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In our screening program on marine-derived actinomycetes, Nonomuraea sp. AKA32 isolated from deep-sea water collected from a depth of 800 m in Sagami Bay, Japan was found to produce compounds cytotoxic to cancer cells. Activity-guided purification led to the isolation of a new aromatic polyketide, akazamicin (1), along with two known compounds, actinofuranone C (2) and N-formylanthranilic acid (3). Structures of these compounds were elucidated through the interpretation of NMR and MS spectroscopic data. Compounds 1, 2, and 3 displayed cytotoxicity against murine B16 melanoma cell line with the IC 50 value of 1.7, 1.2, and 25 μM, respectively.

Taking orostanal (a compound from a Japanese marine sponge, Stelletta hiwasaensis) as a lead compound, some novel B-norcholesteryl benzimidazole and benzothiazole derivatives were synthesized. The antiproliferative activity of the compounds against human cervical carcinoma (HeLa), human lung carcinoma (A549), human liver carcinoma cells (HEPG2) and normal kidney epithelial cells (HEK293T) was assayed. The results revealed that the benzimidazole group was a better substituent than benzothiazole group for increasing the antiproliferative activity of compounds. 2-(3β'-Acetoxy-5β'-hydroxy-6'-B-norcholesteryl)benzimidazole (9b) with the structure of 6-benzimidazole displays the best antiproliferative activity to the cancer cells in all compounds, but is almost inactive to normal kidney epithelial cells (HEK293T). The assay of compound 9b to cancer cell apoptosis by flow cytometry showed that the compound was able to effectively induce cancer cell apoptosis. The research provided a theoretical reference for the exploration of new anti-cancer agents and may be useful for the design of novel chemotherapeutic drugs.

Prostate cancer is a heterogeneous disease that responds variably to available agents, particularly androgen receptor(AR)- targeting agents. In preclinical models, cabazitaxel, a second-generation taxane, demonstrated enhanced antitumor activity when compared with docetaxel. In subsequent clinical trials, cabazitaxel was associated with pharmacokinetic, safety, and tolerability profiles consistent with those of previous taxanes. In the pivotal phase III study(TROPIC; NCT00417079), cabazitaxel led to significantly improved overall survival in patients with metastatic castration-resistant prostate cancer(mCRPC), compared with mitoxantrone, when both were administered in combination with prednisone/prednisolone(median survival: 15.1 months[95%confidence interval(CI): 14.1-16.3]vs 12.7 months[95% CI: 11.6-13.7], hazard ratio(HR): 0.70[95% CI: 0.59-0.83], p<0.0001), and it also extended progression-free survival. Furthermore, a long-term analysis of the TROPIC trial revealed that the survival benefit with cabazitaxel was maintained at 2 years, with 60(15.9%)patients in the cabazitaxel group and 31(8.2%)patients in the mitoxantrone group surviving for B2 years(odds ratio: 2.11, 95% CI: 1.33-3.33). Cabazitaxel also provides pain palliation similar to that provided by using mitoxantrone. The safety profile of cabazitaxel is consistent with that of first-generation taxanes, and gastrointestinal(predominantly diarrhea)and hematologic(mainly neutropenia)adverse events are the most frequently reported. Clinical trial data suggest that these events can be managed with careful monitoring and dose reduction where necessary. In addition, treatment with granulocyte colony-stimulating factor(G-CSF)can mitigate hematologic adverse events, whereas supportive treatment with antiemetic and antidiarrheal agents may ameliorate gastrointestinal symptoms. The treatment paradigm for mCRPC is evolving rapidly with the emergence of data for new agents, leading to maximization of patient benefits. The proven efficacy and tolerability profiles of cabazitaxel suggest the promising role of this agent within this paradigm.

