Lactate Is a Natural Suppressor of RLR Signaling by Targeting MAVS.

RLR-mediated type I IFN production plays a pivotal role in elevating host immunity for viral clearance and cancer immune surveillance. Here, we report that glycolysis, which is inactivated during RLR activation, serves as a barrier to impede type I IFN production upon RLR activation. RLR-triggered MAVS-RIG-I recognition hijacks hexokinase binding to MAVS, leading to the impairment of hexokinase mitochondria localization and activation. Lactate serves as a key metabolite responsible for glycolysis-mediated RLR signaling inhibition by directly binding to MAVS transmembrane (TM) domain and preventing MAVS aggregation. Notably, lactate restoration reverses increased IFN production caused by lactate deficiency. Using pharmacological and genetic approaches, we show that lactate reduction by lactate dehydrogenase A (LDHA) inactivation heightens type I IFN production to protect mice from viral infection. Our study establishes a critical role of glycolysis-derived lactate in limiting RLR signaling and identifies MAVS as a direct sensor of lactate, which functions to connect energy metabolism and innate immunity.

Inositol serves as a natural inhibitor of mitochondrial fission by directly targeting AMPK.

Mitochondrial dynamics regulated by mitochondrial fusion and fission maintain mitochondrial functions, whose alterations underline various human diseases. Here, we show that inositol is a critical metabolite directly restricting AMPK-dependent mitochondrial fission independently of its classical mode as a precursor for phosphoinositide generation. Inositol decline by IMPA1/2 deficiency elicits AMPK activation and mitochondrial fission without affecting ATP level, whereas inositol accumulation prevents AMPK-dependent mitochondrial fission. Metabolic stress or mitochondrial damage causes inositol decline in cells and mice to elicit AMPK-dependent mitochondrial fission. Inositol directly binds to AMPKγ and competes with AMP for AMPKγ binding, leading to restriction of AMPK activation and mitochondrial fission. Our study suggests that the AMP/inositol ratio is a critical determinant for AMPK activation and establishes a model in which AMPK activation requires inositol decline to release AMPKγ for AMP binding. Hence, AMPK is an inositol sensor, whose inactivation by inositol serves as a mechanism to restrict mitochondrial fission.

Copper-catalyzed C2-selective alkynylation of chromones via 1,4-conjugate addition.

Copper-catalyzed selective alkynylation with N-propargyl carboxamides as nucleophiles has been successfully developed for the synthesis of C2-functionalized chromanones. Under optimized reaction conditions, 21 examples were obtained in one-pot procedure through 1,4-conjugate addition. This protocol features readily available feedstocks, easy operations, and moderate to good yields, which provides viable access to pharmacologically active C2-functionalized chromanones.

Macrophorins H and L, two new HMG-conjugate macrophorins from rihzospheric Penicillium sp. NX-05-G-3.

Macrophorins H (4) and L (5), two rare HMG-conjugate macrophorins along with three known macrophorins (1-3), three DMOA-derived meroterpenoids (6-8) and two ergosterol derivates (9-10) were isolated from sterilized rice medium cultured Penicillium sp. NX-05-G-3. Their structures were elucidated by 1D and 2D NMR. The cytotoxicities of all compounds were evaluated, and compounds 1 and 2 showed extensive cytotoxicity against human cancer cell lines Hela, SCC15, MDA-MB-453 and A549, with IC50 values ranging from 17.6 to 32.8 µM.

Unexpected Cascade Sequence Forming the C(sp3)-N/C(sp2)-C(sp2) Bond: Direct Access to γ-Lactam-Fused Pyridones with Anticancer Activity.

An unexpected Ugi cascade reaction was developed for the facile construction of γ-lactam-fused pyridone derivatives with high tolerance of substrates. A C(sp3)-N bond and a C(sp2)-C(sp2) bond were formed together, accompanied by a chromone ring-opening in Ugi adducts, under the basic conditions without any metal catalyst for the whole process. Screening data of several difficult-to-inhibit cancer cell lines demonstrated that 7l displayed a high cytotoxicity against HCT116 cells (IC50 = 5.59 ± 0.78 µM). Taken together, our findings revealed new insights into the molecular mechanisms underlying compound 7l and provided potential usage of this scaffold for cancer therapeutics.

