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2'-Deoxynucleosides and analogues play a vital role in drug development, but their preparation remains a significant challenge. Previous studies have focused on ß-2'-deoxynucleosides with the natural ß-configuration. In fact, their isomeric α-2'-deoxynucleosides also exhibit diverse bioactivities and even better metabolic stability. Herein, we report that both α- and ß-2'-deoxynucleosides can be prepared with high yields and stereoselectivity using a remote directing diphenylphosphinoyl (DPP) group. It is particularly efficient to prepare α-2'-deoxynucleosides with an easily accessible 3,5-di-ODPP donor. Instead of acting as a H-bond acceptor on a 2-(diphenylphosphinoyl)acetyl (DPPA) group in our previous studies for syn-facial O-glycosylation, the phosphine oxide moiety here acts as a remote participating group to enable highly antifacial N-glycosylation. This proposed remote participation mechanism is supported by our first characterization of an important 1,5-briged P-heterobicyclic intermediate via variable-temperature NMR spectroscopy. Interestingly, antiproliferative assays led to a α-2'-deoxynucleoside with IC50 values in the low micromole range against central nervous system tumor cell lines SH-SY5Y and LN229, whereas its ß-anomer exhibited no inhibition at 100 µM. Furthermore, the DPP group significantly enhanced the antitumor activities by 10 times.
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Neuroblastoma , Fosfinas , Humanos , GlicosilaçãoRESUMO
In the current study, tea saponin, identified as the primary bioactive constituent in seed pomace of Camellia oleifera Abel., was meticulously extracted and hydrolyzed to yield five known sapogenins: 16-O-tiglogycamelliagnin B (a), camelliagnin A (b), 16-O-angeloybarringtogenol C (c), theasapogenol E (d), theasapogenol F (e). Subsequent biotransformation of compound a facilitated the isolation of six novel metabolites (a1-a6). The anti-inflammatory potential of these compounds was assessed using pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns molecules (DAMPs)-mediated cellular inflammation models. Notably, compounds b and a2 demonstrated significant inhibitory effects on both lipopolysaccharide (LPS) and high-mobility group box 1 (HMGB1)-induced inflammation, surpassing the efficacy of the standard anti-inflammatory agent, carbenoxolone. Conversely, compounds d, a3, and a6 selectivity targeted endogenous HMGB1-induced inflammation, showcasing a pronounced specificity. These results underscore the therapeutic promise of C. oleifera seed pomace-derived compounds as potent agents for the management of inflammatory diseases triggered by infections and tissue damage.
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Camellia , Proteína HMGB1 , Sapogeninas , Anti-Inflamatórios/farmacologia , Inflamação/tratamento farmacológico , Sementes , Chá , AnimaisRESUMO
The presence of interface defects between the perovskite layer and the underlying substrate has a significant impact on the power conversion efficiency (PCE) and stability of perovskite solar cells (PSCs). S n O 2 thin films are employed in PSCs as electron transport layers to achieve high PCE. However, the significant lattice mismatch between S n O 2 and the perovskite material leads to a large number of uncoordinated defects at the interface between perovskite and substrate, resulting in recombination losses at the interface. In this study, rubidium chloride (RbCl) was introduced as the interface modification layer between the perovskite layer and the S n O 2 electron transport layer to enhance the PCE of PSCs. The research showed that the RbCl interface modification layer effectively passivated the under-coordinated defects of Sn ions and optimized the energy level alignment between the perovskite layer and the S n O 2 film. Moreover, the fabricated PSCs exhibited an open-circuit voltage of 1.11 V and a power conversion efficiency of 21.64%. Furthermore, the device maintained 80% of initial efficiency after storage for 30 days in an inert gas environment and 60% of the value after storage for 30 days in ambient air.
