RESUMO
Decades of previous efforts to develop renal-sparing polyene antifungals were misguided by the classic membrane permeabilization model1. Recently, the clinically vital but also highly renal-toxic small-molecule natural product amphotericin B was instead found to kill fungi primarily by forming extramembraneous sponge-like aggregates that extract ergosterol from lipid bilayers2-6. Here we show that rapid and selective extraction of fungal ergosterol can yield potent and renal-sparing polyene antifungals. Cholesterol extraction was found to drive the toxicity of amphotericin B to human renal cells. Our examination of high-resolution structures of amphotericin B sponges in sterol-free and sterol-bound states guided us to a promising structural derivative that does not bind cholesterol and is thus renal sparing. This derivative was also less potent because it extracts ergosterol more slowly. Selective acceleration of ergosterol extraction with a second structural modification yielded a new polyene, AM-2-19, that is renal sparing in mice and primary human renal cells, potent against hundreds of pathogenic fungal strains, resistance evasive following serial passage in vitro and highly efficacious in animal models of invasive fungal infections. Thus, rational tuning of the dynamics of interactions between small molecules may lead to better treatments for fungal infections that still kill millions of people annually7,8 and potentially other resistance-evasive antimicrobials, including those that have recently been shown to operate through supramolecular structures that target specific lipids9.
Assuntos
Antifúngicos , Rim , Polienos , Esteróis , Animais , Humanos , Camundongos , Anfotericina B/análogos & derivados , Anfotericina B/química , Anfotericina B/toxicidade , Antifúngicos/química , Antifúngicos/metabolismo , Antifúngicos/farmacologia , Antifúngicos/toxicidade , Células Cultivadas , Colesterol/química , Colesterol/metabolismo , Farmacorresistência Fúngica , Ergosterol/química , Ergosterol/metabolismo , Rim/efeitos dos fármacos , Cinética , Testes de Sensibilidade Microbiana , Micoses/tratamento farmacológico , Micoses/microbiologia , Polienos/química , Polienos/metabolismo , Polienos/farmacologia , Inoculações Seriadas , Esteróis/química , Esteróis/metabolismo , Fatores de TempoRESUMO
Successfully interfacing enzymes and biomachinery with polymers affords on-demand modification and/or programmable degradation during the manufacture, utilization and disposal of plastics, but requires controlled biocatalysis in solid matrices with macromolecular substrates1-7. Embedding enzyme microparticles speeds up polyester degradation, but compromises host properties and unintentionally accelerates the formation of microplastics with partial polymer degradation6,8,9. Here we show that by nanoscopically dispersing enzymes with deep active sites, semi-crystalline polyesters can be degraded primarily via chain-end-mediated processive depolymerization with programmable latency and material integrity, akin to polyadenylation-induced messenger RNA decay10. It is also feasible to achieve processivity with enzymes that have surface-exposed active sites by engineering enzyme-protectant-polymer complexes. Poly(caprolactone) and poly(lactic acid) containing less than 2 weight per cent enzymes are depolymerized in days, with up to 98 per cent polymer-to-small-molecule conversion in standard soil composts and household tap water, completely eliminating current needs to separate and landfill their products in compost facilities. Furthermore, oxidases embedded in polyolefins retain their activities. However, hydrocarbon polymers do not closely associate with enzymes, as their polyester counterparts do, and the reactive radicals that are generated cannot chemically modify the macromolecular host. This study provides molecular guidance towards enzyme-polymer pairing and the selection of enzyme protectants to modulate substrate selectivity and optimize biocatalytic pathways. The results also highlight the need for in-depth research in solid-state enzymology, especially in multi-step enzymatic cascades, to tackle chemically dormant substrates without creating secondary environmental contamination and/or biosafety concerns.
