heterogeneity of COVID-19 in China.

In this paper, we propose a novel approach to model spatial heterogeneity for epidemic spreading, which combines the relevance of transport proximity in human movement and the excellent estimation accuracy of deep neural network. We apply this model to investigate the effects of various transportation networks on the heterogeneous propagation of COVID-19 in China. We further apply it to predict the development of COVID-19 in China in two scenarios, i.e., i) assuming that different types of traffic restriction policies are conducted and ii) assuming that the epicenter of the COVID-19 outbreak is in Beijing, so as to illustrate the potential usage of the model in generating various policy insights to help the containment of the further spread of COVID-19. We find that the most effective way to prevent the coronavirus from spreading quickly and extensively is to control the routes linked to the epicenter at the beginning of the pandemic. But if the virus has been widely spread, setting restrictions on hub cities would be much more efficient than imposing the same travel ban across the whole country. We also show that a comprehensive consideration of the epicenter location is necessary for disease control.

Liposomes actively recognizing the glucose transporter GLUT1 and integrin αv ß3 for dual-targeting of glioma.

The treatment of glioma is a great challenge because of the existence of the blood-brain barrier (BBB). In order to develop an efficient glioma-targeting drug delivery system to greatly improve the brain permeability of anti-cancer drugs and target glioma, a novel glioma-targeted glucose-RGD (Glu-RGD) derivative was designed and synthesized as ligand for preparing liposomes to effectively deliver paclitaxel (PTX) to cross the BBB and target glioma. The liposomes were prepared and characterized for particle size, zeta potential, encapsulation efficiency, release profile, stability, hemolysis, and cell cytotoxicity. Also, the Glu-RGD modified liposomes showed superior targeting ability in in vitro and in vivo evaluation as compared to naked PTX, non-coated, singly modified liposomes and liposomes co-modified by physical blending. The relative uptake efficiency and concentration efficiency were enhanced by 4.41- and 4.72-fold compared to that of naked PTX, respectively. What is more, the Glu-RGD modified liposomes also displayed the maximum accumulation of DiD-loaded liposomes at tumor sites compared to the other groups in in vivo imaging. All the results in vitro and in vivo suggested that Glu-RGD-Lip would be a potential delivery system for PTX to treat integrin αv ß3 -overexpressing tumor-bearing mice.

(-)-Calcaridine B, a new chiral aminoimidazole-containing alkaloid from the marine sponge Leucetta chagosensis.

LC-DAD/MS-based dereplication of organic extract of a calcareous sponge Leucetta chagosensis afforded one new chiral aminoimidazole-containing alkaloid, (-)-calcaridine B (1), along with one achiral imidazole analog leucettamine E (2) as well as one known imidazole derivative (2E, 9E)-pyronaamidine-9-(N-methylimine) (3). Their structures were elucidated on the basis of NMR spectroscopic analyses, and comparing with the literature. The cytotoxic activities of all isolates were evaluated against three human cancer cell lines, and compounds 1 and 3 exhibited mild cytotoxicities toward the MCF-7 cell line with IC50 values of 25.3-24.2 µM, respectively.

Dual-targeting for brain-specific liposomes drug delivery system: Synthesis and preliminary evaluation.

The treatment of glioma has become a great challenge because of the existence of brain barrier (BB). In order to develop an efficient brain targeting drug delivery system to greatly improve the brain permeability of anti-cancer drugs, a novel brain-targeted glucose-vitamin C (Glu-Vc) derivative was designed and synthesized as liposome ligand for preparing liposome to effectively deliver paclitaxel (PTX). The liposome was prepared and its particle size, zeta potential, encapsulation efficiency, release profile, stability, hemolysis and cytotoxicity were also characterized. What's more, the cellular uptake of CFPE-labeled Glu-Vc-Lip on GLUT1- and SVCT2-overexpressed C6 cells was 4.79-, 1.95-, 4.00- and 1.53-fold higher than that of Lip, Glu-Lip, Vc-Lip and Glu + Vc-Lip. Also, the Glu-Vc modified liposomes showed superior targeting ability in vivo evaluation compared with naked paclitaxel, non-coated, singly-modified and co-modified by physical blending liposomes. The relative uptake efficiency was enhanced by 7.53 fold to that of naked paclitaxel, while the concentration efficiency was up to 7.89 times. What's more, the Glu-Vc modified liposomes also displayed the maximum accumulation of DiD-loaded liposomes at tumor sites with the strongest fluorescence in the brain in vivo imaging. Our results suggest that chemical modification of liposomes with warheads of glucose and vitamin C represents a promising and efficient strategy for the development of brain-specific liposomes drug delivery system by utilizing the endogenous transportation mechanism of the warheads.

