RESUMEN
The development of safe and effective broad-spectrum antivirals that target the replication machinery of respiratory viruses is of high priority in pandemic preparedness programs. Here, we studied the mechanism of action of a newly discovered nucleotide analog against diverse RNA-dependent RNA polymerases (RdRps) of prototypic respiratory viruses. GS-646939 is the active 5'-triphosphate metabolite of a 4'-cyano modified C-adenosine analog phosphoramidate prodrug GS-7682. Enzyme kinetics show that the RdRps of human rhinovirus type 16 (HRV-16) and enterovirus 71 incorporate GS-646939 with unprecedented selectivity; GS-646939 is incorporated 20-50-fold more efficiently than its natural ATP counterpart. The RdRp complex of respiratory syncytial virus and human metapneumovirus incorporate GS-646939 and ATP with similar efficiency. In contrast, influenza B RdRp shows a clear preference for ATP and human mitochondrial RNA polymerase does not show significant incorporation of GS-646939. Once incorporated into the nascent RNA strand, GS-646939 acts as a chain terminator although higher NTP concentrations can partially overcome inhibition for some polymerases. Modeling and biochemical data suggest that the 4'-modification inhibits RdRp translocation. Comparative studies with GS-443902, the active triphosphate form of the 1'-cyano modified prodrugs remdesivir and obeldesivir, reveal not only different mechanisms of inhibition, but also differences in the spectrum of inhibition of viral polymerases. In conclusion, 1'-cyano and 4'-cyano modifications of nucleotide analogs provide complementary strategies to target the polymerase of several families of respiratory RNA viruses.
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Larval attachment organs (LAOs) are unicellular or multicellular organs that enable the larvae of many actinopterygian fishes to adhere to a substrate before yolk-sac absorption and the free-swimming stage. Bowfins (Amiiformes) exhibit a sizable LAO on the snout, which was first described in the late 19th and early 20th centuries. In this study, we document the LAO of Amia ocellicauda (Richardson, 1836) using a combination of scanning electron microscopy (SEM) and light microscopy, and histochemistry. We examined material representing three stages with SEM ranging in size from 5.8 to 11.2 mm in notochord length and one stage histochemically. We compare the LAO of A. ocellicauda to that of the lepisosteid Atractosteus tropicus Gill, 1863 and show that although the LAOs of A. ocellicauda and A. tropicus are both super-organs, the two differ in the ultrastructure of the entire organ. A. ocellicauda possesses two distinct lobes, with the organs arranged on the periphery with none in the middle, whereas A. tropicus also possesses two lobes, but with the organs scattered evenly across the super-organ. The individual organs of A. ocellicauda possess adhesive cells set deep to support cells with the adhesive substance released through a pore, whereas A. tropicus possesses both support cells and adhesive cells sitting at a similar level, with the adhesive substance released directly onto the surface of the organ. We additionally provide a table summarizing vertebrate genera in which attachment organs have been documented and discuss the implications of our study for hypotheses of the homology of attachment organs in the Holostei.
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Peces , Animales , Larva , Filogenia , Microscopía Electrónica de RastreoRESUMEN
The most recent Ebola virus outbreak in West Africa, which was unprecedented in the number of cases and fatalities, geographic distribution, and number of nations affected, highlights the need for safe, effective, and readily available antiviral agents for treatment and prevention of acute Ebola virus (EBOV) disease (EVD) or sequelae. No antiviral therapeutics have yet received regulatory approval or demonstrated clinical efficacy. Here we report the discovery of a novel small molecule GS-5734, a monophosphoramidate prodrug of an adenosine analogue, with antiviral activity against EBOV. GS-5734 exhibits antiviral activity against multiple variants of EBOV and other filoviruses in cell-based assays. The pharmacologically active nucleoside triphosphate (NTP) is efficiently formed in multiple human cell types incubated with GS-5734 in vitro, and the NTP acts as an alternative substrate and RNA-chain terminator in primer-extension assays using a surrogate respiratory syncytial virus RNA polymerase. Intravenous administration of GS-5734 to nonhuman primates resulted in persistent NTP levels in peripheral blood mononuclear cells (half-life, 14 h) and distribution to sanctuary sites for viral replication including testes, eyes, and brain. In a rhesus monkey model of EVD, once-daily intravenous administration of 10 mg kg(-1) GS-5734 for 12 days resulted in profound suppression of EBOV replication and protected 100% of EBOV-infected animals against lethal disease, ameliorating clinical disease signs and pathophysiological markers, even when treatments were initiated three days after virus exposure when systemic viral RNA was detected in two out of six treated animals. These results show the first substantive post-exposure protection by a small-molecule antiviral compound against EBOV in nonhuman primates. The broad-spectrum antiviral activity of GS-5734 in vitro against other pathogenic RNA viruses, including filoviruses, arenaviruses, and coronaviruses, suggests the potential for wider medical use. GS-5734 is amenable to large-scale manufacturing, and clinical studies investigating the drug safety and pharmacokinetics are ongoing.
