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The role of PI3K and MAPK pathways in tumor initiation and progression is well established; hence, several inhibitors of these pathways are currently in different stages of clinical trials. Recent studies identified a PI3K/mTOR (PF-04691502) and a MEK inhibitor (PD-0325901) with strong potency and efficacy in different cell lines and tumor models. PD-0325901, however, showed adverse effects when administered at or above MTD (maximum tolerated dose) in the clinic. Here, we show in preclinical models that PD-0325901 at doses well below MTD (sub-MTD 1.5 mg/kg SID) is still a potent compound as single agent or in combination with PF-04691502. We first observed that PD-0325901 at 1.5 mg/kg SID and in combination with PF-04691502 (7.5 mg/kg; SID) significantly inhibited growth of H460 (carry Kras and PIK3CA mutations) orthotopic lung tumors. Additionally, we tested efficacy of PD-0325901 in Kras(G12D-LSL) conditional GEMMs (genetically engineered mouse models) which are a valuable tool in translational research to study tumor progression. Intranasal delivery of adenoviruses expressing Cre recombinase (Adeno-Cre) resulted in expression of mutant Kras leading to development of tumor lesions in lungs including adenomatous hyperplasia, large adenoma, and adenocarcinoma. Similar to H460 tumors, PD-0325901 as single agent or in combination with PF-04691502 significantly inhibited growth of tumor lesions in lungs in Kras(G12D-LSL) mice when treatment started at adenocarcinoma stage (at 14 weeks post-Adeno-Cre inhalation). In addition, immunohistochemistry showed inhibition of pS6 (phosphorylated ribosomal S6) in the treated animals particularly in the combination group providing a proof of mechanism for tumor growth inhibition. Finally, m-CT imaging in live Kras(G12D-LSL) mice showed reduction of tumor burdens in PD-0325901-treated animals at sub-MTD dose. In conclusion, our data suggest that PD-0325901 at doses below MTD is still a potent compound capable of tumor growth inhibition where Kras and/or PI3K are drivers of tumor growth and progression. [ABSTRACT FROM AUTHOR]

An increasing variety of organic reactions have been developed for the synthesis of more structurally stable and multifunctional COFs. Here, we report a class of β-ketamine linked covalent organic frameworks that were constructed through the CeCl 3 -catalyzed multi-component Mannich reaction at room temperature. And the TAD-COF obtained based on this method could significantly promote the light-driven oxidative hydroxylation of arylboronic acids., Competing Interests: There are no conflicts to declare., (This journal is © The Royal Society of Chemistry.)

2-Aminobenzothiazoles are widely used in the fields of pharmaceuticals and pesticides. Herein, we report a metal-free protocol for the preparation of 2-aminobenzothiazoles by a covalent organic framework (COF) catalyzed tandem reaction. In the presence of catalytic amount of phenanthroline-decorated COF (Phen-COF), a variety of 2-aminobenzothiazoles are obtained in excellent yields by the cross-coupling of 2-iodoanilines with isothiocyanates at room temperature in water. In addition, the COF-catalyst is very stable and can be reused at least seven times without loss of its catalytic activity., (© 2023 Wiley‐VCH GmbH.)

Covalent organic frameworks (COFs) have recently drawn intense attention due to their potential applications in photocatalysis. Herein, we report a multifunctional COF which consists of triphenylamine (TPA) and 2,2'-bipyridine (2, 2'-bipy) entities. The obtained TAPA-BPy-COF is a heterogeneous photocatalyst and can efficiently catalyze the oxidative coupling of thiols to disulfides. In addition, TAPA-BPy-COF can be further metalated by Pd(II) via 2,2'-bipy-metal coordination. The generated Pd@TAPA-BPy-COF can highly promote photocatalytic synthesis of 3-cyanopyridines via cascade addition/cyclization of arylboronic acids with γ-ketodinitriles in heterogeneous way. This work has demonstrated the way for the rational design and preparation of more efficient photoactive COFs for photocatalysis., (© 2023 Wiley-VCH GmbH.)

Radiotherapy is inevitably accompanied by some degree of radiation resistance, which leads to local recurrence and even therapeutic failure. To overcome this limitation, herein, we report the room-temperature synthesis of an iodine- and ferrocene-loaded covalent organic framework (COF) nanozyme, termed TADI-COF-Fc , for the enhancement of radiotherapeutic efficacy in the treatment of radioresistant esophageal cancer. The iodine atoms on the COF framework not only exerted a direct effect on radiotherapy, increasing its efficacy by increasing X-ray absorption, but also promoted the radiolysis of water, which increased the production of reactive oxygen species (ROS). In addition, the ferrocene surface decoration disrupted redox homeostasis by increasing the levels of hydroxyl and lipid peroxide radicals and depleting intracellular antioxidants. Both in vitro and in vivo experiments substantiated the excellent radiotherapeutic response of TADI-COF-Fc . This study demonstrates the potential of COF-based multinanozymes as radiosensitizers and suggests a possible treatment integration strategy for combination oncotherapy.

Herein, we report the first reactive oxygen species (ROS)-responsive dithioketal-linked covalent organic framework (COF) for synergetic chemotherapy and photodynamic therapy (PDT) of cancer. The singlet oxygen ( 1 O 2 )-responsive COF dissociation and DC_AC50 drug release complement and reinforce each other to allow an efficient combination of PDT and chemotherapy.

Multicomponent reactions (MCRs), as a powerful one-pot combinatorial synthesis tool, have been recently applied to the synthesis of covalent organic frameworks (COFs). Compared with the thermally driven MCRs, the photocatalytic MCR-based COF synthesis has not yet been investigated. Herein, we first report the construction of COFs by a photocatalytic multicomponent reaction. Upon visible-light irradiation, a series of COFs with excellent crystallinity, stability, and permanent porosity are successfully synthesized via photoredox-catalyzed multicomponent Petasis reaction under ambient conditions. Additionally, the obtained Cy-N 3 -COF exhibits excellent photoactivity and recyclability for the visible-light-driven oxidative hydroxylation of arylboronic acids. The concept of photocatalytic multicomponent polymerization not only enriches the methodology for COF synthesis but also opens a new avenue for the construction of COFs that might not be possible with the existing synthetic methods based on thermally driven MCRs.