Assuntos
Lipase/metabolismo , Nanotecnologia , Poliésteres/química , Poliésteres/metabolismo , Polimerização , Biocatálise , Domínio Catalítico , Estabilidade Enzimática , Cinética , Oxirredutases/metabolismo , Polienos/química , Polienos/metabolismo , Especificidade por SubstratoRESUMO
Polyolefins, composed of carbon and hydrogen atoms, dominate global polymer production. This stems from the wide range of physical and mechanical properties that various polyolefins can cover. Their versatile properties are largely tuned by chain microstructure, including molar mass distribution, comonomer content, and long-chain branching (LCB). Specifically, LCB imparts unique characteristics, notably enhances processability crucial for downstream applications. Tailoring LCB structural features has encouraged academic and industrial efforts, chronicle in this review from a chemistry standpoint. While encompassing post-reaction modification based traditional methods like peroxide grafting, ionizing beam irradiation, and coupling reactions, the main focus is given to catalyst-centric strategies and innovative polymerization schemes. The advent of single-site catalysts-metallocenes and late transition metals catalysts-amplifies interest in tailored chemical methods, but the progress in LCB formation flourishes via tandem catalytic systems and bimetallic catalysts under controlled reaction conditions. Specifically, the breakthrough in coordinative chain transfer polymerization unveils a novel avenue for controlled LCB synthesis by sequential chain propagation, transfer, liberation, and enchainment. This short review highlights recent approaches for the production of LCB polyolefins that can provide a roadmap crucial for researchers in academia and industry, steering their efforts toward further advancements in the production of tailored polyolefin.
Assuntos
Polienos , Polimerização , Polienos/química , Catálise , Estrutura MolecularRESUMO
The II-I phase transition of isotactic poly(1-butene) (iPBu) leads to improved mechanical performance. However, this will take several weeks and increase storage and processing costs. In this work, shear forces are introduced into the supercooled iPBu melt, and the effects of isothermal crystallization temperature (Tc) and shear temperature (Tshear) on crystallization and phase transition are explored. Shear-induced transcrystalline morphology of Form II with a significantly shortened crystallization induction period can be observed at relatively high Tc (105 °C). Besides, the shear-induced Form II can transit to Form I faster than the unsheared one. In addition, the phase transition rate increases as the Tshear decreases, with the fastest rate occurring at Tshear of 120 °C. The half transition time (t1/2) is measured as 6.3 h when Tc = 105 °C, Tshear = 120 °C, which is much shorter than the 20.7 h required for unsheared samples. The accelerated phase transition of iPBu can be attributed to the stretching of molecular chains, resulting from shear treatment. This study provides a quantitative analysis of the influence of the shear treatment and the Tshear on the II-I phase transition rate. It also presents a cost-effective and straightforward approach for expediting the phase transition process.
Assuntos
Transição de Fase , Polienos/química , Cristalização , Temperatura , Polímeros/química , Resistência ao CisalhamentoRESUMO
Despite their industrial ubiquity, polyolefin-polyacrylate block copolymers are challenging to synthesize due to the distinct polymerization pathways necessary for respective blocks. This study utilizes MILRad, metal-organic insertion light-initiated radical polymerization, to synthesize polyolefin-b-poly(methyl acrylate) copolymer by combining palladium-catalyzed insertion-coordination polymerization and atom transfer radical polymerization (ATRP). Brookhart-type Pd complexes used for the living polymerization of olefins are homolytically cleaved by blue-light irradiation, generating polyolefin-based macroradicals, which are trapped with functional nitroxide derivatives forming ATRP macroinitiators. ATRP in the presence of Cu(0), that is, supplemental activators and reducing agents , is used to polymerize methyl acrylate. An increase in the functionalization efficiency of up to 71% is demonstrated in this study by modifying the light source and optimizing the radical trapping condition. Regardless of the radical trapping efficiency, essentially quantitative chain extension of polyolefin-Br macroinitiator with acrylates is consistently demonstrated, indicating successful second block formation.
