RESUMEN
Bioprospecting natural products to find prominent agents for medical application is an area of scientific endeavor that has produced many clinically used bioactive compounds, including anticancer agents. These compounds come from plants, microorganisms, and marine life. They are so-called secondary metabolites that are important for a species to survive in the hostile environment of its respective ecosystem. The kingdom of Plantae has been an important source of traditional medicine in the past and is also enormously used today as an exquisite reservoir for detecting novel bioactive compounds that are potent against hard-to-treat maladies such as cancer. Cancer therapies, especially chemotherapies, are fraught with many factors that are difficult to manage, such as drug resistance, adverse side effects, less selectivity, complexity, etc. Here, we report the results of an exploration of the databases of PubMed, Science Direct, and Google Scholar for bioactive anticancer phytochemicals published between 2010 and 2020. Our report is restricted to new compounds with strong-to-moderate bioactivity potential for which mass spectroscopic structural data are available. Each of the phytochemicals reported in this review was assigned to chemical classes with peculiar anticancer properties. In our survey, we found anticancer phytochemicals that are reported to have selective toxicity against cancer cells, to sensitize MDR cancer cells, and to have multitarget effects in several signaling pathways. Surprisingly, many of these compounds have limited follow-up studies. Detailed investigations into the synthesis of more functional derivatives, chemical genetics, and the clinical relevance of these compounds are required to achieve safer chemotherapy.
Asunto(s)
Antineoplásicos , Neoplasias , Humanos , Ecosistema , Fitoquímicos/farmacología , Fitoquímicos/uso terapéutico , Fitoquímicos/química , Medicina Tradicional , Neoplasias/tratamiento farmacológico , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Plantas , Extractos Vegetales/químicaRESUMEN
Covering: 2000 to 2020 The translation of mRNA into proteins is a precisely regulated, complex process that can be divided into three main stages, i.e. initiation, elongation, termination, and recycling. This contribution is intended to highlight how natural products interfere with the elongation phase of eukaryotic protein biosynthesis. Cycloheximide, isolated from Streptomyces griseus, has long been the prototype inhibitor of eukaryotic translation elongation. In the last three decades, a variety of natural products from different origins were discovered to also address the elongation step in different manners, including interference with the elongation factors eEF1 and eEF2 as well as binding to A-, P- or E-sites of the ribosome itself. Recent advances in the crystallization of the ribosomal machinery together with natural product inhibitors allowed characterizing similarities as well as differences in their mode of action. Since aberrations in protein synthesis are commonly observed in tumors, and malfunction or overexpression of translation factors can cause cellular transformation, the protein synthesis machinery has been realized as an attractive target for anticancer drugs. The therapeutic use of the first natural products that reached market approval, plitidepsin (Aplidin®) and homoharringtonine (Synribo®), will be introduced. In addition, we will highlight two other potential indications for translation elongation inhibitors, i.e. viral infections and genetic disorders caused by premature termination of translation.
Asunto(s)
Productos Biológicos/química , Productos Biológicos/farmacología , Extensión de la Cadena Peptídica de Translación/efectos de los fármacos , Antineoplásicos/farmacología , Cicloheximida/química , Cicloheximida/farmacología , Humanos , Extensión de la Cadena Peptídica de Translación/fisiología , Factor 1 de Elongación Peptídica/metabolismo , Inhibidores de la Síntesis de la Proteína/farmacología , Ribosomas/metabolismoRESUMEN
Covering: up to the end of 2018Soraphens are a class of polyketide natural products discovered from the myxobacterial strain Sorangium cellulosum. The review is intended to provide an overview on the biosynthesis, chemistry and biological properties of soraphens, that represent a prime example to showcase the value of natural products as tools to decipher cell biology, but also to open novel therapeutic options. The prototype soraphen A is an inhibitor of acetyl coenzyme A carboxylase (ACC1/2), an enzyme that converts acetyl-CoA to malonyl-CoA and thereby controls essential cellular metabolic processes like lipogenesis and fatty acid oxidation. Soraphens illustrate how the inhibition of a single target (ACC1/2) may be explored to treat various pathological conditions: initially developed as a fungicide, efforts in the past decade were directed towards human diseases, including diabetes/obesity, cancer, hepatitis C, HIV, and autoimmune disease - and led to a synthetic molecule, discovered by virtual screening of the allosteric binding site of soraphen in ACC, that is currently in phase 2 clinical trials. We will summarize how structural analogs of soraphen A have been generated through extensive isolation efforts, genetic engineering of the biosynthetic gene cluster, semisynthesis as well as partial and total synthesis.