Metal-free radiosensitizers, particularly iodine, have shown promise in enhancing radiotherapy due to their suitable X-ray absorption capacities and negligible biotoxicities. However, conventional iodine compounds have very short circulating half-lives and are not retained in tumors very well, which significantly limits their applications. Covalent organic frameworks (COFs) are highly biocompatible crystalline organic porous materials that are flourishing in nanomedicine but have not been developed for radiosensitization applications. Herein, we report the room-temperature synthesis of an iodide-containing cationic COF by the three-component one-pot reaction. The obtained TDI-COF can be a tumor radiosensitizer for enhanced radiotherapy by radiation-induced DNA double-strand breakage and lipid peroxidation and inhibits colorectal tumor growth by inducing ferroptosis. Our results highlight the excellent potential of metal-free COFs as radiotherapy sensitizers., Competing Interests: There are no conflicts to declare., (This journal is © The Royal Society of Chemistry.)

A fully sp 2 -carbon conjugated COF (Py-FTP-COF) was designed and synthesized, exhibiting excellent hydrogen evolution rate of 5.22 mmol g -1 h -1 . More importantly, in situ hydrogenation of nitroarenes under visible-light irradiation without any additional hydrogen source was successfully accomplished for the first time over COF-based materials.

Stimulus-responsive biodegradable nanocarriers with tumor-selective targeted drug delivery are critical for cancer therapy. Herein, we report for the first time a redox-responsive disulfide-linked porphyrin covalent organic framework (COF) that can be nanocrystallized by glutathione (GSH)-triggered biodegradation. After loading 5-fluorouracil (5-Fu), the generated nanoscale COF-based multifunctional nanoagent can be further effectively dissociated by endogenous GSH in tumor cells, releasing 5-Fu efficiently to achieve selective chemotherapy on tumor cells. Together with the GSH depletion-enhanced photodynamic therapy (PDT), an ideal synergistic tumor therapy for MCF-7 breast cancer via ferroptosis is achieved. In this research, the therapeutic efficacy was significantly improved in terms of enhanced combined anti-tumor efficiency and reduced side effects by responding to significant abnormalities such as high concentrations of GSH in the tumor microenvironment (TME)., Competing Interests: There are no conflicts to declare., (This journal is © The Royal Society of Chemistry.)

Two COFs (BT-COF1 and BT-COF2) with isomeric configuration were reported. Compared with BT-COF1, BT-COF2 with the narrower bandgap, smaller resistance and more evident charge transfer property exhibits superior catalytic performance in the photooxidation of sulfides.

Although natural sunlight-mediated photocatalysis is a clean, efficient, and green approach to access organic products, its application in the synthesis of covalent organic frameworks (COFs), however, is still unprecedented. Herein, we first report the sunlight photocatalytic synthesis of COF under ambient conditions. Furthermore, this "window ledge" reaction generated benzoxazole-linked COF is stable and can be applied as a reusable photocatalyst to highly promote visible-light-driven aerobic oxidation of sulfides to sulfoxides. These results not only enrich the COF synthetic methodology but also open a new route to access COFs in a green and sustainable way.

Providing safe and clean domestic water for people is currently one of the greatest worldwide issues. In this context, heavy metal ions and pathogenic microbes are the two major factors in water pollution. The conventional water treatment methods, however, are generally high-energy and high-resource consumptive. Herein, we report, the first of its kind, the room-temperature synthesis of α-aminophosphonate-linked COFs via three-component one-pot in situ Kabachnik-Fields reaction (KF-3CR). Due to the coexistent bioactive α-aminophosphonate and photosensitive porphyrin, the obtained APCOF-1 exhibits highly efficient solar-powered bactericidal and heavy metal ion removal abilities, which allows it to be a promising COF-based multifunctional material for water treatment in an energy- and resource-saving way. Specifically, by incorporating APCOF-1 (up to 50 wt%) with eco-friendly and low-cost chitosan, an APCOF-1 @chitosan aerogel-based helical setup is fabricated via a facile templated freeze-drying approach and it can be a continuous flow-through water purifier model to achieve scaled-up water treatment through adsorptive removal of heavy metal ions and sunlight-driven sterilization. We believe that this research not only can significantly enrich the synthetic methodology of COFs, but also will hopefully bring COFs one step closer to the practical application., (Copyright © 2022 Elsevier B.V. All rights reserved.)

A general and efficient organocatalytic asymmetric polymerization approach for the synthesis of chiral covalent organic frameworks (CCOFs) has been developed. With a chiral 2-methylpyrrolidine catalyst, a series of tris(N-salicylideneamine)-derived β-ketoenamine-CCOFs are directly constructed from prochiral aldehyde- and primary amine-monomers. The adopted aminocatalytic asymmetric Schiff-base condensation herein is performed under ambient conditions with clear green synthetic advantages over the conventional acid-catalysed solvothermal methods. The obtained β-ketoenamine-CCOFs can be further metalated by a solid-state coordination approach, and the resulting Cu II @CCOFs can highly promote an asymmetric A 3 -coupling reaction. Specifically, a Cu II @CCOF@chitosan aerogel was fabricated as a highly efficient fixed-bed model reactor for scaled-up catalysis. The concept of aminocatalytic asymmetric polymerization might open a new way for constructing the CCOFs via asymmetric organocatalysis., (© 2022 Wiley-VCH GmbH.)

