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Glendon R. Shaw - One of the best experts on this subject based on the ideXlab platform.
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Dermal toxicology of Lyngbya majuscula, from Moreton Bay, Queensland, Australia
Harmful Algae, 2008Co-Authors: Nicholas J. Osborne, Alan A. Seawright, Glendon R. ShawAbstract:Lyngbya majuscula is a filamentous marine cyanobacterium with a worldwide distribution in temperate and tropical regions to a depth of 30 m. Over 70 chemicals have been isolated and characterised from this organism, many of which are biologically active. Previously, L. majuscula has been reported as implicated in negative health outcomes only in Hawaii and Okinawa. Recently large blooms of L. majuscula have occurred with increasing repetition in the Moreton Bay region as well as other areas along the Australian coastline. Lyngbya toxin A (LA) and Debromoaplysiatoxin (DAT) were found in samples of L. majuscula collected from Eastern Moreton Bay and North Deception Bay, Queensland, Australia, respectively. Samples of L. majuscula were also obtained from West Maui, Hawaii and the freshwater Lyngbya wollei from Florida. A quantitative measure of the irritant effects of the chemicals found in L. majuscula was made using a mouse ear swelling test. The relative toxicities of two purified toxins, LA and DAT, were examined. These were found to produce swelling to a similar extent. The time course of inflammation and histopathological results were also similar for the two purified toxins. Less than 1 μg per ear of either toxin or a mixture (1:1) of the two toxins caused a measurable increase in ear thickness. When toxins were combined (1:1) there was an additive, not synergistic effect. Increases in ear thickness occurred within 15 min. Crude extracts of L. majuscula from Moreton Bay were also applied to mice ears. The effect of crude extracts from Eastern Moreton Bay was not fully explained by the measured LA content, suggesting other toxin(s) and/or modulating factors were present. The toxic effects of L. majuscula containing DAT from North Deception Bay were explained by the concentrations measured. Some samples of L. majuscula containing no measurable quantities of LA or DAT were found to exert an inflammatory response. This response had a different time course to the response produced by LA or DAT.
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The exposure of green turtles (Chelonia mydas) to tumour promoting compounds produced by the cyanobacterium Lyngbya majuscula and their potential role in the aetiology of fibropapillomatosis
Harmful Algae, 2007Co-Authors: Karen E Arthur, Angela Capper, Glendon R. Shaw, Colin J. Limpus, George H. Balazs, Ursula Keuper-bennett, Peter BennettAbstract:Lyngbya majuscula, a benthic filamentous cyanobacterium found throughout tropical and subtropical oceans, has been shown to contain the tumour promoting compounds lyngbyatoxin A (LA) and Debromoaplysiatoxin (DAT). It grows epiphytically on seagrass and macroalgae, which also form the basis of the diet of the herbivorous green turtle (Chelonia mydas). This toxic cyanobacterium has been observed growing in regions where turtles suffer from fibropapillomatosis (FP), a potentially fatal neoplastic disease. The purpose of this study was to determine whether green turtles consume L. majuscula in Queensland, Australia and the Hawaiian Islands, USA, resulting in potential exposure to tumour promoting compounds produced by this cyanobacterium. L. majuscula was present, though not in bloom, at nine sites examined and LA and DAT were detected in variable concentrations both within and between sites. Although common in green turtle diets, L. majuscula was found to contribute less than 2% of total dietary intake, indicating that turtles may be exposed to low concentrations of tumour promoting compounds during non-bloom conditions. Tissue collected from dead green turtles in Moreton Bay tested positive for LA. An estimated dose, based on dietary intake and average toxin concentration at each site, showed a positive correlation for LA with the proportion of the population observed with external FP lesions. No such relationship was observed for DAT. This does not necessarily demonstrate a cause and effect relationship, but does suggest that naturally produced compounds should be considered in the aetiology of marine turtle FP.
