Published papers

© 2019 by the authors. Cancer remains one of the most lethal diseases worldwide. There is an urgent need for new drugs with novel modes of action and thus considerable research has been conducted for new anticancer drugs from natural sources, especially plants, microbes and marine organisms. Marine populations represent reservoirs of novel bioactive metabolites with diverse groups of chemical structures. This review highlights the impact of marine organisms, with particular emphasis on marine plants, algae, bacteria, actinomycetes, fungi, sponges and soft corals. Anti-cancer effects of marine natural products in in vitro and in vivo studies were first introduced; their activity in the prevention of tumor formation and the related compound-induced apoptosis and cytotoxicities were tackled. The possible molecular mechanisms behind the biological effects are also presented. The review highlights the diversity of marine organisms, novel chemical structures, and chemical property space. Finally, therapeutic strategies and the present use of marine-derived components, its future direction and limitations are discussed.

© 2019 Weed Science Society of Japan Chinese violet (Asystasia gangetica (L.) T. Anderson) is a perennial invasive weed belonging to Acanthaceae. Leaves of this weed have been suggested to possess phytotoxic activity. However, phytotoxic substances in this weed have not yet been reported. Therefore, the present study investigated phytotoxic activity of Chinese violet extracts and phytotoxic substances. The extracts of Chinese violet leaves inhibited the root and shoot growth of cress, lettuce, alfalfa, barnyard grass, ryegrass, and timothy, where the level of inhibition increased with increasing extract concentrations. Bioassay-guided separations of the extracts led to isolation of two phytotoxic substances, indole-3-carboxaldehyde and (6R,9S)-3-oxo-α-ionol. Indole-3-carboxaldehyde significantly inhibited the root and shoot growth of cress at concentrations ≥100 and 30 μmol L −1 , respectively, and concentrations of the substance required for 50% growth inhibition were 210 and 127 μmol L −1 for cress roots and shoots, respectively. The other substance, (6R,9S)-3-oxo-α-ionol, was reported to have strongly inhibited cress roots and shoots. The present results suggest that Chinese violet contains two phytotoxic substances indole-3-carboxaldehyde and (6R,9S)-3-oxo-α-ionol, and those substances may play an important role in the phytotoxic activity of Chinese violet.

© 2019, © 2019 Taylor & Francis Group, LLC. Problems related to weed management such as outbreaks of herbicide-resistant weeds have recently increased. An interesting approach to such problems is to use plant materials with phytotoxic activity. Burdock (Arctium lappa L.) is a biennial herb belonging to Asteraceae and is cultivated in several countries. The present study investigated the phytotoxic activity of burdock and its active substances. Extracts of both burdock leaves and roots inhibited the shoot and root growth of cress and barnyard grass, where the level of inhibition increased with increasing extract concentration. The leaf extracts had 2.0–2.5 times higher activity than the root extracts. Bioassay-guided separations of the leaf extracts led to isolation of a phytotoxic substance, onopordopicrin. Onopordopicrin significantly inhibited the shoot and root growth of cress and barnyard grass. The concentrations of the substance required for 50% growth inhibition were 0.27 and 0.26 mM for cress shoots and roots, respectively, and 1.86 and 0.35 mM for barnyard grass shoots and roots, respectively. The present results suggest that burdock leaves have high phytotoxic activity and onopordopicrin may play a major role in the activity. Burdock leaves may be a good resource for weed management.

© 2019 Elsevier B.V. When aged kiwifruit (Actinidia deliciosa (A. Chev.) C.F. Liang et A.R. Ferguson) plants are replaced with young ones, the growth and productivity of the young plants were occasionally lower than expected. This symptom is typical of the replant problems reported in several fruit trees. Phytotoxic substances released from the plant are assumed to be involved in the replant problems. Although some substances contained in kiwifruit leaves have been reported to have phytotoxic activity, little is known about phytotoxicity and phytotoxic substances in kiwifruit leaves on the growth of the kiwifruit itself. Therefore, this study determined the phytotoxic activity of kiwifruit leaf extracts and soil extracts and identified a phytotoxic substance in kiwifruit leaves. Extracts of kiwifruit leaves inhibited the growth of Lepidium sativum, Lactuca sativa, Medicago sativa, Phleum pratense, Lolium multiflorum, Echinochloa crus-galli, and kiwifruit seedlings. The soil extracts also inhibited the growth of L. sativum. These results suggest that kiwifruit leaf extracts and soil extracts may possess phytotoxic substances. (-)-Epicatechin was isolated from the extracts with bioassay-guided separations using chromatography. The concentrations of (-)-epicatechin required for 50% growth inhibition of the hypocotyls and radicles of L. sativum were 27.9 and 10.7 mM, respectively, and those for the hypocotyls and radicles of kiwifruit were 13.9 and 7.6 mM, respectively. This substance may contribute to the phytotoxic activity of kiwifruit leaf extracts and may be involved in the kiwifruit replant problem.