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Constitutive photomorpogenic dwarf (CPD) is a pivotal enzyme gene for brassinolide (BR) synthesis and plays an important role in plant growth, including increasing plant biomass and plant height, elongating cells, and promoting xylem differentiation. However, little is known about the function of the CPD gene in sugar beet. In the current study, we isolated CPD from Beta vulgaris L. (BvCPD), which encodes protein localized in the nucleus, cell membrane, and cell wall. BvCPD was strongly expressed in parenchyma cells and vascular bundles. The transgenic sugar beet overexpressing BvCPD exhibited larger diameter than that of the wild type (WT), which mainly owing to the increased number and size of parenchyma cells, the enlarged lumen and area of vessel in the xylem. Additionally, overexpression of BvCPD increased the synthesis of endogenous BR, causing changes in the content of endogenous auxin (IAA) and gibberellin (GA) and accumulation of cellulose and lignin in cambium 1-4 rings of the taproot. These results suggest that BvCPD can promote the biosynthesis of endogenous BR, improve cell wall components, promote the development of parenchyma cells and vascular bundle, thereby playing an important role in promoting the growth and development of sugar beet taproot.
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Ursolic acid (UA) is a pentacyclic triterpenoid widely found in in medicinal plants, edible plants, fruits, and flowers. The great interest in this bioactive compound is related to the positive effects in human health. However, its limited solubility, moderate biological activity and poor bioavailability limit the potential and further applications of UA. Here, we explored the efficacy of MeON-Glycosides of UA in inhibiting tumor cell proliferation. A number of compounds showed significant antitumor activity against tested five cancer cell lines. Among them, compound 2a exhibited the most potent activity against HepG2 cells with IC50 values of 3.1 ± 0.5 µM. Especially, compound 2a could induce HepG2 cells apoptosis and reduce mitochondrial membrane potential. Western blot analysis showed that compound 2a up-regulated Bax, cleaved caspase-3/9, cleaved PARP levels and down-regulated Bcl-2 level of HepG2 cells. These results indicated that compound 2a could obviously induce the apoptosis of HepG2 cells. At the same time, compound 2a significantly decreased the expression of p-AKT and p-mTOR, which indicated that compound 2a might exert its cytotoxic effect by targeting PI3K/AKT/mTOR signaling pathway. Moreover, the in silico ADME predictions showed that compound 2a has improved water solubility and other properties. Thus, compound 2a may be a promising antitumor candidate, which may be potentially used to prevent or treat cancers.
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Proteínas Proto-Oncogênicas c-akt , Triterpenos , Humanos , Proteínas Proto-Oncogênicas c-akt/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Linhagem Celular Tumoral , Estrutura Molecular , Apoptose , Serina-Treonina Quinases TOR/metabolismo , Proliferação de Células , Triterpenos/farmacologia , Ácido UrsólicoRESUMO
Checkpoint inhibitors such as PD-1/PD-L1 antibody therapeutics are a promising option for the treatment of multiple cancers. Due to the inherent limitations of antibodies, great efforts have been devoted to developing small-molecule PD-1/PD-L1 signaling pathway inhibitors. In this study we established a high-throughput AlphaLISA assay to discover small molecules with new skeletons that could block PD-1/PD-L1 interaction. We screened a small-molecule library of 4169 compounds including natural products, FDA approved drugs and other synthetic compounds. Among the 8 potential hits, we found that cisplatin, a first-line chemotherapeutic drug, reduced AlphaLISA signal with an EC50 of 8.3 ± 2.2 µM. Furthermore, we showed that cisplatin-DMSO adduct, but not semplice cisplatin, inhibited PD-1/PD-L1 interaction. Thus, we assessed several commercial platinum (II) compounds, and found that bis(benzonitrile) dichloroplatinum (II) disturbed PD-1/PD-L1 interaction (EC50 = 13.2 ± 3.5 µM). Its inhibitory activity on PD-1/PD-L1 interaction was confirmed in co-immunoprecipitation and PD-1/PD-L1 signaling pathway blockade bioassays. Surface plasmon resonance assay revealed that bis(benzonitrile) dichloroplatinum (II) bound to PD-1 (KD = 2.08 µM) but not PD-L1. In immune-competent wild-type mice but not in immunodeficient nude mice, bis(benzonitrile) dichloroplatinum (II) (7.5 mg/kg, i.p., every 3 days) significantly suppressed the growth of MC38 colorectal cancer xenografts with increasing tumor-infiltrating T cells. These data highlight that platinum compounds are potential immune checkpoint inhibitors for the treatment of cancers.