A macrocylic dodecapeptide, cycloforskamide, was isolated from the sea slug Pleurobranchus forskalii, collected off Ishigaki Island, Japan. Its planar structure was deduced by extensive NMR analyses and was further confirmed by MS/MS fragmentation analyses. Finally, the absolute configuration was determined by total hydrolysis and chiral-phase gas chromatographic analysis. This novel dodecapeptide contains three d-amino acids and three thiazoline heterocycles and exhibits cytotoxicity against murine leukemia P388 cells, with an IC50 of 5.8 μM.

New 34-membered polyol macrolides JBIR-129 (1) and JBIR-139 (2) were isolated from the culture of the terrestrial Streptomyces RK74. The planar structures of 1 and 2 were established on the basis of 1D and 2D NMR, ESI-TOF-MS, IR, and UV spectra. The relative configurations of the sugar units were determined by analyzing vicinal ¹H-¹H coupling constants and steric information. Both 1 and 2 showed cytotoxic activity against human ovarian adenocarcinoma SKOV-3 cells with IC₅₀ values of 0.3 and 0.4 μM, respectively.

What Is Known and Objective: Concern about the drug lag, the delay in marketing approval between one country and another, for anticancer drugs has increased in Japan. Although a number of studies have investigated the drug lag, none has investigated it in relation to the transition of anticancer therapy from traditional cytotoxic drugs to molecularly targeted agents. Our aim was to investigate current trend in oncology drug lag between the US and Japan and identify oncology drugs approved in only one of the two countries., Methods: Publicly and commercially available data sources were used to identify drugs approved in the US and Japan as of 31 December 2010 and the data used to calculate the drug lag for individual drugs., Results and Discussion: Fifty-one drugs were approved in both the US and Japan, whereas 34 and 19 drugs were approved only in the US or Japan, respectively. Of the 19 drugs approved only in Japan, 12 had not been subject to development for a cancer indication in the US, and all were approved before 1996 in Japan. Of the 34 drugs approved only in the US, 20 had not been subject to development in Japan, and none was in the top 25 by annual US anticancer drug-class sales. For drugs approved in both countries, the mean approval lag of the molecularly targeted drugs (MTDs) was significantly shorter than that of the non-molecularly targeted drugs (non-MTDs) (3·3 vs. 5·4 years). Further, mean R&D time of the MTDs was significantly shorter than that of non-MTDs (10·0 vs. 13·7 years). The price of MTDs had increased on average by 6·6% annually in the US, whereas it had decreased on average by 4·3% biyearly in Japan., What Is New and Conclusion: The emergence of new molecularly targeted agents has contributed to reducing the approval lag, most likely due to improvements in R&D strategy., (© 2012 Blackwell Publishing Ltd.)

Cyclic peptides containing 5-hydroxytryptophan and thiazole moieties were isolated from the marine sponge Discodermia calyx collected near Shikine-jima Island, Japan. The structures of calyxamides A (1) and B (2), including the absolute configurations of all amino acids, were elucidated by spectroscopic analyses and degradation experiments. The structures are similar to keramamides F and G, previously isolated from Theonella sp. The analysis of the 16S rDNA sequences obtained from the metagenomic DNA of D. calyx revealed the presence of Candidatus Entotheonella sp., an unculturable δ-proteobacterium inhabiting the Theonella genus and implicated in the biosynthesis of bioactive peptides.

A library of extracts established from hundreds of marine organisms was screened by a cytotoxicity test. The active organic extract of an Okinawan marine sponge of the genus Dysidea was subjected to bioassay-guided fractionation to give three new polyoxygenated steroids dysideasterols F-H (1-3), together with two known related compounds (4 and 5). Their structures were confirmed by NMR and mass spectroscopic analyses. A characteristic structural feature of 2, 4 and 5 is an allylic epoxide, whereas this epoxide undergoes ring-opening by a neighbouring hydroxyl group to give a tetrahydrofuran ring in 1 and 3. All compounds 1-5 exhibited a similar cytotoxic effect with IC50 values of 0.15-0.3 µM against human epidermoid carcinoma A431 cells, demonstrating that the allylic epoxide moiety was not responsible for this cytotoxic effect.