Assuntos
Resinas Acrílicas , Polienos , Polimerização , Polienos/química , Polienos/síntese química , Resinas Acrílicas/química , Resinas Acrílicas/síntese química , Catálise , Polímeros/química , Polímeros/síntese química , Paládio/química , Estrutura Molecular , Acrilatos/química , LuzRESUMO
Oxabornyl polyenes represent a unique group of polyketides characterized by a central polyene core flanked by a conserved oxabornyl moiety and a structurally diverse oxygen heterocyclic ring. They are widely distributed in fungi and possess a variety of biological activities. Due to the significant spatial separation between the two stereogenic ring systems, it is difficult to establish their overall relative configurations. Here, we isolated three oxabornyl polyenes, prugosenes A1-A3 (1-3), from Talaromyces sp. JNU18266-01. Although these compounds were first reported from Penicillium rugulosum, their overall relative and absolute configurations remained unassigned. By employing ozonolysis in combination with ECD calculations, we were able to establish their absolute configurations, and additionally obtained seven new chemical derivatives (4-10). Notably, through NMR data analysis and quantum chemical calculations, we achieved the structural revision of prugosene A2. Furthermore, prugosenes A1-A3 exhibited potent antiviral activity against the respiratory syncytial virus, with compound 1 displaying an IC50 value of 6.3 µM. Our study thus provides a valuable reference for absolute configuration assignment of oxabornyl polyene compounds.
Assuntos
Polienos , Polienos/química , Polienos/farmacologia , Estrutura Molecular , Talaromyces/química , Antivirais/farmacologia , Antivirais/química , Vírus Sinciciais Respiratórios/efeitos dos fármacos , HumanosRESUMO
Polyene macrolactams are a special group of natural products with great diversity, unique structural features, and a wide range of biological activities. Herein, a cryptic gene cluster for the biosynthesis of putative macrolactams was disclosed from a sponge-associated bacterium, Streptomyces sp. DSS69, by genome mining. Cloning and heterologous expression of the whole biosynthetic gene cluster led to the discovery of weddellamycin, a polyene macrolactam bearing a 23/5/6 ring skeleton. A negative regulator, WdlO, and two positive regulators, WdlA and WdlB, involved in the regulation of weddellamycin production were unraveled. The fermentation titer of weddellamycin was significantly improved by overexpression of wdlA and wdlB and deletion of wdlO. Notably, weddellamycin showed remarkable antibacterial activity against various Gram-positive bacteria including MRSA, with MIC values of 0.10-0.83 µg/mL, and antifungal activity against Candida albicans, with an MIC value of 3.33 µg/mL. Weddellamycin also displayed cytotoxicity against several cancer cell lines, with IC50 values ranging from 2.07 to 11.50 µM.
Assuntos
Antibacterianos , Lactamas Macrocíclicas , Testes de Sensibilidade Microbiana , Família Multigênica , Streptomyces , Streptomyces/genética , Streptomyces/metabolismo , Antibacterianos/farmacologia , Antibacterianos/biossíntese , Antibacterianos/química , Humanos , Lactamas Macrocíclicas/farmacologia , Lactamas Macrocíclicas/química , Lactamas Macrocíclicas/isolamento & purificação , Polienos/farmacologia , Polienos/isolamento & purificação , Polienos/química , Candida albicans/efeitos dos fármacos , Linhagem Celular Tumoral , Regiões Antárticas , Animais , Poríferos/microbiologia , Antifúngicos/farmacologia , Antifúngicos/química , Antifúngicos/isolamento & purificaçãoRESUMO
One useful technique for increasing the efficiency of organic dye-sensitized solar cells (DSSCs) is to extend the π-conjugated bridges between the donor (D) and the acceptor (A) units. The present study used the DFT and TD-DFT techniques to investigate the effect of lengthening the polyene bridge between the donor N, N-dimethyl-anilino and the acceptor dicyanovinyl. The results of the calculated key properties were not all in line with expectations. Planar structure was associated with increasing the π-conjugation linker, implying efficient electron transfer from the donor to the acceptor. A smaller energy gap, greater oscillator strength values, and red-shifted electronic absorption were also observed when the number of polyene units was increased. However, some results indicated that the potential of the stated dyes to operate as effective dye-sensitized solar cells is limited when the polyene bridge is extended. Increasing the polyene units causes the HOMO level to rise until it exceeds the redox potential of the electrolyte, which delays regeneration and impedes the electron transport cycle from being completed. As the number of conjugated units increases, the terminal lobes of HOMO and LUMO continue to shrink, which affects the ease of intramolecular charge transfer within the dyes. Smaller polyene chain lengths yielded the most favorable results when evaluating the efficiency of electron injection and regeneration. This means that the charge transfer mechanism between the conduction band of the semiconductor and the electrolyte is not improved by extending the polyene bridge. The open circuit voltage (VOC) was reduced from 1.23 to 0.70 V. Similarly, the excited-state duration (τ) decreased from 1.71 to 1.23 ns as the number of polyene units increased from n = 1 to n = 10. These findings are incompatible with the power conversion efficiency requirements of DSSCs. Therefore, the elongation of the polyene bridge in such D-π-A configurations rules out its application in solar cell devices.