Asunto(s)
Fungicidas Industriales/farmacología , Macrólidos/química , Macrólidos/farmacología , Acetilcoenzima A/antagonistas & inhibidores , Acetiltransferasas/antagonistas & inhibidores , Acetiltransferasas/genética , Acetiltransferasas/metabolismo , Agricultura , Animales , Antineoplásicos/química , Antineoplásicos/farmacología , Diseño de Fármacos , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacología , Fungicidas Industriales/química , Ingeniería Genética , Humanos , Hepatopatías/tratamiento farmacológico , Macrólidos/metabolismo , Estructura Molecular , Saccharomyces cerevisiae/genética , Saccharomyces cerevisiae/metabolismo , Relación Estructura-Actividad , Ustilago/enzimologíaRESUMEN
Mutasynthetic supplementation of the AHBA blocked mutant strain of S. hygroscopicus, the geldanamycin producer, with 21 aromatic and heteroaromatic amino acids provided new nonquinoid geldanamycin derivatives. Large scale (5 L) fermentation provided four new derivatives in sufficient quantity for full structural characterisation. Among these, the first thiophene derivative of reblastatin showed strong antiproliferative activity towards several human cancer cell lines. Additionally, inhibitory effects on human heat shock protein Hsp90α and bacterial heat shock protein from H. pylori HpHtpG were observed, revealing strong displacement properties for labelled ATP and demonstrating that the ATP-binding site of Hsps is the target site for the new geldanamycin derivatives.
Asunto(s)
Antineoplásicos/farmacología , Benzoquinonas/farmacología , Proteínas de Choque Térmico/antagonistas & inhibidores , Lactamas Macrocíclicas/farmacología , Antineoplásicos/química , Antineoplásicos/aislamiento & purificación , Benzoquinonas/química , Benzoquinonas/aislamiento & purificación , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Proteínas de Choque Térmico/metabolismo , Helicobacter pylori/química , Humanos , Lactamas Macrocíclicas/química , Lactamas Macrocíclicas/aislamiento & purificación , Estructura Molecular , Streptomyces/química , Relación Estructura-ActividadRESUMEN
Thirteen new reblastatin derivatives, with alkynyl, amino and fluoro substituents on the aromatic ring, were prepared by a chemo-biosynthetic approach using an AHBA(-) mutant strain of Streptomyces hygroscopicus, the geldanamycin producer. The inhibitory potencies of these mutaproducts and of an extended library of natural products and derivatives were probed with purified heat shock proteins (Hsps), obtained from Leishmania braziliensis (LbHsp90) as well as from human sources (HsHsp90). We determined the activities of potential inhibitors by means of a displacement assay in which fluorescence-labelled ATP competes for the ATP binding sites of Hsps in the presence of the inhibitor in question. The results were compared with those of cell-based assays and, in selected cases, of isothermal titration calorimetry (ITC) measurements. In essence, reblastatin derivatives are also able to bind effectively to the ATP-binding site of LbHsp90, and for selected derivatives, moderate differences in binding to LbHsp90 and HsHsp90 were encountered. This work demonstrates that parasitic heat shock proteins can be developed as potential pharmaceutical targets.
Asunto(s)
Antibacterianos/farmacología , Proteínas de Choque Térmico/antagonistas & inhibidores , Quinonas/farmacología , Streptomyces/efectos de los fármacos , Antibacterianos/síntesis química , Antibacterianos/química , Relación Dosis-Respuesta a Droga , Proteínas de Choque Térmico/metabolismo , Humanos , Pruebas de Sensibilidad Microbiana , Estructura Molecular , Quinonas/síntesis química , Quinonas/química , Streptomyces/química , Streptomyces/genética , Relación Estructura-ActividadRESUMEN
Pathogens embedded in biofilms are involved in many infections and are very difficult to treat with antibiotics because of higher resistance compared with planktonic cells. Therefore, new approaches for their control are urgently needed. One way to search for biofilm dispersing compounds is to look at defense strategies of organisms exposed to wet environments, which makes them prone to biofilm infections. It is reasonable to assume that mushrooms have developed mechanisms to control biofilms on their sporocarps (fruiting bodies). A preliminary screening for biofilms on sporocarps revealed several species with few or no bacteria on their sporocarps. From the edible mushroom Coprinus comatus where no bacteria on the sporocarp could be detected (3R,4S)-2-methylene-3,4-dihydroxypentanoic acid 1,4-lactone, named coprinuslactone, was isolated. Coprinuslactone interfered with quorum-sensing and dispersed biofilms of Pseudomonas aeruginosa, where it also reduced the formation of the pathogenicity factors pyocyanin and rhamnolipid B. Coprinuslactone also damaged Staphylococcus aureus cells in biofilms at subtoxic concentrations. Furthermore, it inhibited UDP-N-acetylglucosamine enolpyruvyl transferase (MurA), essential for bacterial cell wall synthesis. These two modes of action ensure the inhibition of a broad spectrum of pathogens on the fruiting body but may also be useful for future clinical applications.
