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.

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.

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.

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.

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 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.

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.

Accurate programmed multifunctional nano-missiles for self-promoted deep delivery and synergistic cascade tumor therapy: Tactfully collaborating chemosynthesis with tumor microenvironment remodeling.

Rationale: Triple-negative breast cancer (TNBC) is considered one of the highest-risk subtypes of breast cancer and has dismal prognosis. The management of aggressive TNBC remains a formidable challenge. Tumor microenvironment (TME), with the unique features, which can serve as the "soil" for the growth and survival of tumor cells (the "seeds"), plays an important regulatory role in the occurrence, proliferation and metastasis of tumors. Catalytic tumor therapy, which can destroy the homeostasis of TME, affect the occurrence and progress of tumors in an all-round way and further magnify chemotherapy, is a quite potential tactic for TNBC-treatment. Methods: Herein, accurate programmed multifunctional cascade nano-missiles (GOx+L-Arg-NM/PTX-NM) composed of novel intelligent all-in-one "nano-rocket" (the drug delivery system) and "ammunitions" (the therapeutic agents) are innovatively constructed by mimicking the functionalities of military precision-guided missiles. Ammunitions can be precisely and effectively transported to the core region of TNBC (the "battlefield") by organic modification on the surface of nano-rocket via chemical means. Once successfully internalized by TNBC cells, the nano-missiles can automatically trigger relevant cascade reactions without external stimulation, prominently disrupt the homeostasis of TME, and produce a "bomb-like" attack on tumors, further promoting the chemotherapy. Results: Both in vitro and in vivo investigations indicated that the innovative nano-missiles could deliver ammunitions to the core area of TNBC to the utmost extent, dramatically ablate tumor and restrain tumor metastasis via orchestrated multimodal synergistic starvation/oxidation/gas/chemotherapy. Conclusion: The well-designed multifunctional nano-missiles may emerge as a new paradigm to suppress the malignant proliferation and metastasis of TNBC, offering a promising approach for the next generation cancer therapy.

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.

Investigation of functionalised nanoplatforms using branched-ligands with different chain lengths for glioblastoma targeting.

Glioblastoma, a common malignancy of the central nervous system, is the most destructive type of brain cancer. Clinical treatment remains a major challenge due to high infiltrative growth and the presence of the blood brain barrier (BBB). Therefore, advanced nanoplatforms that can efficiently cross the BBB and target brain tumours are highly desired. Compared with the targeting efficiency of single ligand nanoplatforms, dual targeting nanoplatforms may lead to better and controllable malignant cell selectivity. In this study, based on our previous research of branched ligands, we finally determined to use tri-branched glucose and two-branched biotin as targeting molecules, and in order to explore the synergetic-targeting capabilities and the mutual influence between the length of the two ligands, we designed three kinds of two-branched biotin ligands with a different linker and co-modified with the tri-branched glucose ligands on the surface of liposomes. The results of in vivo and in vitro experiments showed the (Glu3+Bio2)-2-Lip can exert the greatest synergistic targeting ability. The application of branched ligands, the dual-targeting design concept, and the exploration of the interaction between the chain lengths of the two ligands have brought new ideas and new methods for the targeted therapy of glioma.

Synthesis of medium-ring lactams and macrocyclic peptide mimetics via conjugate addition/ring expansion cascade reactions.

A novel conjugate addition/ring expansion (CARE) cascade reaction sequence is reported that enables medium-sized ring and macrocyclic bis-lactams to be prepared from primary amines and cyclic imides. The reactions are simple to perform, generally high yielding, and very broad in scope, especially with respect to the primary amine component. CARE reactions can also be performed iteratively, enabling ß-peptoid-based macrocyclic peptide mimetics to be 'grown' via well controlled, sequential 4-atom ring expansion reactions, with the incorporation of varied functionalised amines during each iteration.

pH-redox responsive cascade-targeted liposomes to intelligently deliver doxorubicin prodrugs and lonidamine for glioma.

To synergistically treat glioma with a combination chemotherapy, we design and prepare novel cascade-targeted liposomes (Lip-TPGS) using glucose and triphenylphosphonium (TPP) as targeting moieties, which could intelligently deliver redox-sensitive doxorubicin (DOX) prodrugs (SDOX) and chemotherapeutic sensitizer lonidamine (LND). The pH-responsive ligand Chol-TPG modified by PEGylated glucose can overcome the blood-brain barrier and reach tumor cells. Combined with the modification of mitochondria targeting ligand (Chol-TPP), Lip-TPGS are endowed with pH-responsive charge regulation function and multi-stage targeting abilities. After triggered by the excessive glutathione in tumor cells, Lip-TPGS could sufficiently release the parent drugs DOX, which would significantly reduce side effects without compromising anti-glioma efficacy. Therefore, Lip-TPGS possess these characteristics: good pharmacokinetic behavior, superior brain targeting ability, specific tumor recognition and internalization capability, and strong endo/lysosome escaping and mitochondria targeting potential. Furthermore, Lip-TPGS exhibit significant advantages on anti-glioma by inhibiting proliferation, promoting apoptosis, inducing mitochondria dysfunction, inhibiting migration and invasion, prolonging the survival time, narrowing tumor areas, limiting lung metastasis, and reducing toxicity to normal organs. In summary, Lip-TPGS, with cascade targeting abilities from tissue/cell to organelle levels and highly controlled drug release properties, would become a promising drug delivery system for glioma treatment.

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.

Three-Component Couplings among Heteroarenes, Difluorocyclopropenes, and Water via C-H Activation.

Three-component couplings have been realized for efficiently constructing various nitrogen-containing skeletons via C-H activation, where difluorocyclopropenes have been first identified as coupling partners. Many substrates including sp2 and sp3 C-H substrates were well tolerated, furnishing the corresponding products in good yields. Furthermore, a catalyst-dependent reaction was also developed, enabling divergent construction of two different frameworks. The application value of these reactions was demonstrated in gram-scale experiments with as little as 1 mol % catalyst.

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.

Two new 5,6-epoxysterols from calcareous marine sponge Leucetta chagosensis.

Chemical investigation on CH2Cl2 extract of the marine sponge Leucetta chagosensis, collected from the South China Sea, afforded two new 5,6-epoxysterols, 5α,6α-epoxycholesta-8(14),22(E)-diene-3ß,7α-diol (1) and (24R)-24-ethyl-5α,6α-epoxycholesta-8(14),22(E)-diene-3ß,7α-diol (2) along with ten known related steroid analogs (3-12). Their structures were elucidated on the basis of NMR spectroscopic analyses, and comparison with the literature. All isolates were tested for cytotoxicity against three tumor cell lines only known compounds 11 and 12 exhibited notable cytotoxic activity against A549 (IC50: 3.0 and 5.6 µM), PC9 (2.0 and 15.6 µM), and MCF-7 (9.4 and 11.8 µM) cell lines, respectively.