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A bloom of Lyngbya majuscula in Shoalwater Bay, Queensland, Australia: An important feeding ground for the green turtle (Chelonia mydas)
Harmful Algae, 2006Co-Authors: Karen E Arthur, Colin J. Limpus, Chris Roelfsema, Glendon R. ShawAbstract:Lyngbya majuscula, a toxic cyanobacterium, was observed blooming during June-July (winter) 2002 in Shoalwater Bay, Queensland, Australia, an important feeding area for a large population of green turtles (Chelonia mydas). The bloom was mapped and extensive mats of L majuscula were observed overgrowing seagrass beds along at least 18 km of coast, and covering a surface area of more than I I km(2). Higher than average rainfall preceded the bloom and high water temperatures in the preceding summer may have contributed to the bloom. In bloom samples, lyngbyatoxin A (LA) was found to be present in low concentration (26 mu g kg(-1) (dry weight)), but Debromoaplysiatoxin (DAT) was not detected. The diet of 46 green turtles was assessed during the bloom and L. majuscula was found in 51% of the samples, however, overall it contributed only 2% of the animals' diets. L. majuscula contribution to turtle diet was found to increase as the availability of the cyanobacterium increased. The bloom appeared to have no immediate impact on turtle body condition, however, the presence of a greater proportion of damaged seagrass leaves in diet in conjunction with decreases in plasma concentrations of sodium and glucose could suggest that the turtles may have been exposed to a Substandard diet as a result of the bloom. This is the first confirmed report of L. majuscula blooming in winter in Shoalwater Bay, Queensland, Australia and demonstrates that turtles consume the toxic cyanobacterium in the wild, and that they are potentially exposed to tumour promoting compounds produced by this organism. (c) 2005 Elsevier B.V. All rights reserved.
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The Fate of Lyngbya majuscula Toxins in Three Potential Consumers
Journal of Chemical Ecology, 2005Co-Authors: Angela Capper, Ian R. Tibbetts, Judith M. O’neil, Glendon R. ShawAbstract:Blooms of Lyngbya majuscula have been reported with increasing frequency and severity in the last decade in Moreton Bay, Australia. A number of grazers have been observed feeding upon this toxic cyanobacterium. Differences in sequestration of toxic compounds from L. majuscula were investigated in two anaspideans, Stylocheilus striatus , Bursatella leachii , and the cephalaspidean Diniatys dentifer . Species fed a monospecific diet of L. majuscula had different toxin distribution in their tissues and excretions. A high concentration of lyngbyatoxin-a was observed in the body of S. striatus (3.94 mg/kg^−1) compared to bodily secretions (ink 0.12 mg/kg^−1; fecal matter 0.56 mg/kg^−1; eggs 0.05 mg/kg^−1). In contrast, B. leachii secreted greaterconcentrations of lyngbyatoxin-a (ink 5.41 mg/kg^−1; fecal matter 6.71 mg/kg^−1) than that stored in the body (2.24 mg/kg^−1). The major internal repository of lyngbyatoxin-a and Debromoaplysiatoxin was the digestive gland for both S. striatus (6.31 ± 0.31 mg/kg^−1) and B. leachii (156.39 ± 46.92 mg/kg^−1). D. dentifer showed high variability in the distribution of sequestered compounds. Lyngbyatoxin-a was detected in the digestive gland (3.56 ± 3.56 mg/kg^−1) but not in the head and foot, while Debromoaplysiatoxin was detected in the head and foot (133.73 ± 129.82 mg/kg^−1) but not in the digestive gland. The concentrations of sequestered secondary metabolites in these animals did not correspond to the concentrations found in L. majuscula used as food for these experiments, suggesting it may have been from previous dietary exposure. Trophic transfer of Debromoaplysiatoxin from L.majuscula into S. striatus is well established; however, a lack of knowledge exists for other grazers. The high levels of secondary metabolites observed in both the anaspidean and the cephalapsidean species suggest that these toxins may bioaccumulate through marine food chains.
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The toxins of Lyngbya majuscula and their human and ecological health effects.