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Alanina/análogos & derivados , Antivirales/uso terapéutico , Fiebre Hemorrágica Ebola/tratamiento farmacológico , Macaca mulatta/virología , Ribonucleótidos/uso terapéutico , Adenosina Monofosfato/análogos & derivados , Alanina/farmacocinética , Alanina/farmacología , Alanina/uso terapéutico , Secuencia de Aminoácidos , Animales , Antivirales/farmacocinética , Antivirales/farmacología , Línea Celular Tumoral , Ebolavirus/efectos de los fármacos , Femenino , Células HeLa , Fiebre Hemorrágica Ebola/prevención & control , Humanos , Masculino , Datos de Secuencia Molecular , Especificidad de Órganos , Profármacos/farmacocinética , Profármacos/farmacología , Profármacos/uso terapéutico , Ribonucleótidos/farmacocinética , Ribonucleótidos/farmacologíaRESUMEN
Larval attachment organs (LAOs) are unicellular or multicellular organs that allow larvae to adhere to a substrate before yolk-sac absorption and the free-swimming stage. This study documents the LAO of tropical gar, Atractosteus tropicus, using a combination of scanning electron microscopy and light microscopy. It is shown that the LAO of A. tropicus is a super-organ surrounded by a wall and containing at its centre many smaller multicellular organ units, each comprised of attachment and support cells. Attachment cells are secretory and house large vacuoles filled with a glycoprotein. At hatching, the super-organ is well developed and occupies almost the entire anteroventral surface of the head. During subsequent development, the smaller individual units begin to regress, until at 6 days post-hatching the super-organ and its individual units are no longer visible.
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Peces , Branquias , Animales , LarvaRESUMEN
Treatment of hepatitis C virus (HCV) infection has been historically challenging due the high viral genetic complexity wherein there are eight distinct genotypes and at least 86 viral subtypes. While HCV NS3/4A protease inhibitors are an established treatment option for genotype 1 infection, limited coverage of genotypes 2 and/or 3 combined with serum alanine transaminase (ALT) elevations for some compounds has limited the broad utility of this therapeutic class. Our discovery efforts were focused on identifying an NS3/4A protease inhibitor with pan-genotypic antiviral activity, improved coverage of resistance associated substitutions, and a decreased risk of hepatotoxicity. Towards this goal, distinct interactions with the conserved catalytic triad of the NS3/4A protease were identified that improved genotype 3 antiviral activity. We further discovered that protein adduct formation strongly correlated with clinical ALT elevation for this therapeutic class. Improving metabolic stability and decreasing protein adduct formation through structural modifications ultimately resulted in voxilaprevir. Voxilaprevir, in combination with sofosbuvir and velpatasvir, has demonstrated pan-genotypic antiviral clinical activity. Furthermore, hepatotoxicity was not observed in Phase 3 clinical trials with voxilaprevir, consistent with our design strategy. Vosevi® (sofosbuvir, velpatasvir, and voxilaprevir) is now an approved pan-genotypic treatment option for the most difficult-to-cure individuals who have previously failed direct acting antiviral therapy.