Asunto(s)
Transferasas Alquil y Aril/genética , Proteínas Bacterianas/genética , Biopelículas/efectos de los fármacos , Coprinus/química , Lactonas/farmacología , Pseudomonas aeruginosa/fisiología , Percepción de Quorum/efectos de los fármacos , Staphylococcus aureus/efectos de los fármacos , Verduras/microbiología , Transferasas Alquil y Aril/metabolismo , Proteínas Bacterianas/metabolismo , Coprinus/metabolismo , Cuerpos Fructíferos de los Hongos/química , Cuerpos Fructíferos de los Hongos/metabolismo , Glucolípidos/metabolismo , Lactonas/metabolismo , Pseudomonas aeruginosa/efectos de los fármacos , Pseudomonas aeruginosa/enzimología , Staphylococcus aureus/enzimología , Staphylococcus aureus/fisiología , Verduras/química , Verduras/metabolismoRESUMEN
In order to construct the functionalized AB ring system of clifednamide, member of the class of macrocyclic tetramic acid lactams, a synthesis was developed which utilized an Ireland-Claisen rearrangement and an intramolecular Diels-Alder reaction. Starting from di-O-isopropylidene-d-mannitol the allyl carboxylate precursor for the sigmatropic rearrangement was prepared. This rearrangement proceeded diastereoselectively only in the presence of an allyl silyl ether instead of the parent enone in the side chain, as suggested by deuteration experiments. A subsequent Diels-Alder reaction yielded the target ethyl hexahydro-1H-indene-carboxylate with high diastereoselectivity. Quantum-chemical investigations of this intramolecular Diels-Alder reaction support the proposed configuration of the final product.
Asunto(s)
Reacción de Cicloadición , Compuestos Heterocíclicos de 4 o más Anillos/síntesis química , Manitol/química , Pirrolidinonas/síntesis química , Compuestos Heterocíclicos de 4 o más Anillos/química , Manitol/análogos & derivados , Estructura Molecular , Pirrolidinonas/química , Teoría Cuántica , EstereoisomerismoRESUMEN
The synthesis of the diterpene (+)-tonantzitlolone A and a series of derivatives is reported. The study includes the determination of their antiproliferative activities against selected cancer cell lines.
Asunto(s)
Antineoplásicos/síntesis química , Antineoplásicos/farmacología , Diterpenos/síntesis química , Diterpenos/farmacología , Compuestos Macrocíclicos/síntesis química , Compuestos Macrocíclicos/farmacología , Antineoplásicos/química , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Técnicas de Química Sintética , Diterpenos/química , Humanos , Compuestos Macrocíclicos/químicaRESUMEN
Streptomyces hygroscopicus is a natural producer of geldanamycin. Mutasynthetic supplementation of an AHBA-blocked mutant with all possible monofluoro 3-aminobenzoic acids provided new fluorogeldanamycins. These showed strong antiproliferative activity and inhibitory effects on human heat shock protein Hsp90. Binding to Hsp90 in the low nanomolar range was determined from molecular modelling, AFM analysis and by calorimetric studies.
