3-Acyl-4-Pyranone as a Lysine Residue-Selective Bioconjugation Reagent for Peptide and Protein Modification.

Chemoselective protein modification plays extremely important roles in various biological, medical, and pharmaceutical investigations. Mimicking the mechanism of the chemoselective reaction between natural azaphilones and primary amines, this work successfully simplified the azaphilone scaffold into much simpler 3-acyl-4-pyranones. Examinations confirmed that these slim-size mimics perfectly kept the unique reactivity for selective conjugation with the primary amines including lysine residues of peptides and proteins. The newly developed pyranone tool presents remarkably increased aqueous solubility and compatible second-order rate constant by comparison with the original azaphilone. Additional advantages also include the ease of biorthogonal combinative use with a copper-catalyzed azide-alkyne Click reaction, which was conveniently applied to decorate lysozyme with neutral-, positive- and negative-charged functionalities in parallel. Moderate-degree modification of lysozyme with positively charged quaternary ammoniums was revealed to increase the enzymatic activities.

A five-parameter score for predicting saphenous vein graft degenerative and/or occlusive disease in recurring ischemic symptoms after one year post coronary artery bypass grafting.

BACKGROUND: The recurrence rate of ischemic symptoms after coronary artery bypass grafting (CABG) is increasing in recent years. How to prevent and treat saphenous vein graft disease (SVGD [symptomatic ⩾50% stenosis in at least one Saphenous vein graft]) has been a clinical challenge to date. Different pathogenesis may exist in SVGD of different periods. There are currently few available scores for estimating the risk of SVGD after one year post CABG. OBJECTIVE: We sought to develop and validate a simple predictive clinical risk score for SVGD with recurring ischemia after one year post CABG. METHODS AND RESULTS: This was a cross-sectional study and the results were validated using bootstrap resampling on a separate cohort. A nomogram and risk scoring system were developed based on retrospective data from a training cohort of 606 consecutive patients with recurring ischemia >1 year after CABG. Logistic regression model was used to find the predictive factors and to build a nomogram. To assess the generalization, models were validated using bootstrap resampling and an external cross-sectional study of 187 consecutive patients in four other hospitals. In multivariable analysis of the primary cohort, native lesion vessel number, SVG age, recurring ischemia type, very low-density lipoprotein level, and left ventricular end-diastolic diameter were independent predictors. A summary risk score was derived from nomogram, with a cut-off value of 15. In internal and external validation, the C-index was 0.86 and 0.82, indicating good discrimination. The calibration curve for probability of SVGD showed optimal agreement between actual observations and risk score prediction. CONCLUSION: A simple-to-use risk scoring system based on five easily variables was developed and validated to predict the risk of SVGD among patients who recurring ischemia after one year post CABG. This score may be useful for providing patients with individualized estimates of SVGD risk.

Phosphodiesterase 5 and Arginase Inhibitory Activities of the Extracts from Some Members of Nelumbonaceae and Nymphaeaceae Families.

The objectives of this study were (1) to investigate the effect of extracts from some plants in the families Nelumbonaceae and Nymphaeaceae on phosphodiesterase 5 (PDE5) and arginase, which have been used in erectile dysfunction treatment, and (2) to isolate and identify the compounds responsible for such activities. The characterization and quantitative analysis of flavonoid constituents in the active extracts were performed by HPLC. Thirty-seven ethanolic extracts from different parts of plants in the genus Nymphaea and Victoria of Nymphaeaceae and genus Nelumbo of Nelumbonaceae were screened for PDE5 and arginase inhibitory activities. The ethanolic extracts of the receptacles and pollens of Nelumbo nucifera Gaertn., petals of Nymphaea cyanea Roxb. ex G.Don, Nymphaea stellata Willd., and Victoria amazonica (Poepp.) Sowerby and the petals and receptacles of Nymphaea pubescens Willd. showed IC50 values on PDE5 of less than 25 µg/mL while none of the extracts showed effects on arginase. The most active extract, N. pubescens petal extract, was fractionated to isolate and identify the PDE5 inhibitors. The results showed that six flavonoid constituents including quercetin 3'-O-ß-xylopyranoside (1), quercetin 3-methyl ether 3'-O-ß-xylopyranoside (2), quercetin (3), 3-O-methylquercetin (4), kaempferol (5) and 3-O-methylkaempferol (6) inhibited PDE5 with IC50 values at the micromolar level.