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Antivirales/farmacología , Carbamatos/química , Descubrimiento de Drogas , Hepacivirus/efectos de los fármacos , Compuestos Heterocíclicos de 4 o más Anillos/química , Compuestos Macrocíclicos/química , Compuestos Macrocíclicos/farmacología , Inhibidores de Proteasas/farmacología , Sofosbuvir/química , Sulfonamidas/química , Sulfonamidas/farmacología , Proteínas no Estructurales Virales/antagonistas & inhibidores , Ácidos Aminoisobutíricos , Antivirales/síntesis química , Antivirales/química , Ciclopropanos , Relación Dosis-Respuesta a Droga , Combinación de Medicamentos , Hepacivirus/genética , Humanos , Lactamas Macrocíclicas , Leucina/análogos & derivados , Compuestos Macrocíclicos/síntesis química , Pruebas de Sensibilidad Microbiana , Estructura Molecular , Prolina/análogos & derivados , Inhibidores de Proteasas/síntesis química , Inhibidores de Proteasas/química , Quinoxalinas , Relación Estructura-Actividad , Sulfonamidas/síntesis química , Proteínas no Estructurales Virales/genética , Proteínas no Estructurales Virales/metabolismoRESUMEN
Previous studies have revealed variations in the urogenital system morphology of amphibians. Recently, the urogenital system of salamanders was reviewed and terminology was synonymized across taxa. Discrepancies exist in the terminology describing the urogenital system of anurans, which prompted our group to develop a complete, detailed description of the urogenital system in an anuran species and provide nomenclature that is synonymous with those of other amphibian taxa. In Rana catesbeiana, sperm mature within spermatocysts of the seminiferous tubule epithelia and are transported to a series of intratesticular ducts that exit the testes and merge to form vasa efferentia. Vasa efferentia converge into single longitudinal ducts (Bidder's ducts) on the lateral aspects of the kidneys. Branches from the longitudinal ducts merge with genital kidney renal tubules through renal corpuscles. The nephrons travel caudally and empty into the Wöffian ducts. Similar to salamanders, the caudal portion of the kidneys (termed the pelvic kidneys in salamanders) only possesses nephrons involved in urine formation, not sperm transport. Data from the present study provide a detailed description and synonymous nomenclature that can be used to make future comparative analyses between taxa more efficient.
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Genitales Masculinos/anatomía & histología , Rana catesbeiana/anatomía & histología , Sistema Urogenital/anatomía & histología , Animales , MasculinoRESUMEN
Mental glands and their associated delivery behaviors during courtship are unique to the plethodontid salamanders. Because previous interpretations of the evolution of these features were conducted using older phylogenetic hypotheses, we reanalyzed these traits with newer courtship descriptions and contemporary phylogenetic methods. Using Bayesian ancestral state reconstruction methods that have been developed since the first phylogenetic analyses were conducted in the mid-1990s, we reconstructed mental gland and courtship behavior evolution on a Bayesian phylogeny of the nuclear gene Rag1. The most probable ancestral condition for plethodontids was resolved as presence of a mental gland. Loss of a mental gland occurred in each subfamily and was recovered as the most probable ancestral condition for the Spelerpinae. In contrast, parsimony reconstruction recovered the presence of a mental gland in the ancestor to Spelerpinae with multiple secondary losses. We hypothesize that that absence of a mental gland is possibly ancestral in some clades (i.e., Spelerpinae) and secondary in others (e.g., paedomorphic Eurycea). The most probable ancestral form of the mental gland is likely to be the large pad-type distributed extensively in Plethodontinae and Bolitoglossinae. Desmognathans have the most unique mental glands, occurring in an anterior protrusion or bifurcated form (in Desmognathus wrighti). Fan-shaped mental glands evolved independently in Eurycea and Oedipina. Small pads arose independently in Bolitoglossinae, Plethodontinae, and Spelerpinae. Head-rubbing behavior for mental gland delivery mode was recovered as the most probable and parsimonious ancestral state for the Plethodontidae, with independent losses of this behavior in Plethodontinae and Spelerpinae. Because head-rubbing was observed in outgroups, we hypothesize that head-rubbing behavior predated mental gland evolution. Pulling, snapping, slapping, and biting behaviors evolved independently in the Plethodontinae and Spelerpinae and are not homologous with head-rubbing. All hypotheses of mental gland and courtship evolution invoke homoplasy.