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Cisplatino , Inibidores de Checkpoint Imunológico , Neoplasias , Animais , Humanos , Camundongos , Anticorpos , Antígeno B7-H1/metabolismo , Cisplatino/farmacologia , Cisplatino/uso terapêutico , Camundongos Nus , Neoplasias/tratamento farmacológico , Receptor de Morte Celular Programada 1 , Inibidores de Checkpoint Imunológico/farmacologiaRESUMO
Due to the diversity and complexity of the components in traditional Chinese medicine (TCM) extracts, serious membrane fouling has become an obstacle that limits the application of membrane technology in TCM. Pectin, a heteropolysaccharide widely existing in plant cells, is the main membrane-fouling substance in TCM extracts. In this study, a hydrophilic hybrid coating was constructed on the surface of a polyvinylidene fluoride (PVDF) ultrafiltration (UF) membrane co-deposited with polydopamine (pDA) and (3-Aminopropy) triethoxysilane (KH550) for pectin antifouling. Characterization analysis showed that hydrophilic coating containing hydrophilic groups (-NH3, Si-OH, Si-O-Si) formed on the surface of the modified membrane. Membrane filtration experiments showed that, compared with a matched group (FRR: 28.66%, Rr: 26.87%), both the flux recovery rate (FRR) and reversible pollution rate (Rr) of the pDA and KH550 coated membrane (FRR: 48.07%, Rr: 44.46%) increased, indicating that pectin absorbed on the surface of membranes was more easily removed. Based on the extended Derjaguin-Laudau-Verwey-Overbeek (XDLVO) theory, the fouling mechanism of a PVDF UF membrane caused by pectin was analyzed. It was found that, compared with the pristine membrane (144.21 kT), there was a stronger repulsive energy barrier (3572.58 kT) to confront the mutual adsorption between the coated membrane and pectin molecule. The total interface between the modified membrane and the pectin molecule was significantly greater than the pristine membrane. Therefore, as the repulsion between them was enhanced, pectin molecules were not easily adsorbed on the surface of the coated membrane.
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Sugar beet taproot growth and development is a complex biological process involving morphogenesis and dry matter accumulation. However, the molecular regulatory mechanisms underlying taproot growth and development remain elusive. We performed a correlation analysis of the proteome and transcriptome in two cultivars (SD13829 and BS02) at the start and the highest points of the taproot growth rate. The corresponding correlation coefficients were 0.6189, 0.7714, 0.6803, and 0.7056 in four comparison groups. A total of 621 genes were regulated at both transcriptional and translational levels, including 190, 71, 140, and 220 in the BS59-VS-BS82, BS59-VS-SD59, BS82-VS-SD82, and SD59-VS-SD82 groups, respectively. Ten, 32, and 68 correlated-DEGs-DEPs (cor-DEGs-DEPs) were significantly enrdiched in the proteome and transcriptome of the BS59-VS-BS82, SD59-VS-SD82, and BS82-VS-SD82 groups, respectively, which included ribonuclease 1-like protein, DEAD-box ATP-dependent RNA helicase, TolB protein, heat shock protein 83, 20 kDa chaperonin, polygalacturonase, endochitinase, brassinolide and gibberellin receptors (BRI1 and GID1), and xyloglucan endotransglucosylase/hydrolase (XTH). In addition, Beta vulgaris XTH could enhance the growth and development of Arabidopsis primary roots by improving cell growth in the root tip elongation zone. These findings suggested that taproot growth and expansion might be regulated at transcriptional and posttranscriptional levels and also may be attributed to cell wall metabolism to improve cell wall loosening and elongation.
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Real-time wear monitoring of hob cutters is of great significance to the quality and efficiency of gear hobbing. To achieve this goal, a strategy based on statistical analysis is proposed in this paper. First, vibration signals during the entire life cycle of a hob cutter are collected. Then, a feature iterative integration method is proposed to integrate the initial features of vibration signals. The integrated features have obvious stages, reflecting the different wear status of hob cutters. Next, a probability tabular cumulative sum control chart method is established to monitor the wear status of hob cutters in real time. Finally, the verification results of two different data sets prove the effectiveness and transferability of the proposed methods.