Asunto(s)
Antineoplásicos/química , Antineoplásicos/farmacología , Benzoquinonas/química , Proteínas HSP90 de Choque Térmico/antagonistas & inhibidores , Lactamas Macrocíclicas/química , Streptomyces/metabolismo , Antineoplásicos/metabolismo , Calorimetría/métodos , Línea Celular Tumoral/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Fluorobencenos/metabolismo , Fluorobencenos/farmacología , Proteínas HSP90 de Choque Térmico/metabolismo , Humanos , Espectroscopía de Resonancia Magnética , Microscopía de Fuerza Atómica , Modelos Moleculares , Quinonas/química , Streptomyces/genética , metaminobenzoatos/metabolismo , metaminobenzoatos/farmacologíaRESUMEN
The soraphens are natural products that exhibit a molecular structure different from what would have been expected by following its polyketidal assembly line. The most significant differences are the presence of a hemiketal instead of a trisubstituted double bond and a double bond at C9 and C10 where a saturated carbon chain was expected. We were interested in the biological activity of the soraphens with architectures as described by the polyketide synthase since we hypothesized that these modifications reflect the evolutionary optimization of the soraphens. Herein we describe four additional derivatives of the so-called paleo-soraphens and their biological profiling to provide a picture of the hypothetical evolutionary optimization of this family of natural products. The syntheses required a unified and convergent strategy and their biological profiling was performed with the aid of impedance measurements. The results of these biological experiments are consistent with the proposed evolutionary optimization of the soraphens.
Asunto(s)
Macrólidos/síntesis química , Macrólidos/farmacología , Animales , Línea Celular , Análisis por Conglomerados , Impedancia Eléctrica , Cinética , Macrólidos/química , Ratones , Conformación Molecular , EstereoisomerismoRESUMEN
The tedanolides are biologically active polyketides that exhibit a macrolactone constructed from a primary alcohol. Since polyketidal transformations only generate secondary alcohols, it has been hypothesized by Taylor that this unique lactone could arise from a postketidal transesterification. In order to probe this hypothesis and to investigate the biological profile of the putative precursor of all members of the tedanolide family, we embarked on the synthesis of desepoxyisotedanolide and its biological evaluation in comparison to desepoxytedanolide. The biological experiments unraveled a second target for desepoxytedanolide and provided evidence that the proposed transesterification indeed provides a survival advantage for the producing microorganism.
Asunto(s)
Macrólidos/síntesis química , Macrólidos/farmacología , Animales , Línea Celular , Proliferación Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Células Eucariotas/efectos de los fármacos , Células Eucariotas/metabolismo , Fibroblastos/efectos de los fármacos , Humanos , Macrólidos/química , Ratones , Conformación Molecular , Poríferos/química , Conejos , Relación Estructura-ActividadRESUMEN
A combination of mutasynthesis, precursor-directed biosynthesis and semisynthesis provides access to new ansamitocin derivatives including new nanostructured particle-drug conjugates. These conjugates are based on the toxin ansamitocin and superparamagnetic iron oxide-silica core shell particles. New ansamitocin derivatives that are functionalized either with alkynyl- or azido groups in the ester side chain at C-3 are attached to nanostructured iron oxide core-silica shell particles. Upon exposure to an oscillating electromagnetic field these conjugates heat up and the ansamitocin derivatives are released by a retro-Diels-Alder reaction. For example, one ansamitocin derivative exerts strong antiproliferative activity against various cancer cell lines in the lower nanomolar range while the corresponding nanostructured particle-drug conjugate is not toxic. Therefore, these new conjugates can serve as dormant toxins that can be employed simultaneously in hyperthermia and chemotherapy when external inductive heating is applied.
Asunto(s)
Compuestos Férricos/química , Maitansina/análogos & derivados , Nanoestructuras/química , Dióxido de Silicio/química , Línea Celular Tumoral , Proliferación Celular , Reacción de Cicloadición , Fiebre/inducido químicamente , Humanos , Magnetismo , Maitansina/biosíntesis , Maitansina/química , Estructura MolecularRESUMEN
BACKGROUND: The nuclear export of unspliced and partially spliced HIV-1 mRNA is mediated by the recognition of a leucine-rich nuclear export signal (NES) in the HIV Rev protein by the host protein CRM1/Exportin1. This makes the CRM1-Rev complex an attractive target for the development of new antiviral drugs. Here we tested the anti-HIV efficacy of ratjadone A, a CRM1 inhibitor derived from myxobacteria. RESULTS: Ratjadone A inhibits HIV infection in vitro in a dose-dependent manner with EC50 values at the nanomolar range. The inhibitory effect of ratjadone A occurs around 12 hours post-infection and is specific for the Rev/CRM1-mediated nuclear export pathway. By using a drug affinity responsive target stability (DARTS) assay we could demonstrate that ratjadone A interferes with the formation of the CRM1-Rev-NES complex by binding to CRM1 but not to Rev. CONCLUSION: Ratjadone A exhibits strong anti-HIV activity but low selectivity due to toxic effects. Although this limits its potential use as a therapeutic drug, further studies with derivatives of ratjadones might help to overcome these difficulties in the future.