Imidazole Alkaloids and Their Zinc Complexes from the Calcareous Marine Sponge Leucetta chagosensis.

Five new imidazole derivatives (1-5), together with eight related known alkaloids, were isolated from a calcareous marine sponge, Leucetta chagosensis, collected from the South China Sea. Their structures were fully characterized by spectroscopic methods. Structurally, 1 possesses an unusual skeleton featuring imidazole and oxazolone rings linked via a nitrogen atom, whereas 2 bears an intriguing guanylurea-substituted imidazole ring. Compounds 4 and 5 were identified as zinc complexes; they represent the metal complex analogues of naamidine J (6) and pyronaamidine (7), respectively. Among the isolated compounds, 2 and 5 showed significant inhibitory activities toward the LPS-induced production of IL-6 in the human acute monocytic leukemia cell line THP-1, and 7 displayed cytotoxicity against MCF-7, PC9, A549, and breast cancer stem cells (MCF-7-Oct4-GFP) with IC50 values of 5.2, 5.6, 7.8, and 10 µM, respectively.

Impaired GABA Neural Circuits Are Critical for Fragile X Syndrome.

Fragile X syndrome (FXS) is an inheritable neuropsychological disease caused by silence of the fmr1 gene and the deficiency of Fragile X mental retardation protein (FMRP). Patients present neuronal alterations that lead to severe intellectual disability and altered sleep rhythms. However, the neural circuit mechanisms underlying FXS remain unclear. Previous studies have suggested that metabolic glutamate and gamma-aminobutyric acid (GABA) receptors/circuits are two counter-balanced factors involved in FXS pathophysiology. More and more studies demonstrated that attenuated GABAergic circuits in the absence of FMRP are critical for abnormal progression of FXS. Here, we reviewed the changes of GABA neural circuits that were attributed to intellectual-deficient FXS, from several aspects including deregulated GABA metabolism, decreased expressions of GABA receptor subunits, and impaired GABAergic neural circuits. Furthermore, the activities of GABA neural circuits are modulated by circadian rhythm of FMRP metabolism and reviewed the abnormal condition of FXS mice or patients.

Leucanone A and naamine J, glycerol ether lipid and imidazole alkaloid from the marine sponge Leucandra sp.

Chemical investigation on CH2Cl2 extract of the marine sponge Leucandra sp. afforded two new compounds named leucanone A (1) and naamine J (2), together with eight known compounds (3-10). Their structures were elucidated on the basis of NMR spectroscopic analyses, and comparing with the literature. The cytotoxic activities of the compounds were evaluated against four cancer cell lines, and compound 2 showed mild cytotoxic activities against MCF-7, A549, HeLa, and PC9 cancer cell lines with IC50 values in the range of 20.1-45.3 µM.

Robust nonsticky superhydrophobicity by the tapering of aligned ZnO nanorods.