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Novel 4'-substituted ß-d-2'-deoxy-2'-α-fluoro (2'd2'F) nucleoside inhibitors of respiratory syncytial virus (RSV) are reported. The introduction of 4'-substitution onto 2'd2'F nucleoside analogs resulted in compounds demonstrating potent cell based RSV inhibition, improved inhibition of the RSV polymerase by the nucleoside triphosphate metabolites, and enhanced selectivity over incorporation by mitochondrial RNA and DNA polymerases. Selectivity over the mitochondrial polymerases was found to be extremely sensitive to the specific 4'-substitution and not readily predictable. Combining the most potent and selective 4'-groups from N-nucleoside analogs onto a 2'd2'F C-nucleoside analog resulted in the identification of ß-D-2'-deoxy-2'-α-fluoro-4'-α-cyano-5-aza-7,9-dideaza adenosine as a promising nucleoside lead for RSV.
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Adenosina/química , Antivirales/química , ADN Polimerasa Dirigida por ADN/química , Inhibidores de la Síntesis del Ácido Nucleico/química , ARN Polimerasa Dependiente del ARN/antagonistas & inhibidores , ARN/química , Virus Sincitiales Respiratorios/enzimología , Virus Sincitiales Respiratorios/fisiología , Adenosina/síntesis química , Adenosina/farmacología , Antivirales/síntesis química , Antivirales/farmacología , Compuestos Aza/química , ADN Polimerasa Dirigida por ADN/metabolismo , Evaluación Preclínica de Medicamentos , Inhibidores de la Síntesis del Ácido Nucleico/síntesis química , Inhibidores de la Síntesis del Ácido Nucleico/farmacología , ARN/metabolismo , ARN Mitocondrial , ARN Polimerasa Dependiente del ARN/metabolismo , Virus Sincitiales Respiratorios/efectos de los fármacos , Relación Estructura-Actividad , Replicación Viral/efectos de los fármacosRESUMEN
A versatile strategy for C7-selective boronation of tryptophans, tryptamines, and 3-alkylindoles by way of a single-pot C2/C7-diboronation-C2-protodeboronation sequence is described. The combination of a mild iridium-catalyzed C2/C7-diboronation followed by an in situ palladium-catalyzed C2-protodeboronation allows efficient entry to valuable C7-boroindoles that enable further C7-derivatization. The versatility of the chemistry is highlighted by the gram-scale synthesis of C7-boronated N-Boc-L-tryptophan methyl ester and the rapid synthesis of C7-halo, C7-hydroxy, and C7-aryl tryptophan derivatives.
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Alcaloides Indólicos/síntesis química , Iridio/química , Paladio/química , Triptaminas/química , Triptófano/análogos & derivados , Triptófano/química , Catálisis , Alcaloides Indólicos/químicaRESUMEN
The swimbladder plays an important role in buoyancy regulation but is typically reduced or even absent in benthic freshwater fishes that inhabit fast flowing water. Here, we document, for the first time, a remarkable example of swimbladder sexual dimorphism in the highly rheophilic South Asian torrent minnows (Psilorhynchus). The male swimbladder is not only much larger than that of the female (up to five times the diameter and up to 98 times the volume in some cases), but is also structurally more complex, with multiple internal septa dividing it into smaller chambers. Males also exhibit a strange organ of unknown function or homology in association with the swimbladder that is absent in females. Extreme sexual dimorphism of non-gonadal internal organs is rare among vertebrates and the swimbladder sexual dimorphisms that we describe for Psilorhynchus are unique among fishes.