Environment International, 2001Co-Authors: Nicholas J. Osborne, Penny Webb, Glendon R. ShawAbstract:Lyngbya majuscula is a benthic filamentous marine cyanobacterium, which in recent years appears to have been increasing in frequency and size of blooms in Moreton Bay, Queensland. It has a worldwide distribution throughout the tropics and subtropics in water to 30m. It has been found to contain a variety of chemicals that exert a range of biological effects, including skin, eye and respiratory irritation. The toxins lyngbyatoxin A and Debromoaplysiatoxin appear to give the most widely witnessed biological effects in relation to humans, and experiments involving these two toxins show the formation of acute dermal lesions. Studies into the epidemiology of the dermatitic, respiratory and eye effects of the toxins of this organism are reviewed and show that Lyngbya induced dermatitis has occurred in a number of locations. The effects of aerosolised Lyngbya in relation to health outcomes were also reported. Differential effects of bathing behaviour after Lyngbya exposure were examined in relation to the severity of health outcomes. The potential for Lyngbya to exhibit differential toxicologies due to the presence of varying proportions of a range of toxins is also examined. This paper reviews the present state of knowledge on the effects of Lyngbya majuscula on human health, ecosystems and human populations during a toxic cyanobacterial bloom. The potential exists for toxins from Lyngbya majuscula affecting ecological health and in particular marine reptiles.
Hiroshi Nagai - One of the best experts on this subject based on the ideXlab platform.
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neo aplysiatoxin a isolated from okinawan cyanobacterium moorea producens
Molecules, 2020Co-Authors: Mioko Kawaguchi, Yueyun Xiao, Masayuki Fukuoka, Hajime Uchida, Masayuki Satake, Botao Zhang, Hiroshi NagaiAbstract:A new aplysiatoxin derivative, neo-aplysiatoxin A (1), along with seven known compounds, neo-Debromoaplysiatoxin A (2), dolastatin 3 (3), lyngbic acid (4), malyngamide M (5), hermitamide A (6), (−)-loliolide (7), and (+)-epiloliolide (8), was isolated from the Okinawan cyanobacterium Moorea producens. Their structures were elucidated on the basis of spectroscopic data, including high-resolution mass spectrometry and nuclear magnetic resonance. The compounds were evaluated for cytotoxic and diatom growth inhibition activities.
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new aplysiatoxin derivatives from the okinawan cyanobacterium moorea producens
Tetrahedron, 2019Co-Authors: Hiroshi Nagai, Minami Watanabe, Mioko Kawaguchi, Yueyun Xiao, Hajime Uchida, Ryuichi Watanabe, Kazutaka Hayashi, Shingo Sato, Masayuki SatakeAbstract:Abstract The marine cyanobacterium Moorea producens is a rich source of diverse compounds that possess a variety of biological activities. In the present study, eight new aplysiatoxin derivatives, namely 6, 8–13, and 15, along with aplysiatoxin (1), Debromoaplysiatoxin (2), 3-methoxyaplysiatoxin (3), anhydroaplysiatoxin (4), anhydroDebromoaplysiatoxin (5), oscillatoxin B2 (7), and 30-methyloscillatoxin D (14) were isolated and identified from the Okinawan M. producens. In cytotoxicity and diatom growth inhibition tests, the fifteen compounds tested (1–15) showed moderate or no activity at a concentration of 10 μg/mL.
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Structural optimization of 10-methyl-aplog-1, a simplified analog of Debromoaplysiatoxin, as an anticancer lead
Bioscience biotechnology and biochemistry, 2015Co-Authors: Masayuki Kikumori, Hiroshi Nagai, Ryo C. Yanagita, Harukuni Tokuda, Kiyotake Suenaga, Kazuhiro IrieAbstract:Aplog-1 is a simplified analog of Debromoaplysiatoxin (DAT) with potent tumor-promoting and proinflammatory activities. Aplog-1 and DAT exhibited anti-proliferative activities against several human cancer cell lines, whereas aplog-1 did not have tumor-promoting nor proinflammatory activities. We have recently found 10-methyl-aplog-1 (1) to have strong anti-proliferative activity compared with aplog-1. To further investigate the structural factors involved in the tumor-promoting, proinflammatory, and anti-proliferative activities, two dimethyl derivatives of aplog-1 (2, 3) were synthesized, where two methyl groups were installed at positions 4 and 10 or 10 and 12. 10,12-Dimethyl-aplog-1 (2) had stronger inhibitory effects on the growth of several human cancer cell lines than 1 and DAT, but exhibited no tumor-promoting and proinflammatory activities. In contrast, 4,10-dimethyl-aplog-1 (3) displayed weak tumor-promoting and proinflammatory activities along with anti-proliferative activity similar to that of 1 and DAT. Compound 2 would be the optimized seed for anticancer drugs among the simplified analogs of DAT.
