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The twelve principles of green chemistry illuminate the pathway in the direction of sustainable and eco-friendly synthesis, marking a fundamental shift in synthetic organic chemistry paradigms. In this realm, harnessing the power of visible light for the difunctionalization of various skeletons without employing any external oxidant or reductant, specifically termed as redox-neutral difunctionalization, has attracted tremendous interest from synthetic organic chemists due to its low cost, easy availability and environmentally friendly nature in contrast to traditional metal-catalyzed difunctionalizations. This review presents an overview of recent updates on visible-light-induced redox-neutral difunctionalization reactions with literature coverage up to May 2024.
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Triterpenoids (C30-isoprenoids) represent a major group of natural products with various physiological functions in plants. Triterpenoids and their derivatives have medicinal uses owing to diverse bioactivities. Arjuna (Terminalia arjuna) tree bark accumulates highly oxygenated ß-amyrin-derived oleanane triterpenoids (e.g., arjunic acid, arjungenin, and arjunolic acid) with cardioprotective roles. However, biosynthetic routes and enzymes remain poorly understood. We mined the arjuna transcriptome and conducted cytochrome P450 monooxygenase (P450) assays using Saccharomyces cerevisiae and Nicotiana benthamiana to identify six P450s and two P450 reductases for oxidative modifications of oleanane triterpenoids. P450 assays using oleananes revealed a greater substrate promiscuity of C-2α and C-23 hydroxylases/oxidases than C-28 oxidases. CYP716A233 and CYP716A432 catalyzed ß-amyrin/erythrodiol C-28 oxidation to produce oleanolic acid. C-2α hydroxylases (CYP716C88 and CYP716C89) converted oleanolic acid and hederagenin to maslinic acid and arjunolic acid. CYP716C89 also hydroxylated erythrodiol and oleanolic aldehyde. However, CYP714E107a and CYP714E107b catalyzed oleanolic acid/maslinic acid/arjunic acid, C-23 hydroxylation to form hederagenin, arjunolic acid and arjungenin, and hederagenin C-23 oxidation to produce gypsogenic acid, but at a lower rate than oleanolic acid C-23 hydroxylation. Overall, P450 substrate selectivity suggested that C-28 oxidation is the first P450-catalyzed oxidative modification in the arjuna triterpenoid pathway. However, the pathway might branch thereafter through C-2α/C-23 hydroxylation of oleanolic acid. Taken together, these results provided new insights into substrate range of P450s and unraveled biosynthetic routes of triterpenoids in arjuna. Moreover, complete elucidation and reconstruction of arjunolic acid pathway in S. cerevisiae and N. benthamiana suggested the utility of arjuna P450s in heterologous production of cardioprotective compounds.
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CâH Functionalization of heteroarenes stands as a potent instrument in organic synthesis, and with the incorporation of visible light, it emerged as a transformative game-changer. In this domain, electron donor-acceptor (EDA) complex, formed through the pairing of an electron-rich substrate with an electron-accepting molecule, has garnered substantial consideration in recent years due to the related avoidance of the requirement of photocatalyst as well as oxidant. EDA complexes can undergo photoactivation under mild conditions and exhibit high functional group tolerance, making them potentially suitable for the functionalization of biologically relevant heteroarenes. This review article provides an overview of recent advancements in the field of CâH functionalization of heteroarenes via EDA complex photoactivation with literature coverage up to April, 2024.
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The exploration of natural products as potential agents for cancer treatment has garnered significant attention in recent years. In this comprehensive review, we delve into the diverse array of natural compounds, including alkaloids, carbohydrates, flavonoids, lignans, polyketides, saponins, tannins, and terpenoids, highlighting their emerging roles in cancer therapy. These compounds, derived from various botanical sources, exhibit a wide range of mechanisms of action, targeting critical pathways involved in cancer progression such as cell proliferation, apoptosis, angiogenesis, and metastasis. Through a meticulous examination of preclinical and clinical studies, we provide insights into the therapeutic potential of these natural products across different cancer types. Furthermore, we discuss the advantages and challenges associated with their use in cancer treatment, emphasizing the need for further research to optimize their efficacy, pharmacokinetics, and delivery methods. Overall, this review underscores the importance of natural products in advancing cancer therapeutics and paves the way for future investigations into their clinical applications.