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Sacos Aéreos/anatomía & histología , Cyprinidae/anatomía & histología , Caracteres Sexuales , Animales , Femenino , Masculino , Filogenia , RíosRESUMEN
Acute respiratory viral infections, such as pneumovirus and respiratory picornavirus infections, exacerbate disease in COPD and asthma patients. A research program targeting respiratory syncytial virus (RSV) led to the discovery of GS-7682 (1), a novel phosphoramidate prodrug of a 4'-CN-4-aza-7,9-dideazaadenosine C-nucleoside GS-646089 (2) with broad antiviral activity against RSV (EC50 = 3-46 nM), human metapneumovirus (EC50 = 210 nM), human rhinovirus (EC50 = 54-61 nM), and enterovirus (EC50 = 83-90 nM). Prodrug optimization for cellular potency and lung cell metabolism identified 5'-methyl [(S)-hydroxy(phenoxy)phosphoryl]-l-alaninate in combination with 2',3'-diisobutyrate promoieties as being optimal for high levels of intracellular triphosphate formation in vitro and in vivo. 1 demonstrated significant reductions of viral loads in the lower respiratory tract of RSV-infected African green monkeys when administered once daily via intratracheal nebulized aerosol. Together, these findings support additional evaluation of 1 and its analogues as potential therapeutics for pneumo- and picornaviruses.
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Antivirales , Picornaviridae , Profármacos , Infecciones por Virus Sincitial Respiratorio , Animales , Antivirales/farmacología , Antivirales/química , Profármacos/farmacología , Profármacos/química , Profármacos/síntesis química , Chlorocebus aethiops , Infecciones por Virus Sincitial Respiratorio/tratamiento farmacológico , Infecciones por Virus Sincitial Respiratorio/virología , Humanos , Picornaviridae/efectos de los fármacos , Relación Estructura-Actividad , Virus Sincitiales Respiratorios/efectos de los fármacos , Descubrimiento de Drogas , Nucleósidos/química , Nucleósidos/farmacología , Infecciones por Picornaviridae/tratamiento farmacológico , Infecciones por Picornaviridae/virologíaRESUMEN
The full details of our enantioselective total syntheses of (-)-agelastatins A-F (1-6), the evolution of a new methodology for synthesis of substituted azaheterocycles, and the first side-by-side evaluation of all known (-)-agelastatin alkaloids against nine human cancer cell lines are described. Our concise synthesis of these alkaloids exploits the intrinsic chemistry of plausible biosynthetic precursors and capitalizes on a late-stage synthesis of the C-ring. The critical copper-mediated cross-coupling reaction was expanded to include guanidine-based systems, offering a versatile preparation of substituted imidazoles. The direct comparison of the anticancer activity of all naturally occurring (-)-agelastatins in addition to eight advanced synthetic intermediates enabled a systematic analysis of the structure-activity relationship within the natural series. Significantly, (-)-agelastatin A (1) is highly potent against six blood cancer cell lines (20-190 nM) without affecting normal red blood cells (>333 µM). (-)-Agelastatin A (1) and (-)-agelastatin D (4), the two most potent members of this family, induce dose-dependent apoptosis and arrest cells in the G2/M-phase of the cell cycle; however, using confocal microscopy, we have determined that neither alkaloid affects tubulin dynamics within cells.
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Alcaloides/farmacología , Antineoplásicos/farmacología , Alcaloides/síntesis química , Alcaloides/química , Antineoplásicos/síntesis química , Antineoplásicos/química , Apoptosis/efectos de los fármacos , 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 , Células HL-60 , Células HeLa , Humanos , Conformación Molecular , Estereoisomerismo , Relación Estructura-Actividad , Células U937RESUMEN
The lithiation and electrophilic substitution of dimethyl triazones is described. Directed lithiation or tin-lithium exchange of dimethyl triazones afforded the corresponding dipole stabilized nucleophiles that were trapped with various electrophiles. Keto-triazone derivatives accessed by acylation of such nucleophiles were readily converted to the corresponding imidazolone heterocycles.