Silver-Catalyzed Decarboxylative Acylation of Isocyanides Accesses to α-Ketoamides with Air as a Sole Oxidant.

α-Ketoamide moieties, as privileged units, may represent a valuable option to develop compounds with favorable biological activities, such as low toxicity, promising PK and drug-like properties. An efficient silver-catalyzed decarboxylative acylation of α-oxocarboxylic acids with isocyanides was developed to derivatize the α-ketoamide functional group via a multicomponent reaction (MCR) cascade sequence in one pot. A series of α-ketoamides was synthesized with three components of isocyanides, aromatic α-oxocarboxylic acid analogues and water in moderate yields. Based on the research, the silver-catalyzed decarboxylative acylation confirmed that an oxygen atom of the amide moiety was derived from the water and air as a sole oxidant for the whole process.

Metal-Free Catalyzed Oxidation/Decarboxylative [3+2] Cycloaddition Sequences of 3-Formylchromones to Access Pyrroles with Anti-Cancer Activity.

An efficient and direct approach to pyrroles was successfully developed by employing 3-formylchromones as decarboxylative coupling partners, and facilitated by microwave irradiation. The protocol utilizes easily accessible feedstocks, a catalytic amount of DBU without any metals, resulting in high efficiency and regioselectivity. Notably, all synthesized products were evaluated against five different cancer cell lines and compound 3l selectively inhibited the proliferation of HCT116 cells with an IC50 value of 10.65 µM.

Visible-Light-Mediated Catalyst-Free [2+2] Cycloaddition Reaction for Dihydrocyclobuta[b]naphthalene-3,8-diones Synthesis under Mild Conditions.

A facile and efficient visible-light-mediated method for directly converting 1,4-naphthoquinones into dihydrocyclo-buta[b]naphthalene-3,8-diones (DHCBNDOs) under mild and clean conditions without using any photocatalysts is reported. This approach exhibited favorable compatibility with functional groups and afforded a series of DHCBNDOs with excellent regioselectivity and high yields. Moreover, detailed mechanism studies were carried out both experimentally and theoretically. The readily accessible, low-cost and ecofriendly nature of the developed strategy will endow it with attractive applications in organic and medicinal chemistry.

Zn(OTf)2-Promoted Isocyanide-Based Three-Component Reaction: Direct Access to 2-Oxazolines and ß-Amino Amides.

An efficient one-pot reaction of propargylamides, isocyanides, and water catalyzed by zinc was developed for the rapid construction of 2-oxazolines with a wide functional group tolerance. The methylene-3-oxazoline was proven to play a vitally important role to start the tandem cascade transformation through unfunctionalized alkynes with sequential nucleophilic addition approaches of isocyanide and water. Notably, with a slight alteration of the reaction temperature and the addition of one molecule of water, various ß-amino amide derivatives were synthesized in good to excellent yields.

Dieckmann Condensation of Ugi N-Acylamino Amide Product: Facile Access to Functionalized 2,2-Disubstituted Indolin-3-ones.

Structurally unique 2,2-disubstituted indolin-3-ones with a quaternary carbon center have been constructed through a novel C-C bond formation at the C3 position of Ugi N-acylamino amide adducts employing an organic base-mediated Dieckmann condensation. This facile, flexible protocol can be fine-tuned to construct drug-like pyrazino[1,2-a]indole fragments with the same quaternary carbon center only through the variation of the acid part in Ugi input. This novel and expeditious methodology has a broad scope and can rapidly generate the drug-like indolin-3-one core.

Demethylzeylasteral (T-96) initiates extrinsic apoptosis against prostate cancer cells by inducing ROS-mediated ER stress and suppressing autophagic flux.