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Effects of the methoxy group in the side chain of Debromoaplysiatoxin on its tumor-promoting and anti-proliferative activities
Bioorganic & medicinal chemistry letters, 2013Co-Authors: Ryo C. Yanagita, Hiroshi Nagai, Masayuki Kikumori, Harukuni Tokuda, Nobutaka Suzuki, Kiyotake Suenaga, Hiroaki Kamachi, Kazuhiro IrieAbstract:Debromoaplysiatoxin (DAT) is a tumor promoter isolated from sea hare and exhibits anti-proliferative activity against several cancer cell lines. To clarify key residues that are responsible for its tumor-promoting activity, we focused on the chiral methoxy group in the side chain, whose role had not yet been discussed or examined before. Demethoxy-DAT (8) was derived from DAT and we evaluated its tumor-promoting activity, anti-proliferative activity, and ability to bind to protein kinase C (PKC) isozymes. Compound 8 showed somewhat weaker tumor-promoting activity than that of DAT both in vitro and in vivo, but showed higher anti-proliferative activity against several cancer cell lines. Although the affinity to novel PKC isozymes of 8 was comparable to that of DAT, the affinity to conventional PKC isozymes decreased slightly. These results suggest that the methoxy group of DAT is one of the key residues critical for tumor-promoting activity but not for anti-proliferative activity. Since the methoxy group has little influence on the molecular hydrophobicity, this is the first report showing that structural factors other than hydrophobicity in the side chain of DAT affected its biological activities.
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Structure–Activity Studies on the Spiroketal Moiety of a Simplified Analogue of Debromoaplysiatoxin with Antiproliferative Activity
Journal of medicinal chemistry, 2012Co-Authors: Masayuki Kikumori, Hiroshi Nagai, Ryo C. Yanagita, Harukuni Tokuda, Nobutaka Suzuki, Kiyotake Suenaga, Kazuhiro IrieAbstract:Aplog-1, a simplified analogue of tumor-promoting Debromoaplysiatoxin, is antiproliferative but not tumor-promoting. Our recent study has suggested that local hydrophobicity around the spiroketal moiety is a crucial determinant for antiproliferative activity. To further clarify the structural features relevant to the activity, we synthesized two methyl derivatives of aplog-1, where a methyl group was installed at position 4 or 10 of the spiroketal moiety. 10-Methyl-aplog-1 (5) bound to the C1B domains of novel PKCs (δ, η, and θ) with subnanomolar Ki values, approximately 10–20 times stronger than aplog-1, and markedly inhibited the growth of many human cancer cell lines, while 4-methyl-aplog-1 (4) had levels of activity similar to those of aplog-1. Interestingly, 5 showed little tumor-promoting activity unlike the tumor promoter Debromoaplysiatoxin. These results suggest that 5 is a potent PKC ligand without tumor-promoting activity and could be a therapeutic lead for the treatment of cancer, like bryosta...
Kazuhiro Irie - One of the best experts on this subject based on the ideXlab platform.
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Synthesis and biological activities of simplified aplysiatoxin analogs focused on the CH/π interaction.
Bioorganic & medicinal chemistry letters, 2020Co-Authors: Takumi Kobayashi, Ryo C. Yanagita, Kazuhiro IrieAbstract:Abstract Debromoaplysiatoxin (DAT) is a potent protein kinase C (PKC) activator with tumor-promoting and pro-inflammatory activities. Irie and colleagues have found that 10-methyl-aplog-1 (1), a simplified analog of DAT, has strong anti-proliferative activity against several cancer cell lines with few adverse effects. Therefore, 1 is a potential lead compound for cancer therapy. We synthesized a new derivative 2 which has a naphthalene ring at the side chain terminal position instead of a benzene ring, to increase CH/π interactions with Pro-241 of the PKCδ-C1B domain. Based on the synthetic route of 1, 2 was convergently synthesized in 26 linear steps from 6-hydroxy-1-naphthoic acid with an overall yield of 0.18%. Although the anti-proliferative activity of 2 was more potent than that of 1, the binding potency of 2 to the PKCδ-C1B domain did not exceed that of 1. Molecular dynamics simulation indicated the capability of 2 to simultaneously form hydrogen bonds and CH/π interactions with the PKCδ-C1B domain. Focusing on the hydrogen bonds, their geometry in the binding modes involving the CH/π interactions seemed to be sub-optimal, which may explain the slightly lower affinity of 2 compared to 1. This study could be of help in optimizing such interactions and synthesizing a promising lead cancer compound.