RESUMEN
Morphogenesis is an emergent property of biochemical and cellular interactions during development. Genome size and the correlated trait of cell size can influence these interactions through effects on developmental rate and tissue geometry, ultimately driving the evolution of morphology. We tested whether variation in genome and body size is related to morphological variation in the heart and liver using nine species of the salamander genus Plethodon (genome sizes 29-67 gigabases). Our results show that overall organ size is a function of body size, whereas tissue structure changes dramatically with evolutionary increases in genome size. In the heart, increased genome size is correlated with a reduction of myocardia in the ventricle, yielding proportionally less force-producing mass and greater intertrabecular space. In the liver, increased genome size is correlated with fewer and larger vascular structures, positioning hepatocytes farther from the circulatory vessels that transport key metabolites. Although these structural changes should have obvious impacts on organ function, their effects on organismal performance and fitness may be negligible because low metabolic rates in salamanders relax selective pressure on function of key metabolic organs. Overall, this study suggests large genome and cell size influence the developmental systems involved in heart and liver morphogenesis.
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Evolución Biológica , Urodelos , Animales , Tamaño Corporal , Tamaño de la Célula , Tamaño del Genoma , Urodelos/anatomía & histologíaRESUMEN
Plethodontid salamanders possess numerous courtship glands. Previous studies have shown that the glands are more prominent in male individuals than females, and often experience periods of atrophy and hypertrophy throughout the year that correlate to the nonmating and mating seasons, respectively. We sampled male and female Eurycea bislineata throughout the year to test the hypothesis that external nasal glands are courtship glands. External nasal glands are paired, branched tubular glands that extend from excretory ducts dorsal to the nares to terminal secretory units posterior to the eyes. We found that the glands hypertrophy and stain/react more intensely with histochemical procedures during the mating season. Hypertrophy of the glands is more pronounced in males, and seasonal variation in epithelial height of external nasal glands of males is significantly correlated to that of seasonal variation in mental gland epithelial height, a known courtship gland found in males, when compared throughout the year. This correlation was not as strong in females, confirming sexual dimorphism of external nasal glands in terms of seasonal variation. We found no ultrastructural differences between male and female external nasal glands. In all specimens, the glandular tubules were lined by a simple, columnar epithelium that was packed with secretory granules that often obscured other cytoplasmic contents.
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Glándulas Exocrinas , Urodelos , Animales , Cortejo , Glándulas Exocrinas/ultraestructura , Femenino , Hipertrofia , Masculino , Estaciones del Año , Urodelos/anatomía & histologíaRESUMEN
Since the advent of molecular character sets in phylogenetic systematics our understanding of the evolutionary history of snakes has changed considerably. In some cases the novel topologies reconstructed from molecular datasets have left researchers puzzled, as no morphological feature seems to support the new relationships found. This is the case for 'Amerophidia'sensu Vidal et al. (2007; Biology of the Boas and Pythons, Eagle Mountain: Eagle Mountain Publishing; Aniliidae+ Tropidophiidae), a grouping of the Red Pipesnakes and Neotropical Dwarf Boas. We contend that in some cases the apparent lack of historical morphological support for the molecular phylogenies is due to our poor understanding of the organisms as a whole, and not the complete lack of morphological support for controversial clades. For example, we found novel evidence from reproductive anatomy that demonstrates a unique association of the oviducts and cloaca in Amerophidia. Whereas in all other female squamates the oviducts communicate directly with the cloaca, the oviducts of Aniliidae and Tropidophiidae communicate with diverticuli of the cloaca. At present this is the only unambiguous synapomorphy for the Amerophidia. We feel that confirmation of controversial molecular relationships will revolve around the investigation of non-traditional morphological characters such as reproductive anatomy.