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In this paper, we investigated an enhancement of luminance in a perovskite light-emitting diode (PeLED) by inserting periodic microscale gratings. Soft imprinting was employed to pattern the gratings onto the surface of perovskite film in the annealing process. It was found that the grain-refining effect deeply influenced the morphology and crystallinity of the perovskite film. The finite-element analysis was utilized to confirm the light extraction enhancement arising from the inserted microscale gratings. Additionally, the introduction of microscale gratings led to a 1.33 enhancement of the device's optoelectrical field intensity. Thus, the patterned PeLED obtained an enhancement of 2.96 and 2.1 of the luminance and external quantum efficiency, respectively.
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The transcription factor FOXM1 that regulates multiple proliferation-related genes through selective protein-DNA and protein-protein interactions is now considered an attractive oncotarget. There are several small-molecule inhibitors that indirectly suppress the expression of FOXM1 or block its DNA binding domain (FOXM1-DBD). However, insufficient specificity or/and efficacy are two potential drawbacks. Here, we employed in silico modeling of FOXM1-DBD with inhibitors to enable the design of an effective CRBN-recruiting molecule that induced significant FOXM1 protein degradation and exerted promising in vivo antitumor activity against TNBC xenograft models. This study is the first of its kind showcasing the use of an approach described in the literature as protein-targeting chimeras to degrade the elusive FOXM1, providing an alternative strategy to counter the pathological effects resulting from the increased transcriptional activity of FOXM1 observed in cancer cells.
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Proteína Forkhead Box M1/metabolismo , Ubiquitina-Proteína Ligases/metabolismo , Humanos , Ligantes , ProteóliseRESUMO
Increasing crop yield has always been an important goal in agriculture. Brassinosteroids (BRs) are growth-promoting steroid hormones with vital roles in many root developmental processes. Sugar beet (Beta vulgaris L.) is a root crop with a tertiary root structure. The differentiation of vascular bundles and the division of cambial cells increase root diameter. However, little is known about how BRs regulate the transverse growth of beetroot. Therefore, sugar beet with eight leaves was grown in medium containing epibrassinolide or brassinazole, an inhibitor of BR biosynthesis. BRs increased the spacing between the cambial rings by increasing the size of parenchyma cells between the rings and ultimately increasing root diameter. BRs also promoted secondary xylem differentiation. Moreover, the gene expression analysis of BvXTH33, BvSHV3, BvCESA6, BvPARVUS, and BvCEL1, which were related to the cell wall biosynthesis, indicated that BR could promote the growth of cell wall. These findings showed that BRs function in transverse development in beetroot.
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In this research, a series of novel diosgenin-1,4-quinone hybrids were synthesized and evaluated in antiproliferative assays against three human cancer cell lines (MCF-7, HepG2, and HeLa). Structure-activity relationship analysis revealed that the activities depended on the type of 1,4-quinone moiety. Among them, hybrid 11a exhibited significant cytotoxicity against the HepG2 cell line with a IC50 of 1.76 µM, which was 35-fold more potent than diosgenin (IC50 = 43.96 µM). Western blot analysis showed that hybrid 11a upregulated Bax, Cl-caspase-3/9, and Cl-PARP levels, and downregulated Bcl-2 level of HepG2 cell line. Meanwhile, hybrid 11a could increase the generation of intracellular reactive oxygen species. The molecular docking study revealed an interaction between hybrid 11a and NQO1 enzyme. Our present studies suggested that hybrid 11a as a potential substrate for NQO1 enzyme could be a promising anticancer agent for further investigation.