Annonaceous Acetogenin Mimic AA005 Inhibits the Growth of TNBC MDA-MB-468 Cells by Altering Cell Energy Metabolism.

Triple-negative breast cancer (TNBC) is a serious health issue for women worldwide and there is still no suitable treatment option. AA005, a structurally simplified mimic of natural Annonaceous acetogenins, presents outstanding properties with impressive cytotoxicity and cell-type selective actions. The present study was aimed at evaluating the potential of AA005 as a therapeutic agent for TNBC. AA005 potently inhibited the growth of TNBC cells at 50 nM level. Inspired by the finding of the phosphatase and tensin homologue (PTEN) tumor suppressor, the effect of AA005 on aerobic glycolysis was investigated in TNBC MDA-MB-468 cells. A short-term AA005 exposure markedly suppressed mitochondrial function in MDA-MB-468 cells, thus activating the aerobic glycolysis to lessen the risk of decreased ATP generation in mitochondria. Prolonging the incubation time of AA005 clearly weakened the aerobic glycolysis in the cells. This was in part attributed to the PI3K-AKT pathway inactivation and subsequent declined glucose uptake. As a consequence, the energy supply was completely cut from the two major energy-producing pathways. Further experiments showed that AA005 resulted in irreversible damage on cell activity including cell cycle and growth, inducing mitochondrial oxidative stress and ultimately leading to cell death. In addition, the in vivo therapeutic efficacy of AA005 was proved on 4T1 xenograft tumor mice model. Our data demonstrate that AA005 exhibited a great potential for future clinical applications in TNBC therapy.

Total Synthesis of Suberitines A-D Featuring Tunable Biomimetic Late-Stage Oxidative Dearomatization and Acetalization.

Aaptaminoids are a unique family of marine alkaloids bearing a benzo[de][1,6]-naphthyridine core. This work describes the first total synthesis of suberitines A-D (1-4), four typical dimeric natural aaptaminoids, employing a step-saving bidirectional strategy. Key methods applied in the total synthesis include a cationic cascade to construct the bis-isoquinoline(s) with Hendrickson reagent-mediated Friedel-Crafts-type cyclization and eliminative aromatization, and a Bronsted acid-promoted Vilsmeier cyclization to generate the naphthyridine(s). The conditionally tunable PIDA-mediated oxidative dearomatization and subsequent methanolysis or hydrolysis successfully served as a powerful biomimetic tool to elaborate the essential oxygenated functionalities of suberitines A-D (1-4) in proper solvent-combinations at the final stage of total synthesis. The biomimetic proposal employed in the late-stage redox interchanges of related natural products was eventually supported by the isolation of synthetic intermediate 23 a as a natural product from the same natural source. Biological screening revealed that five of the synthetic samples including two natural suberitines and three full-skeleton natural product-like intermediates exhibited low micromolar inhibitory activities against the growth of cancer cell line K562.

Unified Total Synthesis of Tetracyclic Diquinane Lycopodium Alkaloids (+)-Paniculatine, (-)-Magellanine, and (+)-Magellaninone.

A unified route for the total synthesis of three tetracyclic diquinane Lycopodium alkaloids (+)-paniculatine, (-)-magellanine, and (+)-magellaninone has been accomplished in 13-14 overall steps based on late-stage diverse transformations from an advanced tetracyclic common intermediate. In the established synthesis, quick formation of the two five-membered rings was efficiently achieved by an intramolecular reductive coupling of ketone-carbonyl and ester-carbonyl and an organocatalytic intramolecular Michael addition of aldehyde-derived enamine to an internal enone functionality with satisfactory redox and step economies and excellent stereoselectivities, providing the requisite tricyclic carbo-framework possessing multiple dense stereogenic centers, and an intramolecular reductive amination finally furnished the essential piperidine ring.

Simplified hybrids of two anticancer bistetrahydroisoquinoline alkaloids ecteinascidin 743 and cribrostatin 4 and inhibitory activity against proliferation of cancer cells.

Ecteinascidin 743 is a famous marine drug used in anticancer treatments. In this work, a series of simplified hybrids/analogues have been synthesized by employing a newly developed chemistry that integrates the partial structural features of two anticancer bis-tetrahydroisoquinoline alkaloids ecteinascidin 743 and cribrostatin 4. The described Suzuki-coupling protocol enabled us to easily introduce variable functionalities at the C3 position of the basic skeleton of bis-tetrahydroisoquinoline alkaloids for the first time. Cytotoxic examination showed that analogue 21f exhibited inhibitory activities with IC50 values in the low 10-6 M range against the proliferation of the cancer cell lines A549, HepG2, and MDA-MB-231. This work reveals that diversifying the C3/C4 olefin in the skeleton of tetrahydroisoquinoline alkaloids is a useful means to generate potential pharmaceuticals.