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Identification of protein kinase C isozymes involved in the anti-proliferative and pro-apoptotic activities of 10-Methyl-aplog-1, a simplified analog of Debromoaplysiatoxin, in several cancer cell lines.
Biochemical and biophysical research communications, 2017Co-Authors: Yusuke Hanaki, Masayuki Kikumori, Yuki Shikata, Natsuki Hotta, Masaya Imoto, Kazuhiro IrieAbstract:10-Me-aplog-1 is a simplified analog of the tumor-promoting compound Debromoaplysiatoxin (DAT) and a unique protein kinase C (PKC) activator with limited tumor-promoting and pro-inflammatory activities. 10-Me-aplog-1 inhibits the growth of several cancer cell lines, but the inhibitory mechanism involving PKC isozymes remains unclear. We quantified the amount of PKC isozymes in nine human cancer cell lines that differ in 10-Me-aplog-1 sensitivity. PKCα and δ were the predominant isozymes expressed in all cell lines, but there was no significant correlation between expression levels and anti-proliferative activity. Knocking down PKCα, and/or PKCδ in the three aplog-sensitive cell lines indicated their involvement in the anti-proliferative and pro-apoptotic activities of 10-Me-aplog-1. This finding suggests that PKCα and/or PKCδ activation could be effective for treating certain cancers. Since the mechanism underlying 10-Me-aplog-1's anti-proliferative activities resembles that of DAT, 10-Me-aplog-1 may be regarded as a special key derived from pleiotropic DAT as a bunch of keys.
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Structural optimization of 10-methyl-aplog-1, a simplified analog of Debromoaplysiatoxin, as an anticancer lead
Bioscience biotechnology and biochemistry, 2015Co-Authors: Masayuki Kikumori, Hiroshi Nagai, Ryo C. Yanagita, Harukuni Tokuda, Kiyotake Suenaga, Kazuhiro IrieAbstract:Aplog-1 is a simplified analog of Debromoaplysiatoxin (DAT) with potent tumor-promoting and proinflammatory activities. Aplog-1 and DAT exhibited anti-proliferative activities against several human cancer cell lines, whereas aplog-1 did not have tumor-promoting nor proinflammatory activities. We have recently found 10-methyl-aplog-1 (1) to have strong anti-proliferative activity compared with aplog-1. To further investigate the structural factors involved in the tumor-promoting, proinflammatory, and anti-proliferative activities, two dimethyl derivatives of aplog-1 (2, 3) were synthesized, where two methyl groups were installed at positions 4 and 10 or 10 and 12. 10,12-Dimethyl-aplog-1 (2) had stronger inhibitory effects on the growth of several human cancer cell lines than 1 and DAT, but exhibited no tumor-promoting and proinflammatory activities. In contrast, 4,10-dimethyl-aplog-1 (3) displayed weak tumor-promoting and proinflammatory activities along with anti-proliferative activity similar to that of 1 and DAT. Compound 2 would be the optimized seed for anticancer drugs among the simplified analogs of DAT.
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structure activity studies at position 27 of aplog 1 a simplified analog of Debromoaplysiatoxin with anti proliferative activity
Tetrahedron, 2013Co-Authors: Yusuke Hanaki, Masayuki Kikumori, Harukuni Tokuda, Nobutaka Suzuki, Sayo Ueno, Kazuhiro IrieAbstract:Abstract Aplog-1, a simplified analog of Debromoaplysiatoxin with anti-proliferative activity, bound to and activated protein kinase Cδ (PKCδ), that is involved in tumor suppression and apoptosis. To examine the contribution of PKCδ to the anti-proliferative activity of aplog-1, we synthesized 27-methyl and 27-methoxy derivatives that differed in the ability to activate PKCδ. Activators of PKCδ like aplog-1 and 27-(R)-Me-aplog-1 strongly inhibited the growth of several cancer cell lines. On the other hand, 27-(S)-Me-aplog-1 and 27-O-Me-aplog-1 without the ability to activate PKCδ, exhibited only weak growth inhibitory activity against these cell lines. These results suggest indirectly that the activation of PKCδ might be involved in the anti-proliferative activity of aplog-1 against aplog-sensitive cancer cell lines.