Pseudoalteromonas sp. 1020R, isolated from the Pacific coast of Japan, produces prodigiosin family pigments. Structural analysis indicated that these are prodigiosin (2-methyl-3-pentyl-prodiginine) and three other prodigiosin congeners which differ only in the lengths of the alkyl side chains. These compounds exhibited different extents of cytotoxicity against U937 leukemia cells, and cell death was accompanied by typical features of apoptosis.

A green pigment, viridaphin A₁ glucoside (1), was isolated from the green aphid Megoura crassicauda. One- and two-dimensional NMR spectrometric analyses of 1 and its aglycone established the structure as an octacyclic compound. Viridaphin A₁ glucoside exhibited cytotoxicity against HL-60 human tumor cells with an IC₅₀ of 23 μM and antibacterial activity against Bacillus subtilis NBRC 3134 with a minimum inhibitory concentration of 10.0 μg/mL. These results suggested that aphid pigments may protect aphids from invasive species, including viruses and bacteria.

Romidepsin (Istodax), a selective inhibitor of histone deacetylases (HDACs), was approved for the treatment of cutaneous T-cell lymphoma in November 2009 by the US Food and Drug Administration. This unique natural product was discovered from cultures of Chromobacterium violaceum, a Gram-negative bacterium isolated from a Japanese soil sample. This bicyclic compound acts as a prodrug, its disulfide bridge being reduced by glutathione on uptake into the cell, allowing the free thiol groups to interact with Zn ions in the active site of class I and II HDAC enzymes. Due to the synthetic complexity of the compound, as well as the low yield from the producing organism, analogs are sought to create synthetically accessible alternatives. As a T-cell lymphoma drug, romidepsin offers a valuable new treatment for diseases with few effective therapies.

Poria cocos (Polyporaceae) is a saprophytic fungus that grows in diverse species of Pinus. Its sclerotium, called fu-ling or hoelen, is used in traditional Chinese and Japanese medicine for its diuretic, sedative, and tonic effects. Various studies of this fungus have demonstrated its marked anti-inflammatory activity in different experimental models of acute and chronic inflammation. It is widely used as a constituent of many preparations in Asian medicine, but the number of research papers on its clinical properties is insufficient for establishing its efficacy and safety from a scientific point of view. In this review, we have compiled all the published data concerning the chemistry, pharmacology, and clinical uses of this drug in order to evaluate its clinical interest for future use against various pathologies in which inflammation and immunodepression are implicated. We selected the papers for review on the basis of their ethnopharmacological relevance, using the most relevant databases for the biomedical sciences. Studies on various fungus extracts as well as on the major phytochemical compounds (polysaccharides and triterpenoids) present in Poria cocos comprised the principal objectives of this review. In several of the studies reviewed, the inhibitory effects of triterpenes on phospholipase A (2) (PLA (2)) have been clearly demonstrated. In addition, the inhibitory effects of Poria cocoson the secretion of different cytokines from human peripheral blood monocytes have also been described. Triterpenoids are known to have a pivotal influence on certain diseases such as rheumatoid arthritis, psoriasis, autoimmune uveitis, septic shock, and possibly bronchial asthma, while polysaccharides can potentiate the immune response. Reviewing the literature, we found that polysaccharides from Poria cocos enhanced the secretion of immune stimulators and suppressed the secretion of immune suppressors, thus potentiating the immune response. In addition, they showed antitumor activity against different cancer cell lines. This activity is associated with their capacity to inhibit angiogenesis by downregulating both NF- κB and the induction of NF- κB/Rel translocation., (© Georg Thieme Verlag KG Stuttgart · New York.)