Cytotoxic analogues of marine diterpenoid plumisclerin A by shifting the lipophilic branch on the characteristic tricyclic core.

Plumisclerin A is one of the most complex cytotoxic xenicane diterpenes from marine sources, featuring a unique congested and rigid tricyclo[4.3.1.01,5]decane core and a lipophilic acyl chain. This work explored a number of new analogues of plumisclerin A through modifying the characteristic tricyclo[4.3.1.01,5]decane core with lipophilic chains starting from a common lactone intermediate. Bioactivity examination of all the synthetic analogues shows that new analogues 2a, 18 and 21 exhibited comparable inhibitory potencies to that of the natural product against the proliferation of cancer cells. Structural comparison of these bioactive natural and unnatural compounds reveals that the location of lipophilic substituent(s) on the tricyclo[4.3.1.01,5]decane core is spatially flexible, and this work thus offers a new channel to diverse bioactive analogues of plumisclerin A.

Azaphilones as Activation-Free Primary-Amine-Specific Bioconjugation Reagents for Peptides, Proteins and Lipids.

Residue-selective bioconjugation methods for biomolecules are highly sought to expand the scope of their biological and medical applications. Inspired by the mechanism of the generation of natural vinylogous γ-pyridones (vPDNs), we have developed a novel unique azaphilone-based, activation-free primary-amine-selective bioconjugation method for biomolecules. Our strategy allows facile functionalization of primary amine groups in peptides and proteins, including the clinically used therapeutic antibody trastuzumab, by generating a highly stable vPDN linkage. Excellent chemoselectivity toward primary amines also enables the azaphilone derivatives to specifically modify the lipid components of Gram-positive bacteria while bypassing Gram-negative bacteria and mammalian cells. The new method shows significant advantages including chemoselectivity, efficiency, flexibility and biocompatibility, and therefore provides a valuable addition to the current toolbox for biomolecule conjugation.

Diastereoselective Access to Tetracyclic Eight-Membered Lactams through a Dearomative Heck Reaction and an Alkylative Ring-Opening Driven by Photoexcited Spiroindolines.

An external-photocatalyst-free, light-driven alkylative ring-opening of stable spiroindolines was developed to construct indolo- and benzoannulated eight-membered lactams. The spiroindolines were prepared from tetrahydro-ß-carbolines by a dearomative Heck reaction. Mechanistic experimental studies on the alkylative ring opening suggested that a photoredox pathway was involved, in which the spiroindoline performed as both reagent and photosensitizer. DFT calculations showed that the radical addition toward a cyclic alkene was the key to the diastereoselective formation of tetracyclic medium-sized lactams.

A randomized comparison of two paclitaxel-coated balloons for the treatment of in-stent restenosis: The LONGTY ISR China randomized trial (LONGTY DCB vs. SeQuent Please DCB).

OBJECTIVES: This study sought to compare the efficacy and clinical safety of the LONGTY drug-coated balloon (DCB) with those of SeQuent Please DCB in patients with in-stent restenosis (ISR). BACKGROUND: Although DCB technologies have evolved, little is known about the clinical efficacy of the new-generation LONGTY DCB. METHODS: This was a prospective, multicenter, randomized, noninferiority trial comparing LONGTY DCB with SeQuent Please DCB in patients with ISR. The primary endpoint was target lesion late lumen loss at 9 months' follow-up. RESULTS: A total of 211 patients with ISR from 13 Chinese sites were included (LONGTY DCB, n = 105; SeQuent Please DCB, n = 106). Device success was achieved in all patients. At the 9 month angiographic follow-up, target lesion late lumen loss was 0.35 ± 0.42 mm with LONGTY and 0.38 ± 0.45 mm with SeQuent Please (p for noninferiority <.001). The target lesion revascularization rates at 1 year were similar in both DCB groups (15.24 vs. 13.21%; p = .673). Over an extended follow-up of 2 years, the clinical endpoints, including cardiac death, myocardial infarction, and thrombus rate, were extremely low and similar in both groups. CONCLUSIONS: In this multicenter, head-to-head, randomized trial, the new-generation LONGTY DCB was noninferior to the SeQuent Please DCB for the primary endpoint of target lesion late lumen loss at 9 months.