Small interfering RNA (siRNA)-mediated gene silencing is a promising therapeutic approach. Herein, we report the ambient synthesis of a positively charged iminium-linked covalent organic framework by a three-component one-pot reaction. Through anion exchange and siRNA adsorption, the resulting multifunctional siRNA@ABMBP-COF, which possesses both the HK2 inhibitor 3-bromopyruvate and SLC7A11 siRNA, exhibits powerful synergistic antitumor activity against fibrosarcoma via the ferroptosis and apoptosis pathways., Competing Interests: There are no conflicts to declare., (This journal is © The Royal Society of Chemistry.)

Although chiral covalent organic frameworks (CCOFs) presence grows in thermal asymmetric catalysis, their application in equally important asymmetric photocatalysis has yet to begin. Herein, we first report a propargylamine-linked and quaternary ammonium bromide decorated porphyrin-CCOF which can highly promote visible-light-driven enantioselective photooxidation of sulfides to sulfoxides in water and in air. This methodology has also been applied to the synthesis of ( R )-modafinil, a wakefulness-promoting medication used for the treatment of excessive sleepiness. This research might open a new way for the application of CCOFs in asymmetric photocatalysis.

Incorporation of metal catalysis and organocatalysis has emerged as a promising way for developing new and valuable organic reactions. This catalytic strategy would potentially enable unprecedented transformations not possible by the existing metal catalysis or organocatalysis alone. Herein, we report an imine-linked chiral covalent organic framework (CCOF) achieved by the combination of a Au- N -heterocyclic-carbene (NHC-Au) monomer with its chiral secondary amine-containing counterpart via an updated direct synthetic approach. The obtained CCOF can be used as a reusable dual catalyst to highly promote the asymmetric aryl methanol oxidation-aldol relay reaction in a heterogeneous way. In addition, the CCOF-based shaped setup was also realized via a facile templating freeze-drying approach based on an eco-friendly chitosan material, by which the gram-scale asymmetric aerobic alcohol oxidation-aldol relay reaction was successfully achieved. The potential utility of this approach is highlighted by the preparation of many more new CCOF-based multifunctional heterogeneous catalysts to promote various asymmetric organic transformations in a facile and green way, and further progress might eventually allow CCOF catalysts to be developed for industrial processes.

A benzothiadiazole-involving donor-acceptor (D-A) covalent organic framework (COF), which has high crystallinity and strong light-harvesting capability (ranging from 300 to 800 nm), can serve as a highly effective photocatalyst for window ledge aerobic cross-dehydrogenative coupling (CDC) reactions (such as Mannich and aza-Henry reactions) even at a gram level.

We report the construction of a porphyrin and imidazolium-ionic liquid (IL)-decorated and quinoline-linked covalent organic framework (COF, abbreviated as COF-P1-1 ) via a three-component one-pot Povarov reaction. After post-synthetic metallization of COF-P1-1 with Co(II) ions, the metallized COF-PI-2 is generated. COF-PI-2 is chemically stable and displays highly selective CO 2 adsorption and good visible-light-induced photothermal conversion ability (Δ T = 26 °C). Furthermore, the coexistence of Co(II)-porphyrin and imidazolium-IL within COF-PI-2 has guaranteed its highly efficient activity for CO 2 cycloaddition. Of note, the needed thermal energy for the reactions is derived from the photothermal conversion of the Co(II)-porphyrin COF upon visible-light irradiation. More importantly, the CO 2 cycloaddition herein is a "window ledge" reaction, and it can proceed smoothly upon natural sunlight irradiation. In addition, a scaled-up CO 2 cycloaddition can be readily achieved using a COF-PI-2@chitosan aerogel -based fixed-bed model reactor. Our research provides a new avenue for COF-based greenhouse gas disposal in an eco-friendly and energy- and source-saving way.

A benzodifuran-based donor-acceptor covalent organic framework was synthesized and employed for efficient simulated sunlight-driven photocatalytic hydrogen evolution from water, which exhibited a superior and steady hydrogen evolution rate of 1390 μmol g-1 h-1 and an outstanding apparent quantum yield (AQY) of 7.8% was obtained at 420 nm.

A novel covalent organic framework material COF-DM , which contains chelating coordination environments, was synthesized at the gram level under mild conditions. In addition, its Cu(II)-loaded complex of Cu(II)@COF-DM was prepared by impregnating COF-DM in an acetonitrile solution of CuCl 2 via a solid-state coordination approach. The obtained Cu(II)-loaded Cu(II)@COF-DM can be used as a highly active heterogeneous catalyst to catalyze the alkyne-dihalomethane-amine coupling reactions.

We demonstrate herein that the N -heterocyclic-carbene (NHC)-metal complex (NHC-M)-involved covalent organic framework (COF) can be prepared by the direct polymerization of the NHC-M monomer with its counterpart under solvothermal conditions. The NHC-M-COF with different counterions is readily achieved via solid-state anion exchange. The obtained NHC-AuX-COF (X = Cl - and SbF 6 - ) can be a highly active reusable catalyst to separately promote the carboxylation of the terminal alkyne with CO 2 and alkyne hydration under mild conditions.

Synergistic phototherapy combining photodynamic therapy (PDT) and photothermal therapy (PTT) based on near-infrared (NIR) dyes using a single light source offers the opportunity to treat diseases at deep locations. In this study, we reported human serum albumin (HSA)-involving tetra(butylamino)phthalocyanine (Pc)-based nanomaterials of HSA-α-Pc and HSA-β-Pc as highly efficient dual-phototherapy agents, namely 1(4),8(11),15(18),22(25)-tetra(butylamino)phthalocyanine (α-Pc) and 2(3),9(10),16(17),23(24)-tetra(butylamino)phthalocyanine (β-Pc). Both HSA-α-Pc and HSA-β-Pc showed excellent photothermal effects under a single NIR (808 nm) laser irradiation due to the S 1 fluorescence emission quenching of Pcs. Compared to HSA-β-Pc, HSA-α-Pc exhibited better singlet oxygen generation ability and its highly efficient PDT/PTT dual-phototherapy was also well evidenced via in vitro and vivo experiments under a single 808 nm laser irradiation. Overall, this approach would be viable for the fabrication of more new Pc-based metal-free nano agents for PDT/PTT synergistic phototherapy upon a single NIR light source., Competing Interests: There are no conflicts to declare., (This journal is © The Royal Society of Chemistry.)