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Productos Biológicos , Neoplasias , Humanos , Neoplasias/tratamiento farmacológico , Productos Biológicos/uso terapéutico , Productos Biológicos/farmacología , Animales , Antineoplásicos Fitogénicos/uso terapéutico , Antineoplásicos Fitogénicos/farmacología , Antineoplásicos/uso terapéuticoRESUMEN
A new molecular structure 1 has been developed on naphthalimide motif. The amine and triazole binding groups have been employed at the 4-position of naphthalimide to explore the sensing behavior of molecule 1. Single crystal x-ray diffraction and other spectroscopic techniques confirm the identity of 1. Compound 1 exhibits high selectivity and sensitivity for Cu2+ ions in CH3CN. The binding of Cu2+ shows â¼ 70-fold enhancement in emission at 520 nm. The binding follows 1:1 interaction and the detection limit is determined to be 6.49 × 10-7 M. The amine-triazole binding site in 1 also corroborates the detection of F- through a colour change in CH3CN. Initially H-bonding and then deprotonation of amine -NH- in the presence of F- are the sequential steps involved in F- recognition with a detection limit of 4.13 × 10-7 M. Compound 1 is also sensible to CN- like F- ion and they are distinguished by Fe3+ ion. Cu2+-ensemble of 1 fluorimetrically recognizes F- among the tested anions and vice-versa. The collaborative effect of amine and triazole motifs in the binding of both Cu2+ and F-/CN- has been explained by DFT calculation.
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Colorimetría , Cobre , Naftalimidas , Espectrometría de Fluorescencia , Naftalimidas/química , Cobre/química , Cobre/análisis , Colorimetría/métodos , Espectrometría de Fluorescencia/métodos , Cianuros/análisis , Cianuros/química , Límite de Detección , Fluoruros/análisis , Fluoruros/química , Colorantes Fluorescentes/química , Cristalografía por Rayos X/métodos , Enlace de HidrógenoRESUMEN
A metal-free protocol for oxidative carbotrifluoromethylation of maleimides with imidazopyridines and Langlois' reagent has been developed using (diacetoxyiodo)benzene (PIDA) as an oxidant. This three-component strategy enables one-step construction of 3,4-disubstituted maleimides in good yields with high functional group tolerance. Both experimental and theoretical studies support the proposed radical reaction mechanism.
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Kalmegh (Andrographis paniculata) spatiotemporally produces medicinally-important ent-labdane-related diterpenoids (ent-LRDs); andrographolide (AD), 14-deoxy-11,12-didehydroandrographolide (DDAD), neoandrographolide (NAD). ApCPS1 and ApCPS2, the ent-copalyl pyrophosphate (ent-CPP)-producing class II diterpene synthases (diTPSs) were identified, but their contributions to ent-CPP precursor supply for ent-LRD biosynthesis were not well understood. Here, we characterized ApCPS4, an additional ent-CPP-forming diTPS. Further, we elucidated in planta function of the ent-CPP-producing diTPSs (ApCPS1,2,4) by integrating transcript-metabolite co-profiles, biochemical analysis and gene functional characterization. ApCPS1,2,4 localized to the plastids, where diterpenoid biosynthesis occurs in plants, but ApCPS1,2,4 transcript expression patterns and ent-LRD contents revealed a strong correlation of ApCPS2 expression and ent-LRD accumulation in kalmegh. ApCPS1,2,4 upstream sequences differentially activated ß-glucuronidase (GUS) in Arabidopsis and transiently-transformed kalmegh. Similar to higher expression of ApCPS1 in kalmegh stem, ApCPS1 upstream sequence activated GUS in stem/hypocotyl of Arabidopsis and kalmegh. However, ApCPS2,4 upstream sequences weakly activated GUS expression in Arabidopsis, which was not well correlated with ApCPS2,4 transcript expression in kalmegh tissues. Whereas, ApCPS2,4 upstream sequences could activate GUS expression at a considerable level in kalmegh leaf and roots/calyx, respectively, suggesting the involvement of transcriptional regulator(s) of ApCPS2,4 that might participate in kalmegh-specific diterpenoid pathway. Interestingly, ApCPS2-silenced kalmegh showed a drastic reduction in AD, DDAD and NAD contents and compromised defense against insect herbivore Spodoptera litura. However, ent-LRD contents and herbivore defense in ApCPS1 or ApCPS4-silenced plants remained largely unaltered. Overall, these results suggested an important role of ApCPS2 in producing ent-CPP for medicinal ent-LRD biosynthesis and defense against insect herbivore.