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Antineoplásicos/farmacologia , Apoptose , Diosgenina/análise , Células A549 , Linhagem Celular Tumoral , Proliferação de Células , Regulação para Baixo , Desenho de Fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Células HeLa , Células Hep G2 , Humanos , Concentração Inibidora 50 , Células MCF-7 , Espectroscopia de Ressonância Magnética , Mitocôndrias/metabolismo , Simulação de Acoplamento Molecular , Estrutura Molecular , Quinonas/química , Espécies Reativas de Oxigênio , Relação Estrutura-AtividadeRESUMO
Controllable single-photon routing takes the central roles in optical quantum networks for quantum information processing. Given that most of the schemes previously proposed are specifically designed for the photons with selected frequencies, here we investigate how to implement the routings of single photons with different frequencies. We show that the routing capabilities of the photons with different frequencies are manipulatable by properly designing the configuration of the scatters such as the cavity with embedded atoms and the channel boundaries. This is particularly important to implement the bandwidth routings of photons in future.
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A series of C-3 and C-28 MeON-neoglycosides of oleanolic acid were designed and synthesized by neoglycosylation as potential antiproliferative agents. Their cytotoxicity was evaluated in vitro against five human cancer cell lines: human non-small cell lung cancer cell line (A549), human melanoma cell line (A375), human colon cancer cell line (HCT116), human liver carcinoma cell line (HepG2), human breast adenocarcinoma cell line (MCF-7) by the Cell Counting Kit-8 (CCK-8) assay. Most of C-3 and C-28 MeON-neoglycosides of oleanolic acid exhibited notably inhibitory effects against the tested cancer cells and more sensitive to HepG2 cells than 5-Fluorouracil (5-FU). Structure-activities relationship (SAR) analysis revealed that sugar types and the d/l configuration of sugars would significantly affect their antiproliferative activities of neoglycosides. Among them, compound 8a (28-N-methoxyaminooleanane-ß-d-glucoside) exhibited the most potent antiproliferative activities against HepG2 cells with IC50 values of 2.1 µM. Further pharmacological experiments revealed that compound 8a could cause morphological changes and cell cycle arrest at G0/G1 phase and induce apoptosis in HepG2 cells. These results suggested that neoglycosylation could provide a rapid strategy for the discovery of potential antiproliferative agents and their possible pharmacological mechanisms need more further research.
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Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Glicosídeos/química , Ácido Oleanólico/síntese química , Ácido Oleanólico/farmacologia , Antineoplásicos/química , Proliferação de Células/efeitos dos fármacos , Técnicas de Química Sintética , Pontos de Checagem da Fase G1 do Ciclo Celular/efeitos dos fármacos , Glicosilação , Células Hep G2 , Humanos , Ácido Oleanólico/química , Fase de Repouso do Ciclo Celular/efeitos dos fármacosRESUMO
To systematically evaluate the impact of neoglycosylation upon the anticancer activities and selectivity of steroids, four series of neoglycosides of diosgenin, pregnenolone, dehydroepiandrosterone and estrone were designed and synthesized according to the neoglycosylation approach. The structures of all the products were elucidated by NMR analysis, and the stereochemistry of C20-MeON-pregnenolone was confirmed by crystal X-ray diffraction. The compounds' cytotoxicity on five human cancer cell lines was evaluated using a Cell Counting Kit-8 assay, and structure-activity relationships (SAR) are discussed. 2-deoxy-d-glucoside 5 k displayed the most potent antiproliferative activities against HepG2 cells with an IC50 value of 1.5â µM. Further pharmacological experiments on compound 5 k on HepG2 cells revealed that it could cause morphological changes and cell-cycle arrest at the G0/G1 phase and then induced the apoptosis, which might be associated with the enhanced expression of high-mobility group Box 1 (HMGB1). Taken together, these findings prove that the neoglycosylation of steroids could be a promising strategy for the discovery of potential antiproliferative agents.
