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Yoshiki Morimoto - One of the best experts on this subject based on the ideXlab platform.
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one step synthesis of the 1 azaspiro 5 5 undecane skeleton characteristic of Histrionicotoxin alkaloids from linear substrates via hg otf 2 catalyzed cycloisomerization
Chemistry-an Asian Journal, 2021Co-Authors: Kunihiro Matsumura, Keisuke Nishikawa, Hiroaki Yoshida, Matsumi Doe, Toshiki Niwa, Yuichiro Fushii, Yoshiki MorimotoAbstract:Histrionicotoxin (HTX) alkaloids isolated from the poison arrow frogs possess a unique structure characterized by a 1-azaspiro[5.5]undecane skeleton common to the HTX family. The unique molecular architecture of HTXs and the interest as potential target drugs have prompted synthetic chemists to promote the total synthesis so far. However, all of the synthetic strategies to access the 1-azaspiro[5.5]undecane framework of HTXs take a multistep approach from linear starting materials due to stepwise construction of either six-membered carbo- or azacycle. Herein, we report the direct one-step construction of the 1-azaspiro[5.5]undecane skeleton from linear amino ynone substrates bearing an N-methoxycarbonyl group utilizing our mercuric triflate (Hg(OTf)2 )-catalyzed cycloisomerization reaction. The utility of this novel methodology was demonstrated by the total and formal syntheses of HTX-235A and HTX-283A, respectively, from the azaspirocycle.
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formal total synthesis of Histrionicotoxin alkaloids via hg otf 2 catalyzed cycloisomerization and smi2 induced ring expansion
RSC Advances, 2018Co-Authors: Kunihiro Matsumura, Keisuke Nishikawa, Hiroaki Yoshida, Matsumi Doe, Yoshiki MorimotoAbstract:The efficient formal total synthesis of Histrionicotoxin alkaloids was achieved. In this process, two key reactions were used to construct a core 1-azaspiro[5.5]undecane framework common to Histrionicotoxins: a mercuric triflate (Hg(OTf)2)-catalyzed cycloisomerization of a linear substrate, which was developed in our laboratory, and a samarium iodide (SmI2)-mediated ring expansion.
John W Daly - One of the best experts on this subject based on the ideXlab platform.
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n methyldecahydroquinolines an unexpected class of alkaloids from amazonian poison frogs dendrobatidae
Journal of Natural Products, 2009Co-Authors: John W Daly, Thomas F Spande, Ralph A. Saporito, Nathaniel Ware, Martin H GarraffoAbstract:The dominant alkaloids previously identified in skin extracts of Amazonian dendrobatid frogs of the genus Ameerega are Histrionicotoxins and 2,5-disubstituted decahydroquinolines. Analysis of alkaloids in skin extracts of Ameerega picta from Bolivia revealed that the alkaloid 257A, previously reported as a 2,5-disubstituted decahydroquinoline, is an N-methyl-2,5-disubstituted decahydroquinoline. We characterized alkaloids of another 12 of the more than 25 species recently assigned to the genus Ameerega, and five additional N-methyldecahydroquinolines were identified. In some cases, the relative configuration of the N-methyldecahydroquinolines was determined by comparison with the N-methylated products prepared from the corresponding 2,5-disubstituted decahydroquinolines of known relative configuration. A dietary source for N-methyldecahydroquinolines is unknown; however, myrmicine ants are the likely source for the 2,5-disubstituted decahydroquinolines. The alkaloids in skin extracts of three species of another genus of Amazonian poison frog, Adelphobates, were also characterized, but N-methyldecahydroquinolines were not detected.