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Cloaca/anatomía & histología , Filogenia , Serpientes/anatomía & histología , Serpientes/clasificación , Animales , Femenino , Oviductos/anatomía & histologíaRESUMEN
Biological patterns across latitudinal gradients elucidate a number of striking natural clines from which numerous processes can be further explored. The trade-off between reproduction and somatic maintenance and growth represents a suite of life-history traits with variable energy allocation and potential latitudinal patterns. Specifically, male sexually dimorphic traits in female choice systems represent one such reproductive investment constrained by resource acquisition and subsequent allocation. Latitudinal variation in sexual dimorphism has been suggested although the relationship between dimorphic traits and latitude are conflicting. Here, we test alternative hypotheses regarding this pattern using two broadly distributed vertebrates exhibiting sexually dimorphic traits. We hypothesized that the exaggeration of dimorphic traits correlates with latitude, with males having exaggerated sexually dimorphic traits at either higher or lower latitudes. Results indicate that male sexually dimorphic traits are exaggerated at lower latitudes while relative gonopodium size in Poecilia latipinna was larger at higher latitudes. This pattern may be a result of lower latitude populations experiencing greater population densities and longer access to resources that could manifest in females more intensively selecting for higher quality males in lower latitudes. Experimental work should address this pattern and investigate mechanistic processes.
RESUMEN
A discovery program targeting respiratory syncytial virus (RSV) identified C-nucleoside 4 (RSV A2 EC50 = 530 nM) as a phenotypic screening lead targeting the RSV RNA-dependent RNA polymerase (RdRp). Prodrug exploration resulted in the discovery of remdesivir (1, GS-5734) that is >30-fold more potent than 4 against RSV in HEp-2 and NHBE cells. Metabolism studies in vitro confirmed the rapid formation of the active triphosphate metabolite, 1-NTP, and in vivo studies in cynomolgus and African Green monkeys demonstrated a >10-fold higher lung tissue concentration of 1-NTP following molar normalized IV dosing of 1 compared to that of 4. A once daily 10 mg/kg IV administration of 1 in an African Green monkey RSV model demonstrated a >2-log10 reduction in the peak lung viral load. These early data following the discovery of 1 supported its potential as a novel treatment for RSV prior to its development for Ebola and approval for COVID-19 treatment.
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Adenosina Monofosfato/análogos & derivados , Alanina/análogos & derivados , Antivirales/farmacología , Profármacos/farmacología , Infecciones por Virus Sincitial Respiratorio/tratamiento farmacológico , Virus Sincitial Respiratorio Humano/efectos de los fármacos , Adenosina Monofosfato/farmacología , Alanina/farmacología , Animales , Antivirales/química , Antivirales/farmacocinética , Células CACO-2 , Células Cultivadas , Chlorocebus aethiops , Modelos Animales de Enfermedad , Perros , Evaluación Preclínica de Medicamentos/métodos , Células Epiteliales/virología , Humanos , Macaca fascicularis , Masculino , Profármacos/química , Profármacos/farmacocinética , Ratas Sprague-Dawley , Infecciones por Virus Sincitial Respiratorio/virología , Relación Estructura-Actividad , Distribución Tisular , Tubercidina/análogos & derivados , Tubercidina/química , Carga ViralRESUMEN
We report our full account of the enantioselective total synthesis of (-)-acylfulvene (1) and (-)-irofulven (2), which features metathesis reactions for the rapid assembly of the molecular framework of these antitumor agents. We discuss (1) the application of an Evans Cu-catalyzed aldol addition reaction using a strained cyclopropyl ketenethioacetal, (2) an efficient enyne ring-closing metathesis cascade reaction in a challenging setting, (3) the reagent IPNBSH for a late-stage reductive allylic transposition reaction, and (4) the final RCM/dehydrogenation sequence for the formation of (-)-acylfulvene (1) and (-)-irofulven (2).
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Antineoplásicos/síntesis química , Sesquiterpenos/síntesis química , Compuestos Alílicos/química , Antineoplásicos/química , Catálisis , Cobre/química , Hidrógeno/química , Espectroscopía de Resonancia Magnética , Modelos Químicos , Sesquiterpenos/química , Compuestos de Espiro/síntesis química , Compuestos de Espiro/química , EstereoisomerismoRESUMEN
Observations concerning the synthesis of the core spirocyclic AB-ring system of illudins using an enyne ring closing metathesis (EYRCM) cascade are discussed. Substituent effects, in addition to optimization of the reaction conditions and the olefin tether for the key EYRCM reaction, are examined.