The robust nonsticky superhydrophobicity of aligned nanoneedle films is reported. A facile, efficient, cheap, and available method based on the diffusion-limited crystal growth principle is proposed for controlling the tapering of ZnO nanorods, the profiles of which can be tuned effectively by synergetic control over reaction time and temperature in an extremely strong alkaline reaction system. The synthesized nanoneedle, nanopencil, and nanorod arrays are chosen for studying the effects of nanoscale topography on anti-droplet-sticking ability. After silanization, all of them show excellent quasi-static anti-droplet-stickiness, and water adhesion along the normal and lateral directions can be greatly reduced by the tapering of nanorods and eliminated by sharp nanoneedles. However, their antisticking stability is distinct under the droplet impact: the nanoneedle sample is still nonsticky but the nanorod sample loses its antisticking ability. Only ensuring the liquid/air interface is in the suspended nonwetting state is insufficient to obtain robust nonsticky surfaces, which also require extremely low solid-liquid van der Waals attraction.

Novel berberine derivatives as p300 histone acetyltransferase inhibitors in combination treatment for breast cancer.

Adenoviral E1A binding protein p300 (EP300 or p300) and its similar paralog, cyclic-AMP response element binding protein (CBP), are important histone acetyltransferases (HAT) and transcriptional co-activators in epigenetics, participating in numerous cellular pathways including proliferation, differentiation and apoptosis. The overexpression or dysregulation of p300/CBP is closely related to oncology-relevant disease. The inhibition of p300 HAT has been found to be a potential drug target. Berberine has been reported to show anticancer activity and synergistic effect in combination with some of the clinical anticancer drugs via modulation of various pathways. Here, the present study sought to discover more chemotypes of berberine derivatives as p300 HAT inhibitors and to examine the combination of these novel analogues with doxorubicin for the treatment of breast cancer. A series of novel berberine derivatives with modifications of A/B/D rings of berberine have been designed, synthesized and screened. Compound 7b was found to exhibit inhibitory potency against p300 HAT with IC50 values of 1.51 µM. Western blotting proved that 7b decreased H3K27Ac and interfered with the expression of oncology-relevant protein in MCF-7 cells. Further bioactive evaluation showed that combination of compound 7b with doxorubicin could significantly inhibit tumor growth and invasion in vitro and in vivo.

The Pyridotriazole Works as a Traceless Directing Group: A C-H Activation/Annulation Cascade Reaction with Iodonium Ylides.

A novel Rh-catalyzed cascade reaction of pyridotriazoles with iodonium ylides is reported. This one-pot procedure involves a triazole-directed ortho-position C-H carbene insertion, followed by intramolecular denitrogenation annulation. It was noteworthy that this reaction provided straightforward access to 1H-isochromene frameworks with excellent yields (up to 94% yield).

Ring expansion reactions of PO-containing molecules.

A series of ring expansion reactions of PO-containing molecules have been developed for the synthesis of medium-sized ring cyclic phosphonate esters and phosphonamidates. The reactivity trends initially appear to be counter-intuitive, compared with more well established ring expansion reactions of lactam derivatives, but are explained by considering the differences in heteroatom bonding to P and C respectively.

Visible-light-mediated synthesis of non-anomeric S-aryl glycosides via a photoactive electron-donor-acceptor complex.

A visible-light-mediated glycosylation reaction between glycosyl redox-active esters and disulfides has been reported, through which a series of S-aryl glycosides were obtained in good yields with satisfactory stereoselectivity. The preliminary mechanistic studies revealed that this transformation proceeded via an EDA complex. Moreover, the potential application value was demonstrated in the late-stage functionalisation of drug molecules and a gram-scale experiment.

Synthesis of Oxo-Bridged Dibenzoazocines through Ruthenium-Catalyzed [4 + 3]-Cycloannulation of Aza-ortho-quinone Methides with Carbonyl Ylides.

Oxo-bridged dibenzoazocines are furnished within a single synthetic step at room temperature via ruthenium-catalyzed [4 + 3]-cycloannulation of aza-ortho-quinone methides with carbonyl ylides. Exclusive diastereoselectivity, excellent yield, mild reaction conditions, and broad substrate scope are distinguishing features of this protocol. The product could be prepared on a gram scale and could be further functionalized into diverse substituted dihydroisobenzofuran derivatives and a dibenzoazocine scaffold.