Assuntos
Corantes , Polienos , Energia Solar , Polienos/química , Corantes/química , Teoria da Densidade Funcional , Compostos de Anilina/química , Transporte de ElétronsRESUMO
Three types of starch with different amylose content were esterified and blended with polybutylene succinate (PBS) to obtain esterified manioc starch/PBS (EMS/PBS), esterified corn starch/PBS (ECS/PBS), and esterified waxy corn starch/PBS (EWS/PBS) composites. The EMS/PBS and ECS/PBS composites with high amylose content displayed typical V-type crystal structures. The original crystals of EWS, which had low amylose content, were disrupted during the esterification process. EWS exhibited the strongest interaction with PBS and the most favorable interface compatibility. The pyrolysis temperature was in order of EMS/PBS < ECS/PBS < EWS/PBS. The elongation at break of the three blends was higher than that of pure PBS. The esterification and plasticization of the EWS/PBS composite were the most comprehensive. The EWS/PBS composite showed the lowest storage modulus (G') and complex viscosity (η*). The interfacial bonding force of the composite materials increased with more amylopectin, decreasing intermolecular forces and destroying crystal structures, which decreased G' and η* and increased toughness. The EWS/PBS composite, with the least amylose content, had the best hydrophobicity and degradation performance.
Assuntos
Amilose , Amilose/química , Esterificação , Amido/química , Polímeros/química , Viscosidade , Polienos/química , Zea mays/química , Butileno Glicóis/químicaRESUMO
Six new polyene carboxylic acids named serpentemycins E-J (1-6), together with three known analogs (7-9), were isolated from the fermentation medium of Streptomyces sp. TB060207, which was isolated from arid soil collected from Tibet, China. The structures of the new compounds were elucidated mainly on the basis of HR-ESI-MS and NMR spectroscopic analyses. The inhibitory activities of compounds 1-9 against NO production in LPS-activated RAW264.7 cells were evaluated. Compound 9 has an inhibition rate of 87.09% to 60.53% at concentrations ranging from 5.0 to 40.0 µM.
Assuntos
Ácidos Carboxílicos , Streptomyces , Ácidos Carboxílicos/farmacologia , Tibet , Streptomyces/química , Espectroscopia de Ressonância Magnética , Polienos/químicaRESUMO
We report the development of ureas as sterically undemanding pro-ligands for Pd catalysis. N-Arylureas outperform phosphine ligands for the Pd-catalyzed heteroannulation of N-tosyl-o-bromoanilines and 1,3-dienes, engaging diverse coupling partners for the preparation of 2-subsituted indolines, including sterically demanding substrates that have not previously been tolerated. Experimental and computational studies on model Pd-urea and Pd-ureate complexes are consistent with monodentate binding through the nonsubstituted nitrogen, which is uncommon for metal-ureate complexes.
Assuntos
Paládio , Polienos , Catálise , Ligantes , Paládio/química , Polienos/química , UreiaRESUMO
Dinitrogen heterocycles are among the most important molecular structures, and the synthesis of these types of structures through intermolecular 1,2-diamination of olefins is a direct and efficient method. However, the types of nitrogen sources are mostly derived from ureas or arylamines, and nitrogen sources from aliphatic amines are still limited due to their distinct electronic and steric effects. Herein, we report a palladium-catalyzed aerobic intermolecular 1,2-diamination of conjugated dienes, using ethanediamine and α-amino amide derivatives as nitrogen sources respectively, for the synthesis of piperazines and 2-piperazinones in good yields (up to 95 %) and with high regio- and chemoselectivities.