Asunto(s)
Infecciones por VIH/prevención & control , VIH-1/metabolismo , Carioferinas/metabolismo , Myxococcales/metabolismo , Pironas/metabolismo , Receptores Citoplasmáticos y Nucleares/metabolismo , Productos del Gen rev del Virus de la Inmunodeficiencia Humana/metabolismo , Transporte Activo de Núcleo Celular/efectos de los fármacos , Antivirales/farmacología , Línea Celular , Proteína p24 del Núcleo del VIH/metabolismo , Humanos , Carioferinas/antagonistas & inhibidores , Unión Proteica , Pironas/química , Pironas/farmacología , ARN Mensajero/metabolismo , Receptores Citoplasmáticos y Nucleares/antagonistas & inhibidores , Productos del Gen rev del Virus de la Inmunodeficiencia Humana/antagonistas & inhibidores , Proteína Exportina 1RESUMEN
A new series of sulfur, selenium and tellurium peptidomimetic compounds was prepared employing the Passerini and Ugi isocyanide based multicomponent reactions (IMCRs). These reactions were clearly superior to conventional methods traditionally used for organoselenium and organotellurium synthesis, such as classical nucleophilic substitution and coupling methods. From the biological point of view, these compounds are of considerable interest because of suspected anticancer and antimicrobial activities. While the sulfur and selenium containing compounds generally did not show either anticancer or antimicrobial activities, their tellurium based counterparts frequently exhibited antimicrobial activity and were also cytotoxic. Some of the compounds synthesized even showed selective activity against certain cancer cells in cell culture. These compounds induced a cell cycle delay in the G0/G1 phase. At closer inspection, the ER and the actin cytoskeleton appeared to be the primary cellular targets of these tellurium compounds, in line with some of our previous studies. As most of these peptidomimetic compounds also comply with Lipinski's Rule of Five, they promise good bioavailability, which needs to be studied as part of future investigations.
Asunto(s)
Antibacterianos/farmacología , Antifúngicos/farmacología , Antineoplásicos/farmacología , Bacterias/efectos de los fármacos , Hongos/efectos de los fármacos , Peptidomiméticos/farmacología , Antibacterianos/síntesis química , Antibacterianos/química , Antifúngicos/síntesis química , Antifúngicos/química , Antineoplásicos/síntesis química , Antineoplásicos/química , Bacterias/crecimiento & desarrollo , Ciclo Celular/efectos de los fármacos , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Hongos/crecimiento & desarrollo , Humanos , Células MCF-7 , Pruebas de Sensibilidad Microbiana , Estructura Molecular , Péptidos/química , Peptidomiméticos/síntesis química , Peptidomiméticos/química , Selenio/química , Relación Estructura-Actividad , Azufre/química , Telurio/químicaRESUMEN
Structurally diverse bicyclo[3.3.0]octanes were prepared and tested for their biological activity. Both the antiproliferative activity and the results of phenotypic characterization varied with the substitution patterns. Two derivatives displayed high inhibitory (IC50 ≤3µM) activity against the L-929 cell line, but differed in their mode of action. A cluster analysis with impedance profiling data showed the two compounds in relationship to microtubule interfering compounds. In PtK2 cells treated with both derivatives a perturbing effect on the microtubular network was observed, whereas the actin cytoskeleton in incubated PtK2 cells was disturbed only by one compound. The effects on tubulin and actin polymerization could be confirmed by in vitro polymerization experiments.
Asunto(s)
Antineoplásicos/farmacología , Compuestos Bicíclicos con Puentes/farmacología , Lactamas Macrocíclicas/farmacología , Pirrolidinonas/farmacología , Animales , Antineoplásicos/síntesis química , Antineoplásicos/química , Compuestos Bicíclicos con Puentes/síntesis química , Compuestos Bicíclicos con Puentes/química , Línea Celular , Proliferación Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Evaluación Preclínica de Medicamentos , Humanos , Lactamas Macrocíclicas/síntesis química , Lactamas Macrocíclicas/química , Ratones , Conformación Molecular , Pirrolidinonas/síntesis química , Pirrolidinonas/química , Relación Estructura-ActividadRESUMEN
The preparation of alkyne-modified ansamitocins by mutasynthetic supplementation of Actinosynnema pretiosum mutants with alkyne-substituted aminobenzoic acids is described. This modification paved the way to introduce a thiol linker by Huisgen-type cycloaddition which can principally be utilized to create tumor targeting conjugates. In bioactivity tests, only those new ansamitocin derivatives showed strong antiproliferative activity that bear an ester side chain at C-3.