Purpose: Three products can be used in Japan for the reconstitution of cytotoxic agents: PhaSeal, Chemo CLAVE and Chemo Mini Spike (CMS). The low preparation volume may be affected by residual-related volume in their devices. In this study, the residual-related error in their devices was examined and compared., Method: The blank of each component of these devices was weighed using a precision electric balance. After ejecting distilled water (DW) for injection, each was weighed again with the balance. In addition, for etoposide in the cases of PhaSeal and Chemo CLAVE, the components of the devices were similarly weighed., Result: The weight gains of each device after ejecting DW were as follows: CMS-V (440 mg) greater than the combined components of Chemo CLAVE (128-171 mg)/CMS-MT (123 mg) greater than the combined components of PhaSeal (13-56 mg). For etoposide, the weight gains of PhaSeal (208 mg) and Chemo CLAVE (223 mg) showed no significant difference. The priming volume of each device was calculated from the specific gravity of water. The residual-related volume was 'CMS-V > Chemo CLAVE, CMS-MT > PhaSeal', although this was very slight in actual situations., Conclusion: The residual-related volume was marked in its low preparation volume. In water-soluble drugs, the residual volume of PhaSeal was lowest of the devices in this study, but in viscous drugs, such as etoposide, the residual volume of PhaSeal was almost identical to Chemo CLAVE; that is, the residual volume of these devices was affected by the solution property. The residual-related volume in the devices will lead to errors; therefore, residual-related errors need to be considered in the use of these devices.

From the sea hares belonging to two genera, Aplysia and Dolabella, a variety of new cytotoxic substances were isolated as minute constituents: their chemical structures were determined and their cytotoxicity was evaluated. Regarding the highly cytotoxic substances, further chemical and biological studies were performed that included their asymmetric chemical synthesis and elucidation of biological characteristics such as antitumor activity.

Pyrrospirones A and B have been isolated from unpolished rice cultures of the endophytic fungus Neonectria ramulariae Wollenw KS-246. Their absolute stereostructures (1 and 2) were elucidated through spectroscopic methods using 1D and 2D NMR techniques and chemical transformations, including the modified Mosher's method. The compounds exhibited cytotoxicity and induced apoptosis in human promyelocytic leukemia HL-60 cells.

Three sesterterpenoids, aplysinoplides A-C (1- 3), were isolated from the marine sponge Aplysinopsis digitata. Their structures were determined on the basis of spectroscopic data. They exhibited cytotoxic activity against P388 mouse leukemia cells.

Four new briarane-type diterpenoids, brianodins A-D ( 1- 4), were isolated from a soft coral, Pachyclavularia sp., and the structures and relative stereochemistry of 1- 4 were elucidated on the basis of spectroscopic data. The absolute configurations of 3 and 4 were assigned by the MTPA method. Brianodin A ( 1) showed a modest cytotoxicity.

Five new briarane-type diterpenoids, pachyclavulides E (5), F (6), G (7), H (8) and I (9), were isolated from the Okinawan soft coral Pachyclavularia violacea. The structures of these compounds were elucidated based on the results of spectroscopic analysis. Compound 5 showed a weak growth-inhibitory activity in vitro toward cancer cells.

The Halichondria sponge-derived fungus, Gymnacella dankaliensis, was cultured in two different media conditions. A modified malt extract medium containing soluble starch instead of glucose resulted in two extremely unusual steroids, dankasterones A (2) and B (3), while four additional unusual steroids, gymnasterones A (4), B (5), C (6), and D (7), were isolated from the original malt extract medium. Their stereostructures have been established on the basis of spectroscopic analyses along with X-ray crystal structure analyses, modified Mosher's method, CD exciton method, and a chemical transformation. All the steroids except for 4 exhibited significant growth inhibition against the murine P388 cancer cell line. Dankasterone A (2) also exhibited potent growth inhibition against human cancer cell lines.

Six new illudoid sesquiterpenes, russujaponols A-F (1-6), were isolated from the fruiting bodies of Russula japonica Hongo. Their structures were established primarily by 2D NMR experiments, and the structure of the main compound, russujaponol A (1), was confirmed by X-ray crystallographic analysis of its benzoate (1a). Russujaponol A (1) suppressed invasion of human fibrosarcoma (HT1080) cells into Matrigel in a concentration-dependent manner and caused 63% inhibition at 3.73 microM.