BACKGROUND: Demethylzeylasteral (T-96) is a pharmacologically active triterpenoid monomer extracted from Tripterygium wilfordii Hook F (TWHF) that has been reported to exhibit anti-neoplastic effects against several types of cancer cells. However, the potential anti-tumour effects of T-96 against human Prostate cancer (CaP) cells and the possible underlying mechanisms have not been well studied. RESULTS: In the current study, T-96 exerted significant cytotoxicity to CaP cells in vitro and induced cell cycle arrest at S-phase in a dose-dependent manner. Mechanistically, T-96 promoted the initiation of autophagy but inhibited autophagic flux by inducing ROS-mediated endoplasmic reticulum (ER) stress which subsequently activated the extrinsic apoptosis pathway in CaP cells. These findings implied that T-96-induced ER stress activated the caspase-dependent apoptosis pathway to inhibit proliferation of CaP cells. Moreover, we observed that T-96 enhances the sensitivity of CaP cells to the chemotherapeutic drug, cisplatin. CONCLUSIONS: Taken together, our data demonstrated that T-96 is a novel modulator of ER stress and autophagy, and has potential therapeutic applications against CaP in the clinic.

Microwave-Assisted Copper Catalysis of α-Difluorinated gem-Diol toward Difluoroalkyl Radical for Hydrodifluoroalkylation of para-Quinone Methides.

Reported herein is a unified strategy to generate difluoroalkyl radicals from readily prepared α-difluorinated gem-diols by single electron oxidation. Under microwave irradiation, a catalytic amount of oxidant Cu(OAc)2 succeeds in the formation of transient difluoroalkyl radicals in situ, for the first time. The reaction features a simple protocol, short reaction time, scalability, and high yield. The synthetic utility of this new methodology was also explored for the synthesis of difluoroalkylated spiro-cyclohexadienones, which is an important core structure in natural products and pharmaceuticals.

Synthesis of monofluorooxazoles with quaternary C-F centers through photoredox-catalyzed radical addition of methylene-2-oxazolines.

A novel photoredox-catalyzed radical addition of methylene-2-oxazolines has been developed under visible light irradiation to synthesize monofluorooxazoles with a quaternary carbon center using 2-bromo-2-fluoro-3-oxo-3-phenylpropionates as radical source. This method with a simple protocol, scalability and high yield offers a facile path to get diverse monofluorinated oxazoles with quaternary C-F centers, which are a class of highly valuable motifs and synthons.

Microwave-assisted efficient and facile synthesis of tetramic acid derivatives via a one-pot post-Ugi cascade reaction.

A facile microwave-assisted method for the synthesis of tetramic acid derivatives has been developed through an Ugi/Dieckmann cyclization strategy with DBU. This two-step one-pot procedure afforded the targeted tetramic acid analogues in good yields. With commercially available Ugi starting materials, microwave irradiation, a simple operation, excellent yields, and a broad scope, this reaction has the potential to produce a large number of tetramic acid analogues, which cannot be easily accessed by the classic synthetic methods.

Diversity-Oriented Synthesis of Imidazo-Dipyridines with Anticancer Activity via the Groebke-Blackburn-Bienaymé and TBAB-Mediated Cascade Reaction in One Pot.

A facile and metal-free one-pot protocol for the synthesis of fused imidazopyridine scaffolds has been developed. This novel protocol combines the Groebke-Blackburn-Bienaymé reaction (GBBR) with a sequential TBAB-mediated cyclization cascade. Biological evaluation demonstrated that compound 6a inhibits human prostate cancer cell DU-145 proliferation with an IC50 of 1.6 µM. The molecular mechanism study indicates that 6a significantly suppresses the oncogenic Erk kinase phosphorylation at 3 µM.

Microwave-assisted facile construction of quinoxalinone and benzimidazopyrazinone derivatives via two paths of post-Ugi cascade reaction.

A facile and efficient route to synthesize quinoxalinone and benzimidazopyrazinone was developed via two paths of a post-Ugi cascade reaction. By simply alternating the order of nucleophilic substitution reactions, both heterocycles could be accessed selectively from the same Ugi adduct. Microwave-assisted synthesis protocol provided these compounds with one purification procedure for three steps. These two scaffolds with more possible spaces for further modifications provide great benefit toward combinatorial and medicinal chemistry campaigns.

Benzimidazoisoquinoline derivatives inhibit glioblastoma cell proliferation through down-regulating Raf/MEK/ERK and PI3K/AKT pathways.