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spatial and temporal patterns of alkaloid variation in the poison frog oophaga pumilio in costa rica and panama over 30 years
Toxicon, 2007Co-Authors: Ralph A. Saporito, Martin H Garraffo, Poonam Jain, Thomas F Spande, Maureen A Donnelly, John W DalyAbstract:A total of 232 alkaloids, representing 21 structural classes were detected in skin extracts from the dendrobatid poison frog Oophaga pumilio, collected from 53 different populations from over 30 years of research. The highly toxic pumiliotoxins and allopumiliotoxins, along with 5,8-disubstitiuted and 5,6,8-trisubstituted indolizidines, all of which are proposed to be of dietary mite origin, were common constituents in most extracts. One decahydroquinoline (DHQ), previously shown be of ant origin, occurred in many extracts often as a major alkaloid, while other DHQs occurred rather infrequently. Histrionicotoxins, thought to be of ant origin, did not appear to possess a specific pattern of occurrence among the populations, but when present, were usually found as major components. Certain 3,5-disubstituted pyrrolizidines and indolizidines, known to be of ant origin, did occur in extracts, but infrequently. Alkaloid composition differed with regard to geographic location of frog populations, and for populations that were sampled two or more times during the 30-year period significant changes in alkaloid profiles sometimes occurred. The results of this study indicate that chemical defense in a dendrobatid poison frog is dependent on geographic location and habitat type, which presumably controls the abundance and nature of alkaloid-containing arthropods.
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alkaloids from frog skin the discovery of epibatidine and the potential for developing novel non opioid analgesics
Natural Product Reports, 2000Co-Authors: John W Daly, Martin H Garraffo, Michael W Decker, James P Sullivan, Michael WilliamsAbstract:Research on the nature, structure and biological activity of the toxins present in the skin of poison-dart frogs of South America began in the Laboratory of Chemistry at the National Institutes of Health in the mid-1960s. The presence of toxins in the skin of such frogs had been discovered long ago by Indians of Western Colombia, who to this day use skin secretions from three Colombian species of dendrobatid frogs (genus Phyllobates) to poison the grooved tips of blow darts used in hunting small game and birds. Initial field work on a poison-dart frog of the Rio San Juan drainage, and preparation of extracts was first conducted by F. Marki in 1962 and then by Daly in 1964 and 1966. The toxic principles were isolated and proved on structural analysis to be steroidal alkaloids, which were named batrachotoxins.1 These were then shown to be specific and potent activators of sodium channels.2 Both the natural alkaloids and a radioactive analog have proven to be invaluable research tools for the study of sodium channels and their interaction with local anesthetics, anticonvulsants, antiarrythmics and other drugs.3 The structure of batrachotoxin and other alkaloids, subsequently isolated from frog skin, are shown in Fig. 1. These initial studies on the batrachotoxin alkaloids from the poison-dart frogs of Western Colombia might never have been extended to some sixty species of poison-frogs of the neotropical family Dendrobatidae, had not Charles W. Myers, a herpetologist working on the reptiles and amphibians of Panama, contacted Daly and proposed a collaboration on the toxicity of an extremely variable dendrobatid frog (genus Dendrobates) of the Bocas Archipelago of Panama. The initial hypothesis, namely that the more brightly colored populations would contain higher levels of toxic alkaloids, proved incorrect. However, the analyses revealed not the steroidal batrachotoxins, but instead a variety of simpler bicyclic alkaloids, including the relatively toxic pumiliotoxins and relatively nontoxic decahydroquinolines.4 The pumiliotoxins and related alkaloids later were shown to be potent myotonic/cardiotonic agents5 with modulatory effects on sodium channels.6 The initial field work by Myers and Daly led to a thirty year friendship and collaboration with the aim of analyzing the distribution, nature, structure and biological activity of alkaloids in frog skin. A major field trip by Myers and Daly in the early 1970s led to the isolation and structural determination of relatively nontoxic bicyclic Histrionicotoxins,7 later established as highaffinity noncompetitive blockers of nicotinic acetylcholine receptor-channels (nAChRs).3 Over the next three decades more than 500 alkaloids of at least two dozen structural classes were discovered, most of which