Assuntos
Paládio , Piperazinas , Alcenos/química , Aminas/química , Catálise , Nitrogênio/química , Paládio/química , Polienos/químicaRESUMO
Molecular glues are an intriguing therapeutic modality that harness small molecules to induce interactions between proteins that typically do not interact. However, such molecules are rare and have been discovered fortuitously, thus limiting their potential as a general strategy for therapeutic intervention. We postulated that natural products bearing one or more electrophilic sites may be an unexplored source of new molecular glues, potentially acting through multicovalent attachment. Using chemoproteomic platforms, we show that members of the manumycin family of polyketides, which bear multiple potentially reactive sites, target C374 of the putative E3 ligase UBR7 in breast cancer cells, and engage in molecular glue interactions with the neosubstrate tumor-suppressor TP53, leading to p53 transcriptional activation and cell death. Our results reveal an anticancer mechanism of this natural product family, and highlight the potential for combining chemoproteomics and multicovalent natural products for the discovery of new molecular glues.
Assuntos
Antineoplásicos/química , Neoplasias da Mama/tratamento farmacológico , Polienos/química , Policetídeos/química , Alcamidas Poli-Insaturadas/química , Proteína Supressora de Tumor p53/metabolismo , Ubiquitina-Proteína Ligases/metabolismo , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Reagentes de Ligações Cruzadas/química , Descoberta de Drogas , Feminino , Regulação Neoplásica da Expressão Gênica , Técnicas de Silenciamento de Genes , Humanos , Conformação Molecular , Estrutura Molecular , Polienos/farmacologia , Alcamidas Poli-Insaturadas/farmacologia , Eletricidade Estática , Relação Estrutura-Atividade , Proteína Supressora de Tumor p53/genética , Ubiquitina-Proteína Ligases/genéticaRESUMO
Ambreinolide is a natural terpenoid with great value for perfume industry and natural product synthesis. Herein we report a novel total synthesis of ambreinolide on multigram-scale that employs a regio- and diastereoselective, high yielding, proton-initiated polyene cyclization using a catalyst easily generated in situ. Molecular structures were unambiguously confirmed by X-ray crystallography.
Assuntos
Polienos , Terpenos , Cristalografia por Raios X , Ciclização , Estrutura Molecular , Polienos/química , Estereoisomerismo , Terpenos/químicaRESUMO
Alternapyrone is a highly methylated polyene α-pyrone biosynthesised by a highly reducing polyketide synthase. Mutations of the catalytic dyad residues, H1578A/Q and E1604A, of the C-methyltransferase domain resulted in either significantly reduced or no production of alternapyrone, indicating the importance of C-methylation for alternapyrone biosynthesis.
Assuntos
Policetídeo Sintases , Triterpenos , Metilação , Polienos/química , Policetídeo Sintases/metabolismoRESUMO
Over the past few decades (covering 1972 to 2022), astounding progress has been made in the elucidation of structures, bioactivities and biosynthesis of polyene macrolactams (PMLs), but they have only been partially summarized. PMLs possess a wide range of biological activities, particularly distinctive fungal inhibitory abilities, which render them a promising drug candidate. Moreover, the unique biosynthetic pathways including ß-amino acid initiation and pericyclic reactions were presented in PMLs, leading to more attention from inside and outside the natural products community. According to current summation, in this review, the chem- and bio-diversity of PMLs from marine and terrestrial sources are considerably rich. A systematic, critical and comprehensive overview is in great need. This review described the PMLs' general structural features, production strategies, biosynthetic pathways and the mechanisms of bioactivities. The challenges and opportunities for the research of PMLs are also discussed.