Ensemble-Based Assimilation of Satellite All-Sky Microwave Radiances Improves Intensity and Rainfall Predictions for Hurricane Harvey (2017).

Ensemble-based data assimilation of radar observations across inner-core regions of tropical cyclones (TCs) in tandem with satellite all-sky infrared (IR) radiances across the TC domain improves TC track and intensity forecasts. This study further investigates potential enhancements in TC track, intensity, and rainfall forecasts via assimilation of all-sky microwave (MW) radiances using Hurricane Harvey (2017) as an example. Assimilating Global Precipitation Measurement constellation all-sky MW radiances in addition to GOES-16 all-sky IR radiances reduces the forecast errors in the TC track, rapid intensification (RI), and peak intensity compared to assimilating all-sky IR radiances alone, including a 24-hr increase in forecast lead-time for RI. Assimilating all-sky MW radiances also improves Harvey's hydrometeor fields, which leads to improved forecasts of rainfall after Harvey's landfall. This study indicates that avenues exist for producing more accurate forecasts for TCs using available yet underutilized data, leading to better warnings of and preparedness for TC-associated hazards in the future.

A Secure IoT-Based Authentication System in Cloud Computing Environment.

The Internet of Things (IoT) is currently the most popular field in communication and information techniques. However, designing a secure and reliable authentication scheme for IoT-based architectures is still a challenge. In 2019, Zhou et al. showed that schemes pro-posed by Amin et al. and Maitra et al. are vulnerable to off-line guessing attacks, user tracking attacks, etc. On this basis, a lightweight authentication scheme based on IoT is proposed, and an authentication scheme based on IoT is proposed, which can resist various types of attacks and realize key security features such as user audit, mutual authentication, and session security. However, we found weaknesses in the scheme upon evaluation. Hence, we proposed an enhanced scheme based on their mechanism, thus achieving the security requirements and resisting well-known attacks.

Divergent Synthesis of Oxa-Cyclic Nitrones through Gold(I)-Catalyzed 1,3-Azaprotio Transfer of Propargylic α-Ketocarboxylate Oximes: Experimental and DFT Studies.

1,3-Azaprotio transfer of propargylic α-ketocarboxylate oximes, a new type of alkynyl oximes featuring an ester tether, has been explored by taking advantage of gold catalysis. The incorporation of an oxygen atom to the chain of alkynyl oximes led to the formation of two different oxa-cyclic nitrones. It was found that internal alkynyl oximes with an E-configuration deliver five-membered nitrones, whereas terminal alkynyl oximes with an E-configuration afford six-membered nitrones. DFT calculations on four possible pathways supported a stepwise formation of C-N and C-H bonds, in which a 1,3-acyloxy-migration competes with the 1,3-azaprotio-transfer, especially in the case of internal alkynyl oximes. The relative nucleophilic properties of oxygen in the carbonyl group and the nitrogen in the oxime, the electronic effects of alkynes, and the influence of the ring system have been investigated computationally.

Diastereoselective Synthesis of Polysubstituted Piperidines through Visible-Light-Driven Silylative Cyclization of Aza-1,6-Dienes: Experimental and DFT Studies.

A visible-light-driven radical silylative cyclization of aza-1,6-dienes featuring an acrylonitrile or acrylate moiety and an electron-neutral olefin was developed, which allows for stereoselective synthesis of densely functionalized piperidines in a highly atom-economical manner. Depending on the substitution pattern of the electron-neutral olefin, poor-to-excellent diastereoselectivity was observed. It was suggested that the 6-exo-trig cyclization was initiated by a chemoselective addition of silyl radical toward electron-deficient olefin and the geometry of the remaining olefin is closely associated with the cis-stereoselectivity. DFT calculations supported that a transition state with a cyano group locating at the axial position of the forming piperidine ring might be involved, in which either the increase of 1,3-diaxial repulsion or the lack of hydrogen bonding interaction will diminish diastereoselectivity.

Annonaceous acetogenin mimic AA005 suppresses human colon cancer cell growth in vivo through downregulation of Mcl-1.