© 2019 Weed Science Society of Japan The creeping weed, Chrysopogon aciculatus (Retz.) Trin., is widely known for its use as folk medicine, while its phytotoxic potential has not been examined. Therefore, we carried out an investigation into the phytotoxic potential of C. aciculatus to identify phytotoxic substances. C. aciculatus extracts showed inhibitory effects on shoot and root growth of cress, lettuce, rapeseed, and Italian ryegrass. Inhibition was both species-dependent and concentration-dependent. Two substances, (9S,10E,12Z)-9-hydroxyoctadeca-10,12-dienoic acid (9-HO-ODDEA) and rhizopycnin A, were isolated using chromatographies and characterized by spectral analysis. 9-HO-ODDEA retarded shoot and root growth of cress at concentrations higher than 1.0 and 0.3 mM, respectively, while on cress seedling by rhizopycnin A, the inhibition began from 1.0 mM. The concentrations needed for 50% inhibition of the shoot and root growth of test plants ranged from 1.71–2.31, and 0.71–0.72 mM for 9-HO-ODDEA and rhizopycnin A, respectively. These results indicate that these substances may contribute, to a certain extent, to the phytotoxic activity of C. aciculatus.

© 2019 American Chemical Society. Minnamide A is a lipopeptide with a unique repeating structure consisting of hydroxy and proposed β-branched methyl groups. The absolute configuration of minnamide A was determined by a combination of chemical degradation, chiral HPLC analyses, and synthetic methods. Minnamide A showed growth-inhibitory activity toward HeLa cells with an IC 50 value of 0.17 μM and rapidly induced cell death at a concentration of 2 μM. Minnamide A induced the copper-mediated accumulation of reactive oxygen species.

Copyright © 2018 American Chemical Society and American Society of Pharmacognosy. Hoshinoamides A (1) and B (2), new acyclic lipopeptides, were isolated from the marine cyanobacterium Caldora penicillata. Their structures were elucidated by spectroscopic analyses and degradation reactions. Hoshinoamides A (1) and B (2) did not exhibit any cytotoxicity against HeLa cells at 10 μM, but inhibited the in vitro growth of the malarial parasite Plasmodium falciparum (IC50 = 0.52 and 1.0 μM, respectively).

© 2018 Elsevier Ltd Croissamide, a proline-rich cyclic peptide that contains an N-prenylated tryptophan, was isolated from a marine cyanobacterium Symploca sp. Its gross structure was determined by spectroscopic analyses, and the absolute configuration was established based on chiral HPLC analyses of acid hydrolysates.

© 2017 Elsevier Ltd Biselyngbyaside, an 18-membered macrolide glycoside from marine cyanobacteria, and its derivatives are known to be sarco/endoplasmic reticulum Ca2+ ATPase (SERCA) inhibitors. Recently, a SERCA orthologue of the malaria parasite, PfATP6, has attracted attention as a malarial drug target. To provide a novel drug lead, we designed new synthetic analogs of biselyngbyolide B, the aglycone of biselyngbyaside, based on the co-crystal structure of SERCA with biselyngbyolide B, and synthesized them using the established synthetic route for biselyngbyolide B. Their biological activities against malarial parasites were evaluated.

Abstract The first total synthesis of maedamide, an acyclic peptide isolated from a marine cyanobacterial assemblage of Lyngbya sp., was achieved. This synthesis led to reassignment of the allo-d-Ile of maedamide to be l-Ile, which was supported by 1H and 13C NMR data.

Biselyngbyasides (BLSs), macrolides from a marine cyanobacterium, are cytotoxic natural products whose target molecule is unknown. Here we report that BLSs are high affinity (Ki ∼ 10 nM) inhibitors of Ca2+-pumps with a unique binding mode. The crystal structures of the Ca2+-pump in complex with BLSs at 3.2-3.5 Å-resolution show that BLSs bind to the pump near the cytoplasmic surface of the transmembrane region. The crystal structures and activity measurement of BLS analogs allow us to identify the structural features that confer high potency to BLSs as inhibitors of the pump.

Mebamamides A and B, new lipopeptides with four d-amino acid residues and a 3,8-dihydroxy-9-methyldecanoic acid residue, were isolated from the green alga Derbesia marina. Their gross structures were elucidated by spectroscopic and ESI-ITMS analyses. The absolute configurations except for the two leucines were revealed based on chiral-phase HPLC analyses of the acid hydrolysate and a modified Mosher's method. A distinction between d-Leu and l-Leu in the sequence was established by the application of a dansyl-Edman method to the partial acid hydrolysate. Mebamamide A did not exhibit any growth inhibitory activity against HeLa and HL60 cells at 10 μM, and mebamamide B did not exhibit any growth inhibitory activity against those cells at 100 μM. Additionally, it was suggested that mebamamide B induced the differentiation of HL60 cells into macrophage-like cells at 100 μM. (Chemical Equation).