Assuntos
Produtos Biológicos , Polienos , Produtos Biológicos/farmacologia , Vias Biossintéticas , Polienos/química , Polienos/farmacologiaRESUMO
Streptomyces are of great interest in the pharmaceutical industry as they produce a plethora of secondary metabolites that act as antibacterial and antifungal agents. They may thrive on their own in the soil, or associate with other organisms, such as plants or invertebrates. Some soil-derived strains exhibit hemolytic properties when cultivated on blood agar, raising the question of whether hemolysis could be a virulence factor of the bacteria. In this work we examined hemolytic compound production in 23 ß-hemolytic Streptomyces isolates; of these 12 were soil-derived, 10 were arthropod-associated, and 1 was plant-associated. An additional human-associated S. sp. TR1341 served as a control. Mass spectrometry analysis suggested synthesis of polyene molecules responsible for the hemolysis: candicidins, filipins, strevertene A, tetrafungin, and tetrin A, as well as four novel polyene compounds (denoted here as polyene A, B, C, and D) in individual liquid cultures or paired co-cultures. The non-polyene antifungal compounds actiphenol and surugamide A were also identified. The findings indicate that the ability of Streptomyces to produce cytolytic compounds (here manifested by hemolysis on blood agar) is an intrinsic feature of the bacteria in the soil environment and could even serve as a virulence factor when colonizing available host organisms. Additionally, a literature review of polyenes and non-polyene hemolytic metabolites produced by Streptomyces is presented.
Assuntos
Streptomyces , Humanos , Streptomyces/química , Antifúngicos/farmacologia , Antifúngicos/química , Antibacterianos/farmacologia , Antibacterianos/metabolismo , Polienos/farmacologia , Polienos/química , Hemólise , Fatores de Virulência/metabolismoRESUMO
A transmembrane proton gradient is generated and maintained by proton pumps in a cell. Metagenomics studies have recently identified a new category of rhodopsin intermediates between type-1 rhodopsins and heliorhodopsins, named schizorhodopsins (SzRs). SzRs are light-driven inward proton pumps. Comprehensive resonance Raman measurements were conducted to characterize the structure of the retinal chromophore in the unphotolyzed state of four SzRs. The spectra of all four SzRs show that the retinal chromophore is in the all-trans and 15-anti configuration and that the Schiff base is protonated. The polyene chain is planar in the center of the retinal chromophore and is twisted in the vicinity of the protonated Schiff base. The protonated Schiff base in the SzRs forms a stronger hydrogen bond than that in outward proton-pumping rhodopsins. We determined that the hydrogen-bonding partner of the protonated Schiff base is not a water molecule but an amino acid residue, presumably an Asp residue in helix G. The present observations provide valuable insights into the inward proton-pumping mechanism of SzRs.
Assuntos
Proteínas Arqueais/química , Polienos/química , Bombas de Próton/química , Rodopsinas Microbianas/química , Bases de Schiff/química , Archaea/química , Ligação de HidrogênioRESUMO
This review is centered on the linear conjugated polyenes, which encompasses chromatic biomolecules, such as carotenoids, polyunsaturated aldehydes and polyolefinic fatty acids. The linear extension of the conjugated double bonds in these molecules is the main feature that determines the spectroscopic properties as light-absorbing. These classes of compounds are responsible for the yellow, orange, red and purple colors which are observed in their parent flora and fauna in nature. Raman spectroscopy has been used as analytical tool for the characterization of these molecules, mainly due to the strong light scattering produced by the delocalized pi electrons in the carbon chain. In addition, conjugated polyenes are one of the main target molecular species for astrobiology, and we also present a brief discussion of the use of Raman spectroscopy as one of the main analytical tools for the detection of polyenes extra-terrestrially.
Assuntos
Cor , Polienos/química , Análise Espectral Raman/métodosRESUMO
T-cell acute lymphoblastic leukemia (T-ALL) is a hardly curable disease with a high relapse rate. 20 analogs were synthesized based on the structures of two kinds of fungi-derived polyenylpyrrole products (rumbrin (1) and auxarconjugatin-B (2)) to suppress the growth of T-ALL-derived cell line CCRF-CEM and tested for growth-inhibiting activity. The octatetraenylpyrrole analog gave an IC50 of 0.27 µM in CCRF-CEM cells, while it did not affect Burkitt lymphoma-derived cell line Raji and the cervical cancer cell line HeLa, or the oral cancer cell line HSC-3 (IC50 > 10 µM). This compound will be a promising compound for developing T-ALL-specific drugs.