have, as yet, not been found elsewhere in nature.8,9 This is remarkable, since the dendrobatid frogs apparently do not synthesize any of their skin alkaloids, but instead sequester them unchanged into skin glands from dietary sources10 to be used as secreted chemical deterrents to predators. The search over the past five years for the dietary sources of the batrachotoxins, pumiliotoxins and Histrionicotoxins has been frustrating, but some six classes of relatively simple decahydroquinolines, piperidines, pyrrolidines and “izidines” of dendrobatid frog skin have been found in ants, while certain of the tricyclic and spiropyrrolizidine alkaloids occur in beetles and millipedes, respectively.10,11 Fig. 1 Structures of epibatidine and other alkaloids discovered in skin extracts from poison frogs (family Dendrobatidae). Batrachotoxin from Colombian Phyllobates aurotaenia,1 pumiliotoxin B from Panamanian Dendrobates pumilio,4 Histrionicotoxin from Colombian Dendrobates histrionicus,7 and epibatidine and alkaloids 251D, 251H and 341A from Ecuadorian Epipedobates tricolor.12–14,16 EMINENT SCIENTIST REVIEW
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Dietary source for skin alkaloids of poison frogs (Dendrobatidae)
Journal of chemical ecology, 1994Co-Authors: John W Daly, H. Martin Garraffo, Thomas F Spande, César Jaramillo, A. Stanley RandAbstract:A wide range of alkaloids, many of which are unknown elsewhere in nature, occur in skin of frogs. Major classes of such alkaloids in dendrobatid frogs are the batrachotoxins, pumiliotoxins, Histrionicotoxins, gephyrotoxins, and decahydroquinolines. Such alkaloids are absent in skin of frogs (Dendrobates auratus) raised in Panama on wingless fruit flies in indoor terraria. Raised on leaf-litter arthropods that were collected in a mainland site, such terraria-raised frogs contain tricyclic alkaloids including the beetle alkaloid precoccinelline, 1,4-disubstituted quinolizidines, pyrrolizidine oximes, the millipede alkaloid nitropolyzonamine, a decahydroquinoline, a gephyrotoxin, and Histrionicotoxins. The profiles of these alkaloids in the captive-raised frogs are closer to the mainland population ofDendrobates auratus at the leaf-litter site than to the parent population ofDendrobates auratus from a nearby island site. Extracts of a seven-month sampling of leaf-litter insects contained precoccinelline, pyrrolizidine oxime236 (major), and nitropolyzonamine (238). The results indicate a dietary origin for at least some “dendrobatid alkaloids,” in particular the pyrrolizidine oximes, the tricyclic coccinellines, and perhaps the Histrionicotoxins and gephyrotoxins.
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variability in alkaloid profiles in neotropical poison frogs dendrobatidae genetic versus environmental determinants
Toxicon, 1992Co-Authors: John W Daly, Martin H Garraffo, Thomas F Spande, Sherrie Secunda, Anthony Wisnieski, Charles Nishihira, John F CoverAbstract:Dendrobatid frogs produce a diverse set of alkaloids, whose profiles appear characteristic of frogs of each species or, in the case of variable species, of each population. In the case of one widespread species, Dendrobates auratus, alkaloid profiles in extracts of skin are markedly different in three populations, one from a Pacific island, Isla Taboga, Panama, one from central mountains in Panama, and the third from the Caribbean coast in Costa Rica. The first contains three major classes of dendrobatid alkaloids, the Histrionicotoxins, the pumiliotoxin-A class and the decahydroquinolines. The second contains mainly Histrionicotoxins, pumiliotoxin-A class alkaloids and one indolizidine. The third contains Histrionicotoxins, a homopumiliotoxin, one decahydroquinoline, and a variety of indolizidines, quinolizidines and pyrrolizidines. Frogs from Isla Taboga or a nearby island were introduced into the Manoa Valley, Oahu, Hawaii, in 1932. Remarkably, although alkaloids of the pumiliotoxin-A class and one decahydroquinoline are still major constituents in skin extracts of Hawaiian frogs descended from the 1932 founding population, Histrionicotoxins are absent and a novel tricyclic alkaloid is present. Offspring of wild-caught parents from Hawaii, Panama or Costa Rica raised in indoor terrariums on a diet of crickets and fruit flies do not contain detectable amounts of skin alkaloids. Offspring raised in large outside terrariums in Hawaii and fed mainly wild-caught termites and fruit flies do contain the same profile of alkaloids as their wild-caught parents in Hawaii, but at reduced levels. The genetic, environmental and dietary determinants of alkaloid profiles in dendrobatid frogs remain obscure, in particular the underlying cause for total absence in terrarium-reared frogs.