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Effects of the methoxy group in the side chain of Debromoaplysiatoxin on its tumor-promoting and anti-proliferative activities
Bioorganic & medicinal chemistry letters, 2013Co-Authors: Ryo C. Yanagita, Hiroshi Nagai, Masayuki Kikumori, Harukuni Tokuda, Nobutaka Suzuki, Kiyotake Suenaga, Hiroaki Kamachi, Kazuhiro IrieAbstract:Debromoaplysiatoxin (DAT) is a tumor promoter isolated from sea hare and exhibits anti-proliferative activity against several cancer cell lines. To clarify key residues that are responsible for its tumor-promoting activity, we focused on the chiral methoxy group in the side chain, whose role had not yet been discussed or examined before. Demethoxy-DAT (8) was derived from DAT and we evaluated its tumor-promoting activity, anti-proliferative activity, and ability to bind to protein kinase C (PKC) isozymes. Compound 8 showed somewhat weaker tumor-promoting activity than that of DAT both in vitro and in vivo, but showed higher anti-proliferative activity against several cancer cell lines. Although the affinity to novel PKC isozymes of 8 was comparable to that of DAT, the affinity to conventional PKC isozymes decreased slightly. These results suggest that the methoxy group of DAT is one of the key residues critical for tumor-promoting activity but not for anti-proliferative activity. Since the methoxy group has little influence on the molecular hydrophobicity, this is the first report showing that structural factors other than hydrophobicity in the side chain of DAT affected its biological activities.
Masami Suganuma - One of the best experts on this subject based on the ideXlab platform.
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Specific protein interacting with a tumor promoter, Debromoaplysiatoxin, in bovine serum is α_1-acid glycoprotein
Journal of Cancer Research and Clinical Oncology, 1995Co-Authors: Hisao Ueyama, Ichiro Sasaki, Kyoichi Shimomura, Masami SuganumaAbstract:Aplysiatoxin and Debromoaplysiatoxin, a debrominated form of aplysiatoxin, have both been shown to be potent tumor promoters in a two-stage carcinogenesis experiment on mouse skin. However, Debromoaplysiatoxin did not behave like aplysiatoxin in most of the biological assay systems using cultured cells. The discrepancy was supposed to be due to a factor in the bovine serum used for culture, a similar factor not being present in sera of eight other animal species examined. The factor was purified to homogeneity from bovine serum by ammonium sulfate fractionation and chromatographies on DEAE-cellulose, Sephadex G-150, hydroxyapatite, and a reversed-phase HPLC column. The factor was a 40-kDa protein, and partial amino-acid sequencing of its tryptic peptides indicated that the factor is α_1-acid glycoprotein. Both the purified factor and the commercially available bovine α_1-acid glycoprotein abolished in vitro the activation of protein kinase C by Debromoaplysiatoxin but not that by aplysiatoxin. Debromoaplysiatoxin induced differentiation of HL-60 cells into macrophages at a comparable concentration to aplysiatoxin, when serum-free medium was used. These results suggest that α_1-acid glycoprotein, which interacts specifically with Debromoaplysiatoxin, contained in bovine serum must have masked the in vitro properties of the tumor promoter in the biological assay systems.