As one of the noninvasive cancer treatments, photothermal therapy (PTT) has drawn intense attention recently. In this context, an important task is to explore novel and versatile nanoscale photothermal agents (PTAs), especially those with strong NIR-II light absorption, high photothermal conversion efficiency, good photostability and biocompatibility. Phthalocyanines (Pcs), as the second-generation photosensitizers, are a promising class of candidates for PTT due to their strong NIR absorption and high photothermal conversion efficiency. However, the poor water solubility severely limited their application as PTAs in tumor treatment. Herein, we report a molecular phosphorus phthalocyanine (P-Pc)-based nanoagent via incorporation of human serum albumin (HSA) under mild conditions. The obtained nanoscale P-Pc-HSA possesses excellent photothermal conversion efficiency (64.7%) upon 1064 nm light irradiation, furthermore, it can be a highly efficient NIR-II antitumor nanoagent via photothermal treatment (PTT), which is fully evidenced by the in vitro and in vivo experiments., Competing Interests: There are no conflicts to declare., (This journal is © The Royal Society of Chemistry.)

Herein we describe a simple fluorescence quenching method for the selective recognition and determination of the amino acid phenylalanine (Phe). The use of 1 H NMR spectroscopy revealed that the alkaloid palmatine (PAL) can encapsulated partially into the cavity of cucurbit[7]uril (Q[7]) in aqueous solution to form a stable 1:1 host-guest inclusion complex. This host-guest complex exhibits fluorescence of moderate intensity. Interestingly, the addition of the Phe results in a dramatic quenching of the fluorescence intensity associated with the inclusion complex. By contrast, the addition of other natural amino acids resulted in no change in the fluorescence. Based on the linear relationship between the fluorescence intensity and the concentration of Phe, the detection of the concentration of Phe in aqueous solution is facile. Thus, a new fluorescence quenching method for the recognition and determination of the Phe has established herein., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Background and Aim: Open surgery remains the major approach to treat hepatocellular carcinoma, and laparoscopy-assisted liver resection has been recommended as a superior treatment. However, the efficacy of laparoscopic surgery versus open surgery for cirrhotic patients is under debate. Therefore, the aim of this meta-analysis was to compare the clinical outcomes of laparoscopic and open resection of hepatocellular carcinoma in patients with cirrhosis., Methods: Electronic databases were searched for eligible literature updated on November 2018. After rigorous review of quality, the data were extracted from eligible trials. All the data were pooled with the corresponding 95% confidence interval using RevMan software. Sensitivity analyses and heterogeneity were quantitatively evaluated., Results: Fourteen trials met the inclusion criteria. According to the pooled result of surgery duration, laparoscopic surgery was associated with significantly shorter hospital stay [STD mean difference (SMD) = -0.61, 95% confidence interval -0.89 to -0.32; P < 0.0001], lower intraoperative blood loss (SMD = -0.56, 95% confidence interval -0.99 to -0.12; P = 0.01), fewer complications (odds ratio = 0.38, 95% confidence interval 0.28 to 0.52; P < 0.00001) and lower transfusion rate (odds ratio = 0.58, 95% confidence interval 0.36-0.93; P = 0.02). Nevertheless, there was no remarkable difference in operative time (SMD = 0.17, 95% confidence interval -0.25 to -0.59; P = 0.42) between the two groups. The pooled analysis of overall survival showed that laparoscopic surgery did not achieve benefit compared with open surgery (P = 0.02). Moreover, the pooled results of three subgroups indicated that laparoscopic surgery was associated with significantly better disease-free survival (P < 0.05)., Conclusion: The current analysis indicates that laparoscopic liver resection for hepatocellular carcinoma improved intraoperative and disease-free survival, with similar overall survival compared to the open procedure. Laparoscopic surgery may serve as a safe and feasible alternative for selected hepatocellular carcinoma patients with cirrhosis.

Herein, we report an organometallic framework (OMF) generated from a divergent tridentate arylisocyanide ligand and PdI2 under solvothermal conditions. The obtained Pd-C bond-connected two-dimensional Pd-OMF was crystalline and porous. Moreover, it could be a highly active catalyst to promote the Suzuki-Miyaura cross-coupling reaction in a heterogeneous manner.

Photothermal therapy in the second near-infrared window (NIR-II, 1000-1700 nm) exhibits a significant advantage over the first near-infrared window (NIR-I, 650-950 nm) in terms of both maximum permissible exposure (MPE) and penetration depth. However, the thus far reported NIR-II photothermal agents (PTAs) have been focused just on inorganic semiconducting and organic polymeric semiconducting nanoparticles. Herein a novel cruciform phthalocyanine pentad was designed, synthesized, and characterized for the first time. The water-soluble nanoparticles (Zn 4 -H 2 Pc/DP NPs) assembled from this single molecular material with the help of DSPE-PEG 2000 -OCH 3 exhibit characteristic absorption in the NIR-II region at 1064 nm with a large extinction coefficient of 52 L g -1 cm -1 , high photothermal conversion efficiency of 58.3%, and intense photoacoustic signal. Moreover, both in vitro and in vivo studies reveal the good biocompatibility and notable tumor ablation ability of Zn 4 -H 2 Pc/DP NPs under 1064 nm laser irradiation. Theoretical density functional theory calculations interpret the two-dimensional compressional wave energy-dissipation pathway over the broad saddle curved framework of the cruciform conjugated phthalocyanine pentad, rationalizing the efficient photothermal properties of corresponding Zn 4 -H 2 Pc/DP NPs in the NIR-II window., (This journal is © The Royal Society of Chemistry 2019.)