RESUMEN
Myriaporone 3/4, a cytotoxic polyketide, has been reported as an inhibitor of eukaryotic protein synthesis. However, the mechanism by which it inhibits translation was unknown. Here we show that myriaporone 3/4 stalls protein synthesis in the elongation phase by inducing phosphorylation of eukaryotic elongation factor 2. The phosphorylation results from direct binding of myriaporone 3/4 to eukaryotic elongation factor 2 kinase. Our study also shows that myriaporone 3/4 in the nanomolar range inhibits in vitro tube formation by endothelial cells without being cytotoxic. In general, myriaporone 3/4 was at least 300 times less toxic to primary cells than to tumor cells.
Asunto(s)
Inhibidores de la Angiogénesis/farmacología , Antineoplásicos/farmacología , Compuestos Epoxi/farmacología , Factor 2 de Elongación Peptídica/metabolismo , Biosíntesis de Proteínas/efectos de los fármacos , Piranos/farmacología , Animales , Briozoos/química , Línea Celular , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Quinasa del Factor 2 de Elongación/metabolismo , Humanos , Neoplasias/tratamiento farmacológico , Neoplasias/metabolismo , Fosforilación/efectos de los fármacosRESUMEN
BACKGROUND: Drug-resistance and therapy failure due to drug-drug interactions are the main challenges in current treatment against Human Immunodeficiency Virus (HIV) infection. As such, there is a continuous need for the development of new and more potent anti-HIV drugs. Here we established a high-throughput screen based on the highly permissive TZM-bl cell line to identify novel HIV inhibitors. The assay allows discriminating compounds acting on early and/or late steps of the HIV replication cycle. RESULTS: The platform was used to screen a unique library of secondary metabolites derived from myxobacteria. Several hits with good anti-HIV profiles were identified. Five of the initial hits were tested for their antiviral potency. Four myxobacterial compounds, sulfangolid C, soraphen F, epothilon D and spirangien B, showed EC50 values in the nM range with SI > 15. Interestingly, we found a high amount of overlapping hits compared with a previous screen for Hepatitis C Virus (HCV) using the same library. CONCLUSION: The unique structures and mode-of-actions of these natural compounds make myxobacteria an attractive source of chemicals for the development of broad-spectrum antivirals. Further biological and structural studies of our initial hits might help recognize smaller drug-like derivatives that in turn could be synthesized and further optimized.
Asunto(s)
Fármacos Anti-VIH/aislamiento & purificación , Fármacos Anti-VIH/farmacología , Myxococcales/química , Resistencia a Medicamentos , Ensayos Analíticos de Alto Rendimiento/métodos , HumanosRESUMEN
Two diasteroisomers of the Penicillium metabolite penicillenol C1 were synthesized for the first time by 3-acylation of an L-threonine-derived tetramic acid with enantiopure 2-methyloct-(6E)-enoic acids. The 5S,6R,9S isomer has NMR spectra and optical rotation identical with those of the natural compound. A bis-azide-tagged penicillenol analogue was also synthesized for photoaffinity labeling of target proteins. The photolysis of the bis-azide in the presence of methanol as a protein-mimicking nucleophile led to reaction only of the aryl azide, while leaving the benzyl azide available for pull-downs or the attachment of fluorescent tracers. As a proof of concept, the distribution of this bis-azide-tagged tetramic acid in living cells was visualized via a Staudinger ligation between the azide tag and a phosphane fluorophore.
Asunto(s)
Marcadores de Afinidad/síntesis química , Azidas/química , Azidas/síntesis química , Colorantes Fluorescentes/química , Pirrolidinonas/química , Pirrolidinonas/síntesis química , Treonina/química , Acilación , Marcadores de Afinidad/química , Espectroscopía de Resonancia Magnética , Fotólisis , Estereoisomerismo , Treonina/metabolismoRESUMEN
An efficient procedure for the concise synthesis of hetero-bis-metallated alkenes as useful building blocks for the modular access to highly elaborate polyenes and stabilized analogues is reported. By applying these bifunctional olefins in convergent Stille/Suzuki-Miyaura couplings, novel, carefully selected side chain analogues of the potent RNA polymerase inhibitor etnangien were synthesized by a modular late stage coupling strategy and evaluated for antibacterial and antiproliferative activities.