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Transferasas Alquil y Aril , Andrographis , Arabidopsis , Diterpenos , Glucósidos , Tetrahidronaftalenos , Andrographis paniculata , Arabidopsis/metabolismo , Herbivoria , NAD/metabolismo , Transferasas Alquil y Aril/metabolismo , Diterpenos/metabolismo , Andrographis/genética , Andrographis/metabolismoRESUMEN
Objective: This comprehensive literature scoping review outlines available infection prevention and control (IPC) methods for viral-mediated gene therapies and provides one IPC strategy for the healthcare setting based on a single-center recommendation. Methods: A team of experts in pharmacy, healthcare epidemiology, and biosafety with experience in viral-mediated gene therapy was assembled within a pediatric hospital to conduct a comprehensive literature scoping review. The comprehensive review included abstracts and full-text articles published since 2009 and utilized prespecified search terms of the five viral vectors of interest: adenovirus (AV), retrovirus (RV), adeno-associated virus (AAV), lentivirus (LV), and herpes simplex virus (HSV). Case reports, randomized controlled trials, and bench research studies were all included, while systematic reviews were excluded. Results: A total of 4473 case reports, randomized control trials, and benchtop research studies were identified using the defined search criteria. Chlorine compounds were found to inactivate AAV and AV, while alcohol-based disinfectants were ineffective. There was a relative paucity of studies investigating surface-based disinfection for HSV, however, alcohol-based disinfectants were effective in one study. Ultraviolent irradiation was also found to inactivate HSV in numerous studies. No studies investigated disinfection for LV and RV vectors. Conclusions: The need to define IPC methods is high due to the rapid emergence of viral-mediated gene therapies to treat rare diseases, but published clinical guidance remains scarce. In the absence of these data, our center recommends a 1:10 sodium hypochlorite solution in clinical and academic environments to ensure complete germicidal activity of viral-mediated gene therapies.
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INTRODUCTION: Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive disorder, in which genetic and environmental factors are involved in disease onset. Although, by definition, the disease is considered idiopathic in nature, evidence-based studies have indicated familial cases of pulmonary fibrosis, in which genetic factors contribute to IPF pathogenesis. METHODS: Both common as well as rare genetic variants are associated with sporadic as well as familial forms of IPF. Although clinical inferences of the genetic association have still not been explored properly, observation-based studies have found a genotypic influence on disease development and outcome. RESULTS: Based on genetic studies, individuals with a risk of IPF can be easily identified and can be classified more precisely. Identification of genetic variants also helps to develop more effective therapeutic approaches. CONCLUSION: Further comprehensive research is needed to get a blueprint of IPF pathogenesis. The rapidly evolving field of genetic engineering and molecular biology, along with the bioinformatics approach, will possibly explore a new horizon very soon to achieve this goal.