The new fungal metabolite awajanomycin (1), which has gamma-lactone-delta-lactam rings, was isolated from the marine-derived fungus Acremonium sp. AWA16-1, which had been collected from sea mud off Awajishima Island in Japan. The structure of 1 was elucidated by spectroscopic analysis and chemical methods. Awajanomycin (1) and its derivative (2) inhibited the growth of A549 cells with IC(50) values of 27.5 and 46.4 microg/mL, respectively.

Four novel biscembranes have been isolated from the soft coral Sarcophyton glaucum, collected at Amami Oshima, two of which showed weak activity against proliferation of human promyelocytic leukemia cells (HL-60). Their absolute structures were determined on the basis of the CD spectra.

Three new lanostane triterpenoids (1, 7, 8) and five new lanostane triterpene glucosides (2-6) have been isolated from the fruit bodies of Daedalea dickinsii. Their structures were established primarily by NMR experiments, and their biological activity against HL-60 and HCT-15 cell lines was investigated. Compounds 3-6 induced internucleosomal DNA fragmentation characteristic of apoptotic cell death in the HL-60 cell line.

A new polyketide glycoside, cladionol A (1), was isolated from the cultured broth of a fungus Gliocladium sp., which was separated from sea grass Syringodium isoetifolium, and the structure was elucidated by spectroscopic data. The relative stereochemistry of C-2-C-3 was assigned by mainly J-based configuration analysis, while those of two sugar units were elucidated to be beta-mannopyranoside and arabitol on the basis of NOESY data and/or 1H-1H couplings. Furthermore, the absolute configuration of the mannose moiety was determined as the D-form on the basis of chiral HPLC analysis of a benzoyl derivative of the acid hydrolysate of 1. Cladionol A (1) exhibited modest cytotoxicity.

Two new 3-alkylpiperidine alkaloids, tetradehydrohalicyclamine A (2) and 22-hydroxyhalicyclamine A (3), have been isolated from a marine sponge Amphimedon sp. as cytotoxic constituents. Their structures were elucidated by spectroscopic analysis. Compounds 2 and 3 inhibited growth of P388 cells with IC50 values of 2.2 and 0.45 microg/mL, respectively.

This review describes biologically active natural products isolated from Aphyllophorales, many of which are known as polypores. Polypores are a large group of terrestrial fungi of the phylum Basdiomycota (basidiomycetes), and they along with certain Ascomycota are a major source of pharmacologically active substances. There are about 25 000 species of basidiomycetes, of which about 500 are members of the Aphyllophorales, a polyphyletic group that contains the polypores. Many of these fungi have circumboreal distributions in North America, Europe, and Asia and broad distributions on all inhabited continents and Africa; only a small number of the most common species with the most obvious fruiting bodies (basidiocarps) have been evaluated for biological activity. An estimated 75% of polypore fungi that have been tested show strong antimicrobial activity, and these may constitute a good source for developing new antibiotics. Numerous compounds from these fungi also display antiviral, cytotoxic, and/or antineoplastic activities. Additional important components of this vast arsenal of compounds are polysaccharides derived from the fungal cell walls. These compounds have attracted significant attention in recent years because of their immunomodulatory activities, resulting in antitumor effects. These high molecular weight compounds, often called biological response modifiers (BRM), or immunopotentiators, prevent carcinogenesis, show direct anticancer effects, and prevent tumor metastasis. Some of the protein-bound polysaccharides from polypores and other basidiomycetes have found their way to the market in Japan as anticancer drugs. Finally, numerous compounds with cardiovascular, phytotoxic, immunomodulatory, analgesic, antidiabetic, antioxidant, insecticidal, and nematocidal activities, isolated from polypores, are also presented. In fact many of the fungi mentioned in this paper have long been used in herbal medicine, including polypores such as Ganoderma lucidum (Reishi or Ling Zhi), Laetiporus sulphureus (Chicken-of-the-Woods), Trametes versicolor (Yun Zhi), Grifola umbellata (Zhu Lin), Inonotus obliquus (Chaga), and Wolfiporia cocos (Hoelen).