Annonaceous acetogenins are a well-established family of natural products with significant bioactivities, especially high cytotoxic and antitumor activities. AA005 is an annonaceous acetogenin mimic that has shown significant cytotoxicity against a variety of cancer cell lines, but its in vivo antitumor effects have not been demonstrated so far, and its anticancer mechanisms remain ambiguous. In this study, we investigated the effects of AA005 on human colon cancer cell lines in vivo. Human colon carcinoma cell line SW620 xenograft nude mice were treated with AA005 (5 mg/kg/day, i.p.) for 21 days. AA005 administration markedly inhibited the tumor growth via promoting nuclear translocation of apoptosis-inducing factor (AIF) and inducing AIF-dependent cell death. Subsequent studies in human colon carcinoma cell lines SW620 and RKO in vitro revealed that after the colon cancer cells exposed to AA005, downregulation of a B-cell lymphoma 2 family protein, myeloid cell leukemia-1 (Mcl-1), was an early event due to the inhibition of Mcl-1 mRNA level and protein synthesis in a time-dependent manner. Intriguingly, knockdown of Mcl-1 using small interfering RNA markedly accelerated the nuclear translocation of AIF and upregulation of receptor interacting protein-1, and enhanced AA005-mediated lethality, whereas ectopic expression of Mcl-1 substantially attenuated AA005-mediated lethality in the colon cancer cells. Finally, silencing Mcl-1 expression markedly enhanced AA005-induced lethality in SW620 xenograft nude mice, demonstrating a pivotal role of Mcl-1 downregulation in mediating the in vivo antitumor effects of AA005. Taken together, this study demonstrates for the first time the anticancer effects of AA005 against human colon cancer cell lines in vivo, which is mediated through the downregulation of Mcl-1.

Visible Light-Driven Radical trans-Hydrosilylation of Electron-Neutral and -Rich Alkenes with Tertiary and Secondary Hydrosilanes.

A visible light-driven radical hydrosilylation of electron-neutral and -rich alkenes has been investigated on the basis of a newly developed catalytic reaction system composed of eosin Y, thiol, and base additives. A variety of linear and cyclic alkenes with different substitution patterns were found to undergo such metal-free hydrosilylation with tertiary and secondary hydrosilanes in a chemo-, regio-, and stereoselective manner. Comparison of the reactivity of diene compounds and late-stage hydrosilylation of steroid drugs were also explored. Deuterium labeling experiments reveal that a stepwise formation of C-Si and C-H bonds with a trans stereochemistry is preferred, in which the thiol may behave as a hydrogen atom transfer agent.

Enantioselective Total Synthesis of (+)-Plumisclerin†A.

The first and enantioselective total synthesis of (+)-plumisclerin A, a novel unique complex cytotoxic marine diterpenoid, has been accomplished. Around the central cyclopentane anchorage, a sequential ring-formation protocol was adopted to generate the characteristic tricycle[4.3.1.01,5 ]decane and trans-fused dihyrdopyran moiety. Scalable enantioselective LaIII -catalyzed Michael reaction, palladium(0)-catalyzed carbonylation and SmI2 -mediated radical conjugate addition were successfully applied in the synthesis, affording multiple grams of the complex and rigid B/C/D-ring system having six continuous stereogenic centers and two all-carbon quaternary centers. The trans-fused dihyrdopyran moiety with an exo side-chain was furnished in final stage through sequential redox transformations from a lactone precursor, which overcome the largish steric strain of the dense multiring system. The reported total synthesis also confirms the absolute chemistries of natural (+)-plumisclerin A.

Azepinoindole Synthesis via a N-Bromosuccinimide-Induced Cycloisomerization of Enaminoester/Enaminone.

A protocol based on a newly developed N-bromosuccinimide (NBS)-induced cycloisomerization was described to prepare tricyclic azepino[4,5-b]indoles from simple ß-enaminoesters or ß-enaminones containing an indole unit. A mechanism involving a Pictet-Spengler cyclization, an aziridine ring formation, and a regioselective C-N bond cleavage was proposed to account for the medium-sized ring formation and the migration of electron-withdrawing group (ester, ketone).

Gram-Scale Laboratory Synthesis of UM171, a Potent Agonist of Human Hematopoietic Stem Cell Self-Renewal.

A short economic synthesis of pyrimidoindole derivative UM171, a potent agonist for the ex vivo expansion of hematopoietic stem cells, has been developed in this work. A unique [3,3]-sigmatropic rearrangement upon a hydroxamic precursor followed by base-promoted cyclization was successfully applied as the key step, furnishing the fully functionalized indole nucleus. The current synthesis is not only capable of affording UM171 in gram quantities but also offers great flexibility in late-stage diversification. Three new analogues of UM171 were synthesized accordingly in excellent yields using the common indole-carboxamide intermediate.