BACKGROUND: Recent studies showed that benzimidazoleisoquinolinone derivatives exhibit anticancer activity against human cancer cell lines. The aim of this study is to evaluate the anti-tumor effects and mechanisms of benzimidazoleisoquinolinones in isocitrate dehydrogenase-wildtype subtype of human glioblastoma (GBM) cells. METHODS: Human U87 and LN229 cell lines were used to perform the experiments. MTT was applied to screen the effective small molecular inhibitors suppressing growth of GBM cells. Colony formation and BrdU staining assays were performed to assess the inhibition effect of compound-1H on the proliferation of GBM cells. The cell cycle and apoptosis were measured by flow cytometry and western blot to analyze the changes of the relative protein expressions and their signal pathways. RESULTS: Compound-1H could suppress GBM cells in a time- and dose-dependent manner. Treatment of compound-1H could arrest cell cycle in S phase through up-regulating P21 and P53, and down-regulating cyclin A and E in a dose-dependent manner. Compound-1H also induced mitochondrial-dependent apoptosis by increasing Bax, cleaved caspase-3, cleaved caspase-9 and poly ADP-ribose polymerase expression, and decreasing Bcl-2 expression. Moreover, phosphorylated (p)-AKT and p-ERK levels relating to cell proliferation were dramatically decreased in U87 and LN229 cells. CONCLUSIONS: Our results suggest that it is the first time to report the compound-1H with benzimidazoleisoquinolinone core playing antitumor activity in human glioblastoma cells by inhibiting Raf/MEK/ERK and PI3K/AKT signaling pathways, and it could be as a lead compound for the further development of targeted glioblastoma cancer therapy.

Functionalized Spiroindolines with Anticancer Activity through a Metal-Free Post-Ugi Diastereoselective One-Pot Cascade Reaction.

A post-Ugi diastereoselective one-pot cascade reaction requiring no metal catalyst was developed. The reaction scope was wide with mild conditions and good yields. A collection of spiroindolines was prepared by the protocol and screening tests in several difficult-to-inhibit cancer cell lines were conducted. The relationship of structure and anticancer activities was promising and in the Huh7 cell lines compound 16 j is more potent than Vinbalstine. The cyclization design strategy could be applicable to other multicomponent reactions (MCRs) for synthesizing bioactive and drug-like heterocycles.

Facile construction of fused benzimidazole-isoquinolinones that induce cell-cycle arrest and apoptosis in colorectal cancer cells.

Colorectal cancer (CRC) is one of the most frequent, malignant gastrointestinal tumors, and strategies and effectiveness of current therapy are limited. A series of benzimidazole-isoquinolinone derivatives (BIDs) was synthesized and screened to identify novel scaffolds for CRC. Of the compounds evaluated, 7g exhibited the most promising anti-cancer properties. Employing two CRC cell lines, SW620 and HT29, 7g was found to suppress growth and proliferation of the cell lines at a concentration of ∼20 µM. Treatment followed an increase in G2/M cell cycle arrest, which was attributed to cyclin B1 and cyclin-dependent kinase 1 (CDK1) signaling deficiencies with simultaneous enhancement in p21 and p53 activity. In addition, mitochondrial-mediated apoptosis was induced in CRC cells. Interestingly, 7g decreased phosphorylated AKT, mTOR and 4E-BP1 levels, while promoting the expression/stability of PTEN. Since PTEN controls input into the PI3K/AKT/mTOR pathway, antiproliferative effects can be attributed to PTEN-mediated tumor suppression. Collectively, these results suggest that BIDs exert antitumor activity in CRC by impairing PI3K/AKT/mTOR signaling. Against a small kinase panel, 7g exhibited low affinity at 5 µM suggesting anticancer properties likely stem through a non-kinase mechanism. Because of the novelty of BIDs, the structure can serve as a lead scaffold to design new CRC therapies.

Recent advances in the development of polycyclic skeletons via Ugi reaction cascades.

Isocyanide-based multicomponent reactions are among the most powerful synthetic tools available. Particularly, the isocyanide-based Ugi reaction can allow rapid preparation of [Formula: see text]-aminoacyl amide derivatives and polyazaheterocycles with extensive pharmaceutical applications. Moreover, bridged polyazaheterocycles, including one or more quaternary carbon centers, can be constructed via the Ugi cascade reaction in a few steps. This review will emphasize synthesis and bioactivities of bridged compounds with quaternary centers constructed through Ugi cascade reactions.