The authors wish to make the following correction to their paper [...].

We report an allyl-decorated and hydrazine-connected covalent organic framework (COF-AO, 1), which could support Pd nanoparticles (Pd NPs) to generate Pd@COF-AO, 2. The incorporation of 2 with thiol-functionalized polysiloxane (termed as PSI-SH) via thiol-ene click reaction provided the stand-alone and elastic membrane (3). The obtained COF-involved and Pd NP-loaded covalently linked membrane of 3 is robust, permanently porous, uniform, processable, and water permeable. Moreover, it can be used to construct highly efficient membrane-based microreactor for continuous-flow operation to catalyze chlorobenzenes (CBs) dechlorination in water at room temperature. The provided approach herein allows the processability and practical application of the powdered COF materials to be feasible.

Nanocrystallization of organic molecular photosensitizers (PSs) by means of NMOF platforms has been demonstrated to be a promising approach to build up highly efficient PDT therapeutics. We report herein a new UiO-66 type of NMOF-based PS (UiO-66-TPP-SH), which is generated from UiO-66 NMOF and S-ethylthiol ester monosubstituted metal free porphyrin (TPP-SH) via a facile postsynthetic approach under mild conditions. The obtained NMOF (size less than 150 nm) with surface-decorated porphyrinic PS can not only retain MOF crystallinity, structural feature, and size, but also exhibit highly efficient singlet oxygen generation. Compared to the interior-located porphyrinic NMOF, UiO-66-TPP-SH shows significantly higher photodynamic activity and more efficient PDT tumor treatment.

Condensation of benzene-1,3,5-tricarbohydrazide with benzene-1,4-dicarboxaldehyde generated a new covalent organic framework, COF-ASB (1), in which the organic units are held together via hydrazone linkage to form porous frameworks. COF-ASB (1) is highly crystalline and displays good chemical and thermal stability and is permanently porous. In addition, 1 can be an ideal support to load Ru nanoparticles (Ru NPs) to generate Ru@COF-ASB (2). The obtained composite material is able to highly promote one-pot tandem synthesis of imine products from benzyl alcohols and corresponding amines under solvent-free conditions in air.

Interactions between inverted cucurbit[7]uril (iQ[7]) and essential amino acids have been studied at pH = 7.0 by 1 H NMR spectroscopy, electronic absorption spectroscopy, isothermal titration calorimetry, and mass spectrometry. The interactions can be divided into three binding types at pH = 7.0. Experimental results from the present study showed that the host displays a strong binding to the aromatic amino acids, Trp and Phe, and the guests of Lys, Arg, and His lie outside the cavity portal of the host. Meanwhile, the alkyl moieties of the guests Met, Leu, and Ile were accommodated within the cavity of iQ[7], but there was no significant interaction between iQ[7] and Thr or Val. The complexation behavior of iQ[7] with essential amino acids was explored at pH = 3, and the binding of Lys, Arg, and His revealed an unexpected behavior, with their side chains located in the cavity of iQ[7], whereas those of the aromatic Trp and Phe were deeper within the iQ[7] cavity. The alkyl side chains of the guests Met, Leu, Ile, Thr, and Val were also located inside the iQ[7] cavity and formed the host-guest complexes., Competing Interests: The authors declare no competing financial interest.

Heating a mixture of Nd(NO₃)₃·6H₂O, KCl, Q[10] and Q[5] in HCl for 10 min affords the inclusion complex {NdQ[5]K@Q[10](H₂O)₄}·4NO₃·20H₂O. The structure of the inclusion complex has been investigated by single crystal X-ray diffraction and by X-ray Photoelectron spectroscopy (XPS)., Competing Interests: The authors declare no conflict of interest.

A new composite Au@Cu(II)-MOF catalyst has been synthesized via solution impregnation and full characterized by HRTEM, SEM-EDS, XRD, gas adsorption-desorption, XPS, and ICP analysis. It has been shown here that the Cu(II)-framework can be a useful platform to stabilize and support gold nanoparticles (Au NPs). The obtained Au@Cu(II)-MOF exhibits a bifunctional catalytic behavior and is able to promote selective aerobic benzyl alcohol oxidation-Knoevenagel condensation in a stepwise way.

Targeted blockade of aberrantly activated signaling pathways is an attractive therapeutic strategy for solid tumors, but drug resistance is common. KRAS is a frequently mutated gene in human cancer but remains a challenging clinical target. Inhibitors against KRAS signaling mediators, namely, PI3K (phosphatidylinositol 3-kinase) and mTOR (mechanistic target of rapamycin), have limited clinical efficacy as single agents in KRAS-mutant colorectal cancer (CRC). We investigated potential bypass mechanisms to PI3K/mTOR inhibition in KRAS-mutant CRC. Using genetically engineered mouse model cells that had acquired resistance to the dual PI3K/mTOR small-molecule inhibitor PF-04691502, we determined with chemical library screens that inhibitors of the ERBB [epidermal growth factor receptor (EGFR)] family restored the sensitivity to PF-04691502. Although EGFR inhibitors alone have limited efficacy in reducing KRAS-mutant tumors, we found that PF-04691502 induced the abundance, phosphorylation, and activity of EGFR, ERBB2, and ERBB3 through activation of FOXO3a (forkhead box O 3a), a transcription factor inhibited by the PI3K to AKT pathway. PF-04691502 also induced a stem cell-like gene expression signature. KRAS-mutant patient-derived xenografts from mice treated with PF-04691502 had a similar gene expression signature and exhibited increased EGFR activation, suggesting that this drug-induced resistance mechanism may occur in patients. Combination therapy with dacomitinib (a pan-ERBB inhibitor) restored sensitivity to PF-04691502 in drug-resistant cells in culture and induced tumor regression in drug-resistant allografts in mice. Our findings suggest that combining PI3K/mTOR and EGFR inhibitors may improve therapeutic outcome in patients with KRAS-mutant CRC., (Copyright © 2014, American Association for the Advancement of Science.)