Kunihiro Matsumura - One of the best experts on this subject based on the ideXlab platform.
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one step synthesis of the 1 azaspiro 5 5 undecane skeleton characteristic of Histrionicotoxin alkaloids from linear substrates via hg otf 2 catalyzed cycloisomerization
Chemistry-an Asian Journal, 2021Co-Authors: Kunihiro Matsumura, Keisuke Nishikawa, Hiroaki Yoshida, Matsumi Doe, Toshiki Niwa, Yuichiro Fushii, Yoshiki MorimotoAbstract:Histrionicotoxin (HTX) alkaloids isolated from the poison arrow frogs possess a unique structure characterized by a 1-azaspiro[5.5]undecane skeleton common to the HTX family. The unique molecular architecture of HTXs and the interest as potential target drugs have prompted synthetic chemists to promote the total synthesis so far. However, all of the synthetic strategies to access the 1-azaspiro[5.5]undecane framework of HTXs take a multistep approach from linear starting materials due to stepwise construction of either six-membered carbo- or azacycle. Herein, we report the direct one-step construction of the 1-azaspiro[5.5]undecane skeleton from linear amino ynone substrates bearing an N-methoxycarbonyl group utilizing our mercuric triflate (Hg(OTf)2 )-catalyzed cycloisomerization reaction. The utility of this novel methodology was demonstrated by the total and formal syntheses of HTX-235A and HTX-283A, respectively, from the azaspirocycle.
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formal total synthesis of Histrionicotoxin alkaloids via hg otf 2 catalyzed cycloisomerization and smi2 induced ring expansion
RSC Advances, 2018Co-Authors: Kunihiro Matsumura, Keisuke Nishikawa, Hiroaki Yoshida, Matsumi Doe, Yoshiki MorimotoAbstract:The efficient formal total synthesis of Histrionicotoxin alkaloids was achieved. In this process, two key reactions were used to construct a core 1-azaspiro[5.5]undecane framework common to Histrionicotoxins: a mercuric triflate (Hg(OTf)2)-catalyzed cycloisomerization of a linear substrate, which was developed in our laboratory, and a samarium iodide (SmI2)-mediated ring expansion.
Lauren A. O’connell - One of the best experts on this subject based on the ideXlab platform.
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Ant and Mite Diversity Drives Toxin Variation in the Little Devil Poison Frog
Journal of Chemical Ecology, 2016Co-Authors: Jenna R. Mcgugan, Alexandre B Roland, Stephanie N Caty, Elicio E Tapia, Gary D. Byrd, Nisha Kabir, Sunia A. Trauger, Luis A Coloma, Lauren A. O’connellAbstract:Poison frogs sequester chemical defenses from arthropod prey, although the details of how arthropod diversity contributes to variation in poison frog toxins remains unclear. We characterized skin alkaloid profiles in the Little Devil poison frog, Oophaga sylvatica (Dendrobatidae), across three populations in northwestern Ecuador. Using gas chromatography/mass spectrometry, we identified Histrionicotoxins, 3,5- and 5,8-disubstituted indolizidines, decahydroquinolines, and lehmizidines as the primary alkaloid toxins in these O. sylvatica populations. Frog skin alkaloid composition varied along a geographical gradient following population distribution in a principal component analysis. We also characterized diversity in arthropods isolated from frog stomach contents and confirmed that O. sylvatica specialize on ants and mites. To test the hypothesis that poison frog toxin variability reflects species and chemical diversity in arthropod prey, we (1) used sequencing of cytochrome oxidase 1 to identify individual prey specimens, and (2) used liquid chromatography/mass spectrometry to chemically profile consumed ants and mites. We identified 45 ants and 9 mites in frog stomachs, including several undescribed species. We also showed that chemical profiles of consumed ants and mites cluster by frog population, suggesting different frog populations have access to chemically distinct prey. Finally, by comparing chemical profiles of frog skin and isolated prey items, we traced the arthropod source of four poison frog alkaloids, including 3,5- and 5,8-disubstituted indolizidines and a lehmizidine alkaloid. Together, the data show that toxin variability in O. sylvatica reflects chemical diversity in arthropod prey.