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Germacrene D, a sesquiterpenoid compound found mainly in plant essential oils at a low level as (+) and/or (-) enantiomeric forms, is an ingredient for the fragrance industry, but a process for the sustainable supply of enantiopure germacrene D is not yet established. Here, we demonstrate metabolic engineering in yeast (Saccharomyces cerevisiae) achieving biosynthesis of enantiopure germacrene D at a high titer. To boost farnesyl pyrophosphate (FPP) flux for high-level germacrene D biosynthesis, a background yeast chassis (CENses5C) was developed by genomic integration of the expression cassettes for eight ergosterol pathway enzymes that sequentially converted acetyl-CoA to FPP and by replacing squalene synthase promoter with a copper-repressible promoter, which restricted FPP flux to the competing pathway. Galactose-induced expression of codon-optimized plant germacrene D synthases led to 13-30 fold higher titers of (+) or (-)-germacrene D in CENses5C than the parent strain CEN.PK2.1C. Furthermore, genomic integration of germacrene D synthases in GAL80, LPP1 and rDNA loci generated CENses8(+D) and CENses8(-D) strains, which produced 41.36 µg/ml and 728.87 µg/ml of (+) and (-)-germacrene D, respectively, without galactose supplementation. Moreover, coupling of mitochondrial citrate pool to the cytosolic acetyl-CoA, by expressing a codon-optimized ATP-citrate lyase of oleaginous yeast, resulted in 137.71 µg/ml and 815.81 µg/ml of (+) or (-)-germacrene D in CENses8(+D)* and CENses8(-D)* strains, which were 67-120 fold higher titers than in CEN.PK2.1C. In fed-batch fermentation, CENses8(+D)* and CENses8(-D)* produced 290.28 µg/ml and 2519.46 µg/ml (+) and (-)-germacrene D, respectively, the highest titers in shake-flask fermentation achieved so far. KEY POINTS: ⢠Engineered S. cerevisiae produced enantiopure (+) and (-)-germacrene D at high titers ⢠Engineered strain produced up to 120-fold higher germacrene D than the parental strain ⢠Highest titers of enantiopure (+) and (-)-germacrene D achieved so far in shake-flask.
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Galactosa , Saccharomyces cerevisiae , Saccharomyces cerevisiae/genética , Acetilcoenzima A , CodónRESUMEN
Additive manufacturing enables the fabrication of patient-specific implants of complex geometries. Although selective laser melting (SLM) of 316L stainless steel (SS) is well established, post-processing is essential to preparing high-performance biomedical implants. The goal of this study was to investigate surface mechanical attrition treatment (SMAT) as a means to enhance the electrochemical, biomechanical, and biological performances of 316L SS fabricated by SLM in devices for the repair of bone tissues. The SMAT conditions were optimized to induce surface nanocrystallization on the additively manufactured samples. SMAT resulted in a thicker oxide layer, which provided corrosion resistance by forming a passive layer. The fretting wear results showed that the rate of wear decreased after SMAT owing to the formation of a harder nanostructured layer. Surface modification of the alloy by SMAT enhanced its ability to support the attachment and proliferation of pre-osteoblasts in vitro. The study of the response in vivo to the additively manufactured alloy in a critical-sized cranial defect murine model revealed enhanced interactions with the cellular components after the alloy was subjected to SMAT without inducing any adverse immune response. Taken together, the results of this work establish SMAT of additively manufactured metallic implants as an effective strategy for engineering next-generation, high-performance medical devices for orthopedics and craniomaxillofacial applications.
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Prótesis e Implantes , Acero Inoxidable , Humanos , Animales , Ratones , Acero Inoxidable/química , ÓxidosRESUMEN
Dengue is the foremost cause of arthropod-borne viral disease in the world. It is and commonly found in tropical and subtropical parts of the world. Dengue fever is caused by one of the four distinct serotypes (DENV 1-4) of single-stranded RNA Flavivirus genus and transmitted through Aedes mosquito. Infection caused by one serotype develops lifelong immunity to that serotype, but not to others. Dengue fever (DF) presents with high fever, headache, myalgia, and arthralgia, and rash. Severe dengue, dengue haemorrhagic fever (DHF), and dengue shock syndrome (DSS) are accompanied by thrombocytopenia, vascular leakage, and hypotension. DSS is characterized by shock, which can be fatal with case fatality high as 12% to 44%. There are few atypical manifestations of dengue fever growing with rising disease burden, often missed and sometimes difficult to diagnosis. In this case report, we will discuss atypical manifestations of bilateral psoas muscle hematoma, intrahepatic cholestatic hepatitis, pancreatitis and pancytopenia observed in dengue fever patient.