The fern Gleichenia japonica often dominates plant communities by forming large monospecific stands throughout the temperate to tropical Asia. The objective of this study was the investigation of allelopathic property and substances of the decomposing litter of the fern to evaluate the possible involvement of its allelopathy in the domination. An aqueous methanol extract of G. japonica litter inhibited the growth of garden cress (Lepidium sativum), lettuce (Lactuca sativa), barnyard grass (Echinochloa crus-galli), and ryegrass (Lolium multiflorum). This result suggests that G. japonica litter contains growth inhibitory substances. The extract was purified by chromatography while monitoring the inhibitory activity, and a growth inhibitory substance was isolated. The chemical structure of the substance was determined by spectral data to be a novel compound, 13-. O-β-fucopyranosyl-3β-hydroxymanool. This compound inhibited root and shoot growth of garden cress and barnyard grass at concentrations ranging from 89.7 to 271. μM for 50% inhibition. In addition, the compound had potent growth inhibitory activity with the soil taken from near the colony. The concentration of the compound in soil under a pure colony of G. japonica was 790. μM, suggesting that the compound may contribute to the establishment of monocultural stands by this fern.

An acetylene-containing lipopeptide, jahanyne, was isolated from the marine cyanobacterium Lyngbya sp. Its gross structure was established by spectroscopic analyses, and the absolute configuration was clarified based on a combination of chiral HPLC analyses, spectroscopic analyses, and derivatization reactions. Jahanyne significantly inhibited the growth of human cancer cells and induced apoptosis in HeLa cells.

Izenamides A, B, and C (1-3), new linear depsipeptides, were isolated from a taxonomically distinct marine cyanobacterium. Izenamides A and B contain a statine moiety [(3S,4S)-4-amino-3-hydroxy-6-methylheptanoic acid] and inhibited the activity of cathepsin D, an aspartic peptidase. Meanwhile, izenamides did not show growth-inhibitory activity against HeLa, HL60, or MCF-7 cells at up to 10 μM.

Cogongrass (Imperata cylindrica [L.] Raeusch.) is a perennial rhizomatous grass that belongs to the Poaceae and is widely distributed in tropical, subtropical and temperate regions over the world. The grass is strongly invasive and is suggested to have allelopathic potential. However, limited information is available on allelopathic substances in cogongrass rhizomes. Therefore, the allelopathic potential and substances in cogongrass rhizomes were investigated. The extracts of cogongrass rhizomes inhibited the root and shoot growth of barnyard grass, ryegrass, timothy, cress, lettuce and alfalfa. After bioassay-guided separations of the extracts, four growth inhibitory substances, 5-methoxyflavone, 5,2'-dimethoxyflavone, methyl caffeate and abscisic acid, were isolated. 5-Methoxyflavone, 5,2'-dimethoxyflavone and methyl caffeate significantly inhibited the root and shoot growth of cress at concentrations of ≥0.03-0.3m mol L-1 and their concentrations required for 50% growth inhibition were 0.079-0.24, 0.23-1.1 and 0.59-0.88m mol L-1, respectively. The other isolated substance, abscisic acid, has been reported to have strong growth inhibitory activity. Its concentrations required for 50% growth inhibition on cress were 0.31-0.61μ mol L-1. The present study suggests that cogongrass rhizomes might have allelopathic potential and that those four substances might contribute to that potential.

Caesalpinia mimosoides (Fabaceae) has been used as a folk medicine and reported to have pharmacological properties. However, the phytotoxicity of C. mimosoides has not yet been studied. Therefore, the phytotoxic activity of C. mimosoides leaf and stem extracts was evaluated against the growth of dicotyledonous and monocotyledonous plants. Aqueous methanol extracts of C. mimosoides leaves and stems exhibited inhibitory effects on the growth of all the test plants. The growth of the test plants decreased with the increase of concentrations of the extracts. Comparison of the concentrations required for 50% growth inhibition (I50 values) indicates that the leaf extracts had more inhibitory effects than the stem extracts. Thus, the active substances in the leaf extracts were purified using column chromatographic separations and a growth inhibitory substance was isolated and identified as methyl gallate by using spectral analysis. This study reports the first isolation of methyl gallate in C. mimosoides leaves. Methyl gallate at 10 mM completely inhibited the growth of cress shoots and inhibited its roots by 4.7% of control growth. At the same concentration, the shoots and roots of barnyard grass were inhibited by 84.2 and 1.7% of control growth, respectively. I50 values of methyl gallate for the growth of cress and barnyard grass ranged from 2.3 to 2.9 and 0.3 to 30.5 mM, respectively. The results suggest that methyl gallate may be responsible for the phytotoxic effects of C. mimosoides.