Figitumumab (CP-751,871), a potent and fully human monoclonal anti-insulin-like growth factor 1 receptor (IGF1R) antibody, has been investigated in clinical trials of several solid tumors. To identify biomarkers of sensitivity and resistance to figitumumab, its in vitro antiproliferative activity was analyzed in a panel of 93 cancer cell lines by combining in vitro screens with extensive molecular profiling of genomic aberrations. Overall response was bimodal and the majority of cell lines were resistant to figitumumab. Nine of 15 sensitive cell lines were derived from colon cancers. Correlations between genomic characteristics of cancer cell lines with figitumumab antiproliferative activity revealed that components of the IGF pathway, including IRS2 (insulin receptor substrate 2) and IGFBP5 (IGF-binding protein 5), played a pivotal role in determining the sensitivity of tumors to single-agent figitumumab. Tissue-specific differences among the top predictive genes highlight the need for tumor-specific patient selection strategies. For the first time, we report that alteration or expression of the MYB oncogene is associated with sensitivity to IGF1R inhibitors. MYB is dysregulated in hematologic and epithelial tumors, and IGF1R inhibition may represent a novel therapeutic opportunity. Although growth inhibitory activity with single-agent figitumumab was relatively rare, nine combinations comprising figitumumab plus chemotherapeutic agents or other targeted agents exhibited properties of synergy. Inhibitors of the ERBB family were frequently synergistic and potential biomarkers of drug synergy were identified. Several biomarkers of antiproliferative activity of figitumumab both alone and in combination with other therapies may inform the design of clinical trials evaluating IGF1R inhibitors., (©2013 AACR.)

Purpose: Effective therapies for KRAS-mutant colorectal cancer (CRC) are a critical unmet clinical need. Previously, we described genetically engineered mouse models (GEMM) for sporadic Kras-mutant and non-mutant CRC suitable for preclinical evaluation of experimental therapeutics. To accelerate drug discovery and validation, we sought to derive low-passage cell lines from GEMM Kras-mutant and wild-type tumors for in vitro screening and transplantation into the native colonic environment of immunocompetent mice for in vivo validation., Experimental Design: Cell lines were derived from Kras-mutant and non-mutant GEMM tumors under defined media conditions. Growth kinetics, phosphoproteomes, transcriptomes, drug sensitivity, and metabolism were examined. Cell lines were implanted in mice and monitored for in vivo tumor analysis., Results: Kras-mutant cell lines displayed increased proliferation, mitogen-activated protein kinase signaling, and phosphoinositide-3 kinase signaling. Microarray analysis identified significant overlap with human CRC-related gene signatures, including KRAS-mutant and metastatic CRC. Further analyses revealed enrichment for numerous disease-relevant biologic pathways, including glucose metabolism. Functional assessment in vitro and in vivo validated this finding and highlighted the dependence of Kras-mutant CRC on oncogenic signaling and on aerobic glycolysis., Conclusions: We have successfully characterized a novel GEMM-derived orthotopic transplant model of human KRAS-mutant CRC. This approach combines in vitro screening capability using low-passage cell lines that recapitulate human CRC and potential for rapid in vivo validation using cell line-derived tumors that develop in the colonic microenvironment of immunocompetent animals. Taken together, this platform is a clear advancement in preclinical CRC models for comprehensive drug discovery and validation efforts., (©2013 AACR)

P-glycoprotein (P-gp), a member of the ATP-binding cassette transporter family, is overexpressed in a number of different cancers and some studies show that P-gp overexpression can be correlated to poor prognosis or therapeutic resistance. Here we sought to elucidate if PF-3758309 (PF-309), a novel p-21 activated kinase inhibitor, efficacy was influenced by tumor P-gp. Based on in vitro proliferation data, a panel of colorectal cancer cell lines were ranked as sensitive or resistant and ABCB1 (P-gp) expression was evaluated by microarray for these cell lines. P-gp expression was determined by western blot and activity determined by rhodamine efflux assay. Knock down of P-gp and pharmacologic inhibition of P-gp to restore PF-309 activity was performed in vitro. PF-309 activity was evaluated in vivo in cell line xenograft models and in primary patient derived tumor xenografts (PDTX). Mice were treated with 25 mg/kg PF-309 orally, twice daily. On the last day of treatment, tumor and plasma were collected for PF-309 analysis. Here we show that ABCB1 gene expression correlates with resistance to PF-309 treatment in vitro and the expression and activity of P-gp was verified in a panel of resistant cells. Furthermore, inhibition of P-gp increased the sensitivity of resistant cells, resulting in a 4-100-fold decrease in the IC50s. Eleven cell line xenografts and 12 PDTX models were treated with PF-309. From the cell line xenografts, we found a significant correlation between ABCB1 gene expression profiles and tumor response. We evaluated tumor and plasma concentrations for eight tumor models (three cell line xenografts and five PDTX models) and a significant correlation was found between tumor concentration and response. Additionally, we show that tumor concentration is approximately fourfold lower in tumors that express P-gp, verified by western blot. Our in vitro and in vivo data strongly suggests that PF-309 efficacy is influenced by the expression of tumor P-gp.