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Specific protein interacting with a tumor promoter, Debromoaplysiatoxin, in bovine serum is α1-acid glycoprotein
Journal of cancer research and clinical oncology, 1995Co-Authors: Hisao Ueyama, Ichiro Sasaki, Kyoichi Shimomura, Masami SuganumaAbstract:Aplysiatoxin and Debromoaplysiatoxin, a debrominated form of aplysiatoxin, have both been shown to be potent tumor promoters in a two-stage carcinogenesis experiment on mouse skin. However, Debromoaplysiatoxin did not behave like aplysiatoxin in most of the biological assay systems using cultured cells. The discrepancy was supposed to be due to a factor in the bovine serum used for culture, a similar factor not being present in sera of eight other animal species examined. The factor was purified to homogeneity from bovine serum by ammonium sulfate fractionation and chromatographies on DEAE-cellulose, Sephadex G-150, hydroxyapatite, and a reversed-phase HPLC column. The factor was a 40-kDa protein, and partial amino-acid sequencing of its tryptic peptides indicated that the factor is α1-acid glycoprotein. Both the purified factor and the commercially available bovine α1-acid glycoprotein abolished in vitro the activation of protein kinase C by Debromoaplysiatoxin but not that by aplysiatoxin. Debromoaplysiatoxin induced differentiation of HL-60 cells into macrophages at a comparable concentration to aplysiatoxin, when serum-free medium was used. These results suggest that α1-acid glycoprotein, which interacts specifically with Debromoaplysiatoxin, contained in bovine serum must have masked the in vitro properties of the tumor promoter in the biological assay systems.
Ryo C. Yanagita - One of the best experts on this subject based on the ideXlab platform.
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Synthesis and biological activities of simplified aplysiatoxin analogs focused on the CH/π interaction.
Bioorganic & medicinal chemistry letters, 2020Co-Authors: Takumi Kobayashi, Ryo C. Yanagita, Kazuhiro IrieAbstract:Abstract Debromoaplysiatoxin (DAT) is a potent protein kinase C (PKC) activator with tumor-promoting and pro-inflammatory activities. Irie and colleagues have found that 10-methyl-aplog-1 (1), a simplified analog of DAT, has strong anti-proliferative activity against several cancer cell lines with few adverse effects. Therefore, 1 is a potential lead compound for cancer therapy. We synthesized a new derivative 2 which has a naphthalene ring at the side chain terminal position instead of a benzene ring, to increase CH/π interactions with Pro-241 of the PKCδ-C1B domain. Based on the synthetic route of 1, 2 was convergently synthesized in 26 linear steps from 6-hydroxy-1-naphthoic acid with an overall yield of 0.18%. Although the anti-proliferative activity of 2 was more potent than that of 1, the binding potency of 2 to the PKCδ-C1B domain did not exceed that of 1. Molecular dynamics simulation indicated the capability of 2 to simultaneously form hydrogen bonds and CH/π interactions with the PKCδ-C1B domain. Focusing on the hydrogen bonds, their geometry in the binding modes involving the CH/π interactions seemed to be sub-optimal, which may explain the slightly lower affinity of 2 compared to 1. This study could be of help in optimizing such interactions and synthesizing a promising lead cancer compound.
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Structural optimization of 10-methyl-aplog-1, a simplified analog of Debromoaplysiatoxin, as an anticancer lead
Bioscience biotechnology and biochemistry, 2015Co-Authors: Masayuki Kikumori, Hiroshi Nagai, Ryo C. Yanagita, Harukuni Tokuda, Kiyotake Suenaga, Kazuhiro IrieAbstract:Aplog-1 is a simplified analog of Debromoaplysiatoxin (DAT) with potent tumor-promoting and proinflammatory activities. Aplog-1 and DAT exhibited anti-proliferative activities against several human cancer cell lines, whereas aplog-1 did not have tumor-promoting nor proinflammatory activities. We have recently found 10-methyl-aplog-1 (1) to have strong anti-proliferative activity compared with aplog-1. To further investigate the structural factors involved in the tumor-promoting, proinflammatory, and anti-proliferative activities, two dimethyl derivatives of aplog-1 (2, 3) were synthesized, where two methyl groups were installed at positions 4 and 10 or 10 and 12. 10,12-Dimethyl-aplog-1 (2) had stronger inhibitory effects on the growth of several human cancer cell lines than 1 and DAT, but exhibited no tumor-promoting and proinflammatory activities. In contrast, 4,10-dimethyl-aplog-1 (3) displayed weak tumor-promoting and proinflammatory activities along with anti-proliferative activity similar to that of 1 and DAT. Compound 2 would be the optimized seed for anticancer drugs among the simplified analogs of DAT.