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Boswellia tree bark exudes oleo-gum resin in response to wounding, which is rich in terpene volatiles. But, the molecular and biochemical basis of wound-induced formation of resin volatiles remains poorly understood. Here, we combined RNA-sequencing (RNA-seq) and metabolite analysis to unravel the terpene synthase (TPS) family contributing to wound-induced biosynthesis of resin volatiles in B. serrata, an economically-important Boswellia species. The analysis of large-scale RNA-seq data of bark and leaf samples representing more than 600 million sequencing reads led to the identification of 32 TPSs, which were classified based on phylogenetic relationship into various TPSs families found in angiosperm species such as TPS-a, b, c, e/f, and g. Moreover, RNA-seq analysis of bark samples collected at 0-24 h post-wounding shortlisted 14 BsTPSs that showed wound-induced transcriptional upregulation in bark, suggesting their important role in wound-induced biosynthesis of resin volatiles. Biochemical characterization of a bark preferentially-expressed and wound-inducible TPS (BsTPS2) in vitro and in planta assays revealed its involvement in resin terpene biosynthesis. Bacterially-expressed recombinant BsTPS2 catalyzed the conversion of GPP and FPP into (S)-( +)-linalool and (E)-(-)-nerolidol, respectively, in vitro assays. However, BsTPS2 expression in Nicotiana benthamiana found that BsTPS2 is a plastidial linalool synthase. In contrast, cytosolic expression of BsTPS2 did not form any product. Overall, the present work unraveled a suite of TPSs that potentially contributed to the biosynthesis of resin volatiles in Boswellia and biochemically characterized BsTPS2, which is involved in wound-induced biosynthesis of (S)-( +)-linalool, a monoterpene resin volatile with a known role in plant defense.
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Transferasas Alquil y Aril , Boswellia , Humanos , Boswellia/genética , Boswellia/metabolismo , Filogenia , Terpenos/metabolismo , Transferasas Alquil y Aril/genéticaRESUMEN
Selective initiation of programmed cell death in cancer cells than normal cells is reflected as an attractive chemotherapeutic strategy. In the current study, a series of synthetic bis-coumarin derivatives were synthesized possessing reactive oxygen species (ROS) modulating functional groups and examined in four cancerous and two normal cell lines for their cytotoxic ability using MTT assay. Among these compounds, 3 l emerged as the most promising derivative in persuading apoptosis in human renal carcinoma cells (SKRC-45) among diverse cancer cell lines. 3 l causes significantly less cytotoxicity to normal kidney cells compared to cisplatin. This compound was able to induce apoptosis and cell-cycle arrest by modulating the p53 mediated apoptotic pathways via the generation of ROS, decreasing mitochondrial membrane potential, and causing DNA fragmentation. Unlike cisplatin, the 3 l derivative was found to inhibit the nuclear localisation of NF-κB in SKRC-45 cells. It was also found to reduce the proliferation, survival and migration ability of SKRC-45 cells by downregulating COX-2/ PTGES2 cascade and MMP-2. In an in vivo tumor model, 3 l showed an anticancer effect by reducing the mean tumor mass, volume and inducing caspase-3 activation, without affecting kidney function. Further studies are needed to establish 3 l as a promising anti-cancer drug candidate.
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Antineoplásicos , Neoplasias , Humanos , Especies Reactivas de Oxígeno/metabolismo , Cisplatino/farmacología , Antineoplásicos/farmacología , Apoptosis , Cumarinas/farmacología , Proliferación Celular , Línea Celular TumoralRESUMEN
Triterpenoids are among the most assorted class of specialized metabolites found in all the taxa of living organisms. Triterpenoids are the leading active ingredients sourced from plant species and are utilized in pharmaceutical and cosmetic industries. The triterpenoid precursor 2,3-oxidosqualene, which is biosynthesized via the mevalonate (MVA) pathway is structurally diversified by the oxidosqualene cyclases (OSCs) and other scaffold-decorating enzymes such as cytochrome P450 monooxygenases (P450s), UDP-glycosyltransferases (UGTs) and acyltransferases (ATs). A majority of the bioactive triterpenoids are harvested from the native hosts using the traditional methods of extraction and occasionally semi-synthesized. These methods of supply are time-consuming and do not often align with sustainability goals. Recent advancements in metabolic engineering and synthetic biology have shown prospects for the green routes of triterpenoid pathway reconstruction in heterologous hosts such as Escherichia coli, Saccharomyces cerevisiae and Nicotiana benthamiana, which appear to be quite promising and might lead to the development of alternative source of triterpenoids. The present review describes the biotechnological strategies used to elucidate complex biosynthetic pathways and to understand their regulation and also discusses how the advances in triterpenoid pathway engineering might aid in the scale-up of triterpenoid production in engineered hosts.