PF-03814735 is a novel, reversible inhibitor of Aurora kinases A and B that finished a phase I clinical trial for the treatment of advanced solid tumors. To find predictive biomarkers of drug sensitivity, we screened a diverse panel of 87 cancer cell lines for growth inhibition upon PF-03814735 treatment. Small cell lung cancer (SCLC) and, to a lesser extent, colon cancer lines were very sensitive to PF-03814735. The status of the Myc gene family and retinoblastoma pathway members significantly correlated with the efficacy of PF-03814735. Whereas RB1 inactivation, intact CDKN2A/p16, and normal CCND1/Cyclin D1 status are hallmarks of SCLC, activation or amplification of any of the three Myc genes (MYC, MYCL1, and MYCN) clearly differentiated cell line sensitivity within the SCLC panel. By contrast, we found that expression of Aurora A and B were weak predictors of response. We observed a decrease in histone H3 phosphorylation and polyploidization of sensitive lines, consistent with the phenotype of Aurora B inhibition. In vivo experiments with two SCLC xenograft models confirmed the sensitivity of Myc gene-driven models to PF-03814735 and a possible schedule dependence of MYC/c-Myc-driven tumors. Altogether our results suggest that SCLC and other malignancies driven by the Myc family genes may be suitable indications for treatment by Aurora B kinase inhibitors.

Deregulation of the phosphoinositide 3-kinase (PI3K) signaling pathway such as by PTEN loss or PIK3CA mutation occurs frequently in human cancer and contributes to resistance to antitumor therapies. Inhibition of key signaling proteins in the pathway therefore represents a valuable targeting strategy for diverse cancers. PF-04691502 is an ATP-competitive PI3K/mTOR dual inhibitor, which potently inhibited recombinant class I PI3K and mTOR in biochemical assays and suppressed transformation of avian fibroblasts mediated by wild-type PI3K γ, δ, or mutant PI3Kα. In PIK3CA-mutant and PTEN-deleted cancer cell lines, PF-04691502 reduced phosphorylation of AKT T308 and AKT S473 (IC(50) of 7.5-47 nmol/L and 3.8-20 nmol/L, respectively) and inhibited cell proliferation (IC(50) of 179-313 nmol/L). PF-04691502 inhibited mTORC1 activity in cells as measured by PI3K-independent nutrient stimulated assay, with an IC(50) of 32 nmol/L and inhibited the activation of PI3K and mTOR downstream effectors including AKT, FKHRL1, PRAS40, p70S6K, 4EBP1, and S6RP. Short-term exposure to PF-04691502 predominantly inhibited PI3K, whereas mTOR inhibition persisted for 24 to 48 hours. PF-04691502 induced cell cycle G(1) arrest, concomitant with upregulation of p27 Kip1 and reduction of Rb. Antitumor activity was observed in U87 (PTEN null), SKOV3 (PIK3CA mutation), and gefitinib- and erlotinib-resistant non-small cell lung carcinoma xenografts. In summary, PF-04691502 is a potent dual PI3K/mTOR inhibitor with broad antitumor activity. PF-04691502 has entered phase I clinical trials.

The progression of cancer from non-metastatic to metastatic is the critical transition in the course of the disease. The epithelial to mesenchymal transition (EMT) is a mechanism by which tumor cells acquire characteristics that improve metastatic efficiency. Targeting EMT processes in patients is therefore a potential strategy to block the transition to metastatic cancer and improve patient outcome. To develop models of EMT applicable to in vitro and in vivo settings, we engineered NCI-H358 non-small cell lung carcinoma cells to inducibly express three well-established drivers of EMT: activated transforming growth factor β (aTGFβ), Snail or Zeb1. We characterized the morphological, molecular and phenotypic changes induced by each of the drivers and compared the different end-states of EMT between the models. Both in vitro and in vivo, induction of the transgenes Snail and Zeb1 resulted in downregulation of epithelial markers and upregulation of mesenchymal markers, and reduced the ability of the cells to proliferate. Induced autocrine expression of aTGFβ caused marker and phenotypic changes consistent with EMT, a modest effect on growth rate, and a shift to a more invasive phenotype. In vivo, this manifested as tumor cell infiltration of the surrounding mouse stromal tissue. Overall, Snail and Zeb1 were sufficient to induce EMT in the cells, but aTGFβ induced a more complex EMT, in which changes in extracellular matrix remodeling components were pronounced.

Epithelial to mesenchymal transition (EMT) plays a dual role in tumor progression. It enhances metastasis of tumor cells by increasing invasive capacity and promoting survival, and it decreases tumor cell sensitivity to epithelial cell-targeting agents such as epithelial growth factor receptor kinase inhibitors. In order to study EMT in tumor cells, we have characterized 3 new models of ligand-driven EMT: the CFPAC1 pancreatic tumor model and the H358 and H1650 lung tumor models. We identified a diverse set of ligands that drives EMT in these models. Hepatocyte growth factor and oncostatin M induced EMT in all models, while transforming growth factor-β induced EMT in both lung models. We observed morphologic, marker and phenotypic changes in response to chronic ligand treatment. Interestingly, stimulation with 2 ligands resulted in more pronounced EMT compared with single-ligand treatment, demonstrating a spectrum of EMT states induced by parallel signaling, such as the JAK and PI3K pathways. The EMT changes observed in response to the ligand were reversed upon ligand withdrawal, demonstrating the 'metastable' nature of these models. To study the impact of EMT on cell morphology and invasion in a 3D setting, we cultured cells in a semisolid basement membrane extract. Upon stimulation with EMT ligands, the colonies exhibited changes to EMT markers and showed phenotypes ranging from modest differences in colony architecture (CFPAC1) to complex branching structures (H358, H1650). Collectively, these 3 models offer robust cell systems with which to study the roles that EMT plays in cancer progression., (Copyright © 2010 S. Karger AG, Basel.)