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Antineoplásicos/síntese química , Desenho de Fármacos , Glicoconjugados/química , Esteroides/química , Antineoplásicos/química , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Cristalografia por Raios X , Diosgenina/química , Ensaios de Seleção de Medicamentos Antitumorais , Estrona/química , Pontos de Checagem da Fase G1 do Ciclo Celular/efeitos dos fármacos , Glicoconjugados/síntese química , Glicoconjugados/farmacologia , Proteína HMGB1/metabolismo , Humanos , Conformação Molecular , Pregnenolona/química , Relação Estrutura-AtividadeRESUMO
Organic-inorganic hybrid perovskites have attracted much attention due to their high color purity, low material cost, ease of tuning of bandgap, and flexible manufacture. They are considered to be a new generation of promising light-emitting materials. In this paper, an appropriate doping of polyethylene oxide (PEO) into the perovskite precursor solution acquires the high quality and low defect density of perovskite film. In addition, the passivation of perovskite grain boundaries by PEO are investigated. The perovskite light-emitting diode (PeLED) is fabricated with a structure of ITO/PEDOT:PSS/MAPbBr3/TPBi/LiF/Ag. As the doping concentration of PEO is at 10 mg/ml, MAPbBr3-PEO-based PeLEDs exhibit a maximum luminance of 4665.1cdm-2, while their external quantum efficiency (EQE) and current efficiency (CE) are also maximized to be 1.355% and 5.556cdA-1, respectively.
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As one of the three most famous brewed wines in the world, Chinese rice wine is made from rice and husked millet, containing 14 percent to 20 percent alcohol. Highly original, yellow wine brewing techniques are regarded as the model of the wine brewing industry in Asia. Shaoxing Huangjiu is produced in Zhejiang province and remains the oldest and most representative Chinese rice wine. During storage, Shaoxing Huangjiu is susceptible to environmental disturbance and produces colloidal haze to result in turbidity. In this study, the main composition and source of colloidal haze protein in Shaoxing Huangjiu were analyzed by two-dimensional electrophoresis and matrix-assisted laser ionization time-of-flight tandem mass spectrometry (MALDI-TOF/TOF MS). The results showed that the proteins in colloidal haze mainly consisted of oat protein b1, oat-like protein, di-amylase inhibitor, pathogenesis-related protein, pathogenesis-related protein-4, chitinase II derived from wheat and oat-like protein, and beta-amylase derived from rice. The amino acid composition and secondary structure of haze protein and supernatant protein in Huangjiu were further explored by high-performance liquid chromatography and Fourier transform infrared spectroscopy. The study has broadened knowledge of the main composition and source of colloidal haze protein in Shaoxing Huangjiu. The corresponding results indicated that the amino acid composition from colloidal haze had the main characteristics of high hydrophobicity and low water solubility.
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Remote distribution of secret keys is a challenging task in quantum cryptography. A significant step in this direction is the measurement-device independence quantum key distribution (MDI-QKD). For two remote (or independent) parties Alice and Bob who initially no share secret information, the MDI-QKD enables them to share a secret key by the measurement of an untrusted relay. Unfortunately, the MDI-QKD yields the assumption that the devices of both Alice and Bob have to be trusted. Here, we show that QKD between two independent parties can also be realized even if the device of either Alice or Bob is untrusted. We tackle the problem by resorting to the recently developed one-sided device-independent QKD protocol. We derive conditions on the extracted secret key to be unconditionally secure against arbitary attacks in the limit of asymptotic keys. In the presence of Gaussian states and measurements, we theoretically demonstrate our scheme is feasible, which could be an attractive candidate for long distance secret communication.
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In this study, we described the microbial catalyzed allylic oxidation by Bacillus megaterium CGMCC 1.1741 of three Δ12-pentacyclic triterpenes, erythrodiol (1), uvaol (2), hederagenin (3) and of four steroids including Δ5-steroids, diosgenin (4), pennogenin (5), 25(R,S)-ruscogenin (6) and Δ4-steroid, diosgenone (7). As a result, fourteen metabolites were generated with allyl hydroxyl moiety. Ten (1a-c, 2a, 2c, 3a, 5a-b, and 6a-b) of them were new natural products and their structures were determined on the basis of 1D/2D NMR and HR-MS data. Biocatalytic allylic oxidation by B. megaterium CGMCC 1.1741 is thus a potential non-toxic and efficient alternative method toward metal-mediated oxidation procedures in the synthesis of natural products and medicines.