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Triterpenos , Plantas/metabolismo , Biotecnología/métodos , Sistema Enzimático del Citocromo P-450/genética , Sistema Enzimático del Citocromo P-450/metabolismo , Ingeniería Metabólica/métodos , Saccharomyces cerevisiae/metabolismoRESUMEN
Harnessing visible-light in organic synthesis is one of the most effective methods that aligns with green and sustainable chemistry principles and hence skyrocketed in the last two decades. Similarly, three-component 1,2-dicarbofunctionalization of alkenes and alkynes has recently been a great choice to construct complex molecular systems in an easy and rapid manner. Therefore, light-induced reactions can be an excellent alternative to carry out 1,2-dicarbofunctionalization reactions, and very recently, organic chemists across the globe have fascinated us with their interesting articles. In this present review, we have summarized the recent advancements in the area of visible light induced three-component 1,2-dicarbofunctionalization of alkenes and alkynes till March 2023. We have categorized the discussion based on the catalysts used to carry out the transformations for better understanding and different important aspects of these transformations have also been covered.
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The essences of the quenching and partitioning (Q&P) process are to stabilize the finely divided retained austenite (RA) via carbon (C) partitioning from supersaturated martensite during partitioning. Competitive reactions, i.e., transition carbide precipitation, C segregation, and decomposition of austenite, might take place concurrently during partitioning. In order to maintain the high volume fraction of RA, it is crucial to suppress the carbide precipitation sufficiently. Since silicon (Si) in the cementite θ (Fe3C) is insoluble, alloying Si in adequate concentrations prolongs its precipitation during the partitioning step. Consequently, C partitioning facilitates the desired chemical stabilization of RA. To elucidate the mechanisms of formation of transition η (Fe2C) carbides as well as cementite, θ (Fe3C), besides the transformation of transition carbides to more stable θ during the quenching and partitioning (Q&P) process, samples of 0.4 wt% C steels tailored with different Si contents were extensively characterized for microstructural evolution at different partitioning temperatures (TP) using high resolution transmission electron microscopy (HR-TEM) and three-dimensional atom probe tomography (3D-APT). While 1.5 wt% Si in the steel allowed only the formation of η carbides even at a high TP of 300 °C, reduction in Si content to 0.75 wt% only partially stabilized η carbides, allowing limited η â θ transformation. With 0.25 wt% Si, only θ was present in the microstructure, suggesting a η â θ transition during the early partitioning stage, followed by coarsening due to enhanced growth kinetics at 300 °C. Although η carbides precipitated in martensite under paraequilibrium conditions at 200 °C, θ carbides precipitated under negligible partitioning local equilibrium conditions at 300 °C. Competition with the formation of orthorhombic η and θ precipitation further examined via ab initio (density functional theory, DFT) computation and a similar probability of formation/thermodynamic stability were obtained. With an increase in Si concentration, the cohesive energy decreased when Si atoms occupied C positions, indicating decreasing stability. Overall, the thermodynamic prediction was in accord with the HR-TEM and 3D-APT results.
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Aleaciones , Acero , Silicio , ComprensiónRESUMEN
Recently, visible-light-mediated photoredox catalysis has been emerging as one of the fastest growing fields in organic chemistry because of its low cost, easy availability and environmental benignness. In the past five years, a new yet challenging trend, visible-light-induced redox-neutral carbon-heteroatom bond formation reaction involving presumed radical intermediates, has been flourishing rapidly. Although mostly transition metal-based photoredox catalysts were reported, a few organophotoredox catalysts have also shown efficacy towards carbon-heteroatom bond formation reactions. This review intends to summarize the recent research progress in redox-neutral carbon-heteroatom bond formations based on active intermediate(s) involved under photoredox catalysis.