Abnormal accumulation and activation of receptor tyrosine kinase Ron (recepteur d'origine nantais) has been demonstrated in a variety of primary human cancers. We show that RNA interference-mediated knockdown of Ron kinase in a highly tumorigenic colon cancer cell line led to reduced proliferation as compared with the control cells. Decreased Ron expression sensitized HCT116 cells to growth factor deprivation stress-induced apoptosis as reflected by increased DNA fragmentation and caspase 3 activation. In addition, cell motility was decreased in Ron knockdown cells as measured by wound healing assays and transwell assays. HCT116 cells are heterozygous for gain of function mutant PIK3CA H1047R. Analysis of signaling proteins that are affected by Ron knockdown revealed that phosphatidylinositol 3-kinase (PI3K) activity of the mutant PI3K as well as AKT phosphorylation was substantially reduced in the Ron knockdown cells compared with the control cells. Moreover, we demonstrated in vivo that knockdown of Ron expression significantly reduced lung metastasis as compared with the control cells in the orthotopic models. In summary, our results demonstrate that Ron plays an essential role in maintaining malignant phenotypes of colon cancer cells through regulating mutant PI3K activity. Therefore, targeting Ron kinase could be a potential strategy for colon cancer treatment, especially in patients bearing gain of function mutant PI3K activity.

PIK3CA, encoding the p110alpha catalytic subunit of phosphatidylinositol 3-kinase (PI3K), is mutated in a variety of human cancers. We screened the colon cancer cell lines previously established in our laboratory for PIK3CA mutations and found that four of them harbored gain of function mutations. We have now compared a panel of mutant and wild-type cell lines for cell proliferation and survival in response to stress. There was little difference in PI3K activity between mutant PIK3CA-bearing cells (mutant cells) and wild-type PIK3CA-bearing cells (wild-type cells) under optimal growth conditions. However, the mutant cells showed constitutive PI3K activity during growth factor deprivation stress (GFDS), whereas PI3K activity decayed rapidly in the wild-type cells. Importantly, constitutively active PI3K rendered the mutant cells resistant to GFDS-induced apoptosis relative to the wild-type cells, indicating a biological advantage under stress conditions that is imparted by the mutant enzymes. Compared with the wild-type cells, the mutant cells were hypersensitive to the apoptosis induced by the PI3K inhibitor LY294002. In addition, PIK3CA small interfering RNA significantly decreased DNA synthesis and/or induced apoptosis in the mutant cells but not in the wild-type cells. Furthermore, ecotopic expression of a mutant PIK3CA in a nontumorigenic PIK3CA wild-type cell line resulted in resistance to GFDS-induced apoptosis, whereas transfection of wild-type PIK3CA or empty vector had little effect. Taken together, our studies show that mutant PIK3CA increases the capacity for proliferation and survival under environmental stresses, such as GFDS while also imparting greater dependency on the PI3K pathway for proliferation and survival.

3-[6-(2-Dimethylamino-1-imidazol-1-yl-butyl)-naphthalen-2-yloxy]-2,2-dimethyl-propionic acid and analogs were designed and synthesized as highly potent and selective CYP26 inhibitors, serving as retinoic acid metabolic blocking agents (RAMBAs), with demonstrated in vivo efficacy to increase the half-life of exogenous atRA.

A series of [2-imidazol-1-yl-2-(6-alkoxy-naphthalen-2-yl)-1-methyl-ethyl]-dimethyl-amines were designed and synthesized as CYP26 inhibitors, serving as retinoic acid metabolic blocking agents (RAMBA's).

Splicing of mouse immunoglobulin (IgM) exons M1 and M2 is directed by two juxtaposed regulatory elements, an enhancer and an inhibitor, located within the M2 exon. A primary function of the enhancer is to counteract the inhibitor, allowing splicing to occur. Here we show that the inhibitor contains two binding sites for polypyrimidine tract binding protein (PTB). Mutational analysis indicates that only one of these sites is necessary and sufficient to direct splicing inhibition both in vitro and in vivo. We demonstrate that the difference in activity of the two sites is explained by proximity to the intron. We further show that the presence of the enhancer results in the disruption of the PTB-inhibitor interaction, enabling splicing to occur. In the absence of the enhancer, splicing can be artificially activated by immuno-inhibition of PTB. Collectively, our results indicate that a single PTB binding site can function as an inhibitor that regulates alternative splicing both in vitro and in vivo.

Exonic splicing enhancers (ESEs) are required for splicing of certain pre-mRNAs and function by providing binding sites for serine-arginine (SR) proteins, which contain an arginine-serine-rich (RS) domain. How an RS domain bound at the ESE promotes splicing is poorly understood. We have developed an RNA-protein crosslinking procedure to identify the target of the ESE-bound RS domain. Using this approach, we show that the ESE-bound RS domain specifically contacts the pre-mRNA branchpoint. The interaction between the ESE-bound RS domain and the branchpoint occurs in the prespliceosome and is dependent upon the same splicing signals, biochemical factors, and reaction conditions required to support prespliceosome assembly. Analysis of RS domain mutants demonstrates that the ability to interact with the branchpoint, to promote prespliceosome assembly, and to support splicing are related activities. We conclude that the ESE-bound RS domain functions by contacting the branchpoint to promote prespliceosome assembly.

Splicing of certain pre-mRNA introns is dependent on an enhancer element, which is typically purine-rich. It is generally thought that enhancers increase the use of suboptimal splicing signals, and one specific proposal is that enhancers stabilize binding of U2AF65 to weak polypyrimidine (Py) tracts. Here, we test this model using an IgM pre-mRNA substrate, which contains a well-characterized enhancer. Although the enhancer was required for in vitro splicing, we found it had no effect on U2AF65 binding. Unexpectedly, replacement of the natural IgM Py tract, branchpoint, and 5' splice site with consensus splicing signals did not circumvent the enhancer requirement. These observations led us to identify a novel regulatory element within the IgM M2 exon that acts as a splicing inhibitor; removal of the inhibitor enabled splicing to occur in the absence of the enhancer. The IgM M2 splicing inhibitor is evolutionarily conserved, can inhibit the activity of an unrelated, constitutively spliced pre-mRNA, and acts by repressing splicing complex assembly. Interestingly, the inhibitor itself forms an ATP-dependent complex that contains U2 snRNP. We conclude that splicing of IgM exons M1 and M2 is directed by two juxtaposed regulatory elements-an enhancer and an inhibitor-and that a primary function of the enhancer is to counteract the inhibitor.