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Effects of the methoxy group in the side chain of Debromoaplysiatoxin on its tumor-promoting and anti-proliferative activities
Bioorganic & medicinal chemistry letters, 2013Co-Authors: Ryo C. Yanagita, Hiroshi Nagai, Masayuki Kikumori, Harukuni Tokuda, Nobutaka Suzuki, Kiyotake Suenaga, Hiroaki Kamachi, Kazuhiro IrieAbstract:Debromoaplysiatoxin (DAT) is a tumor promoter isolated from sea hare and exhibits anti-proliferative activity against several cancer cell lines. To clarify key residues that are responsible for its tumor-promoting activity, we focused on the chiral methoxy group in the side chain, whose role had not yet been discussed or examined before. Demethoxy-DAT (8) was derived from DAT and we evaluated its tumor-promoting activity, anti-proliferative activity, and ability to bind to protein kinase C (PKC) isozymes. Compound 8 showed somewhat weaker tumor-promoting activity than that of DAT both in vitro and in vivo, but showed higher anti-proliferative activity against several cancer cell lines. Although the affinity to novel PKC isozymes of 8 was comparable to that of DAT, the affinity to conventional PKC isozymes decreased slightly. These results suggest that the methoxy group of DAT is one of the key residues critical for tumor-promoting activity but not for anti-proliferative activity. Since the methoxy group has little influence on the molecular hydrophobicity, this is the first report showing that structural factors other than hydrophobicity in the side chain of DAT affected its biological activities.
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Structure–Activity Studies on the Spiroketal Moiety of a Simplified Analogue of Debromoaplysiatoxin with Antiproliferative Activity
Journal of medicinal chemistry, 2012Co-Authors: Masayuki Kikumori, Hiroshi Nagai, Ryo C. Yanagita, Harukuni Tokuda, Nobutaka Suzuki, Kiyotake Suenaga, Kazuhiro IrieAbstract:Aplog-1, a simplified analogue of tumor-promoting Debromoaplysiatoxin, is antiproliferative but not tumor-promoting. Our recent study has suggested that local hydrophobicity around the spiroketal moiety is a crucial determinant for antiproliferative activity. To further clarify the structural features relevant to the activity, we synthesized two methyl derivatives of aplog-1, where a methyl group was installed at position 4 or 10 of the spiroketal moiety. 10-Methyl-aplog-1 (5) bound to the C1B domains of novel PKCs (δ, η, and θ) with subnanomolar Ki values, approximately 10–20 times stronger than aplog-1, and markedly inhibited the growth of many human cancer cell lines, while 4-methyl-aplog-1 (4) had levels of activity similar to those of aplog-1. Interestingly, 5 showed little tumor-promoting activity unlike the tumor promoter Debromoaplysiatoxin. These results suggest that 5 is a potent PKC ligand without tumor-promoting activity and could be a therapeutic lead for the treatment of cancer, like bryosta...
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structure activity studies on the spiroketal moiety of a simplified analogue of Debromoaplysiatoxin with antiproliferative activity
Journal of Medicinal Chemistry, 2012Co-Authors: Masayuki Kikumori, Hiroshi Nagai, Ryo C. Yanagita, Harukuni Tokuda, Nobutaka Suzuki, Kiyotake Suenaga, Kazuhiro IrieAbstract:Aplog-1, a simplified analogue of tumor-promoting Debromoaplysiatoxin, is antiproliferative but not tumor-promoting. Our recent study has suggested that local hydrophobicity around the spiroketal moiety is a crucial determinant for antiproliferative activity. To further clarify the structural features relevant to the activity, we synthesized two methyl derivatives of aplog-1, where a methyl group was installed at position 4 or 10 of the spiroketal moiety. 10-Methyl-aplog-1 (5) bound to the C1B domains of novel PKCs (δ, η, and θ) with subnanomolar Ki values, approximately 10–20 times stronger than aplog-1, and markedly inhibited the growth of many human cancer cell lines, while 4-methyl-aplog-1 (4) had levels of activity similar to those of aplog-1. Interestingly, 5 showed little tumor-promoting activity unlike the tumor promoter Debromoaplysiatoxin. These results suggest that 5 is a potent PKC ligand without tumor-promoting activity and could be a therapeutic lead for the treatment of cancer, like bryosta...