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Convergent Substitutions in a Sodium Channel Suggest Multiple Origins of Toxin Resistance in Poison Frogs
Molecular biology and evolution, 2016Co-Authors: Rebecca D. Tarvin, Lauren A. O’connell, Juan C. Santos, Harold H. Zakon, David C CannatellaAbstract:Complex phenotypes typically have a correspondingly multifaceted genetic component. However, the genotype–phenotype association between chemical defense and resistance is often simple: genetic changes in the binding site of a toxin alter how it affects its target. Some toxic organisms, such as poison frogs (Anura: Dendrobatidae), have defensive alkaloids that disrupt the function of ion channels, proteins that are crucial for nerve and muscle activity. Using protein-docking models, we predict that three major classes of poison frog alkaloids (Histrionicotoxins, pumiliotoxins, and batrachotoxins) bind to similar sites in the highly conserved inner pore of the muscle voltage-gated sodium channel, Nav1.4. We predict that poison frogs are somewhat resistant to these compounds because they have six types of amino acid replacements in the Nav1.4 inner pore that are absent in all other frogs except for a distantly related alkaloid-defended frog from Madagascar, Mantella aurantiaca. Protein-docking models and comparative phylogenetics support the role of these replacements in alkaloid resistance. Taking into account the four independent origins of chemical defense in Dendrobatidae, phylogenetic patterns of the amino acid replacements suggest that 1) alkaloid resistance in Nav1.4 evolved independently at least seven times in these frogs, 2) variation in resistance-conferring replacements is likely a result of differences in alkaloid exposure across species, and 3) functional constraint shapes the evolution of the Nav1.4 inner pore. Our study is the fi rst to demon strate the genetic basis of autoresistance in frogs with alkaloid defenses.
Keisuke Nishikawa - One of the best experts on this subject based on the ideXlab platform.
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one step synthesis of the 1 azaspiro 5 5 undecane skeleton characteristic of Histrionicotoxin alkaloids from linear substrates via hg otf 2 catalyzed cycloisomerization
Chemistry-an Asian Journal, 2021Co-Authors: Kunihiro Matsumura, Keisuke Nishikawa, Hiroaki Yoshida, Matsumi Doe, Toshiki Niwa, Yuichiro Fushii, Yoshiki MorimotoAbstract:Histrionicotoxin (HTX) alkaloids isolated from the poison arrow frogs possess a unique structure characterized by a 1-azaspiro[5.5]undecane skeleton common to the HTX family. The unique molecular architecture of HTXs and the interest as potential target drugs have prompted synthetic chemists to promote the total synthesis so far. However, all of the synthetic strategies to access the 1-azaspiro[5.5]undecane framework of HTXs take a multistep approach from linear starting materials due to stepwise construction of either six-membered carbo- or azacycle. Herein, we report the direct one-step construction of the 1-azaspiro[5.5]undecane skeleton from linear amino ynone substrates bearing an N-methoxycarbonyl group utilizing our mercuric triflate (Hg(OTf)2 )-catalyzed cycloisomerization reaction. The utility of this novel methodology was demonstrated by the total and formal syntheses of HTX-235A and HTX-283A, respectively, from the azaspirocycle.
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formal total synthesis of Histrionicotoxin alkaloids via hg otf 2 catalyzed cycloisomerization and smi2 induced ring expansion
RSC Advances, 2018Co-Authors: Kunihiro Matsumura, Keisuke Nishikawa, Hiroaki Yoshida, Matsumi Doe, Yoshiki MorimotoAbstract:The efficient formal total synthesis of Histrionicotoxin alkaloids was achieved. In this process, two key reactions were used to construct a core 1-azaspiro[5.5]undecane framework common to Histrionicotoxins: a mercuric triflate (Hg(OTf)2)-catalyzed cycloisomerization of a linear substrate, which was developed in our laboratory, and a samarium iodide (SmI2)-mediated ring expansion.