New strongylophorines-22 (1), -23 (2), -24 (3), and -25 (4) were isolated from the Okinawan sponge Petrosia (Strongylophora) corticata along with other known strongylophorines. The structures of these strongylophorines were determined on the basis of spectroscopic analysis and chemical conversions. Assessment was also made of the cytotoxicity of strongylophorines-1, -2, -3, -4, -22 (1), -23 (2), and -24 (3) toward HeLa cells.

Renieramycin J (1), a new tetrahydroisoquinoline alkaloid, has been isolated from a marine sponge Neopetrosia sp. as a potent cytotoxin that induced morphological changes in 3Y1 cells. Such changes are characteristic of RNA and/or protein synthesis inhibitors. The structure of 1 including the absolute stereochemistry was determined by spectroscopic and chemical methods.

The cytotoxic activity of ethanol extracts from 53 parts of 36 species of medicinal and edible plants cultivated in Okinawa was measured by using K562 human leukemia cells by a flow cytometric method. Two extracts from Rhodea japonica and Hypericum chinense were cytotoxic at a concentration of 10 microg/ml. The main cytotoxic constituent of Rhodea japonica was isolated and identified to be rhodexin A, which has been isolated as a cardetonic agent of the plant. The IC(50) value for rhodexin A against the growth of K562 cells was 19 nM, this activity being much stronger than that of ouabain (IC(50), 60 nM).

A new cytotoxic diterpene, (Z)-sarcodictyin A, was isolated from the Japanese soft coral Bellonella albiflora.(1) Its structure was elucidated on the basis of 1D and 2D NMR analysis and chemical degradation. (Z)-Sarcodictyin A showed strong cytotoxicity against HeLa human cervix cells.

An investigation of the polar extracts from two starfish, Luidia quinaria and Psilaster cassiope, led to the isolation of five sulfated "asterosaponins". Two of them, named luidiaquinoside (1) and psilasteroside (2), are new compounds. Luidiaquinoside (1) contains a novel pentasaccharide chain composed of d-glucose, d-quinovose, and d-fucose, with the d-glucose unit being the branching point. Psilasteroside (2) contains a hexasaccharide chain in which an arabinose residue is detectable in the furanose form. Both of these compounds possess a Delta(9(11)),3beta,6alpha-dihydroxysteroidal nucleus with a 20-hydroxy, 23-oxo functionality. The structures of the new asterosaponins were elucidated by a combination of NMR techniques including (1)H-(1)H (COSY, TOCSY, and ROESY) and (1)H-(13)C (HMQC and HMBC) spectroscopy, ESIMS and HRFABMS spectrometry, and GC analyses. The new asterosaponins show marginal in vitro cytotoxicity against RBL-2H3 (rat basophilic leukemia) cell lines.

Three new sesterterpenes (1-3) were isolated from a marine sponge of the genus Spongia, and their structures were determined on the basis of spectroscopic analysis. The compounds 1-3 exhibited cytotoxicity against HeLa cells with IC(50) values of 19.5, 15.0, and 5.3 microg/mL, respectively.

Five new sesterterpenes have been isolated from a lipophilic extract of a sponge, Ircinia sp., and their structures elucidated by spectroscopic and chemical methods. The absolute configurations of two metabolites (1, 3) were established by chemical degradation. These compounds showed moderate cytotoxicity against KB cells.

A new bisabolane-type sesquiterpenoid, (E)-3-isocyanobisabolane-7,10-diene (1), and a new epidioxyergostane-type steroid, 9(11)-dehydroaxinysterol (2), were isolated from the Okinawan sponge of the genus Axinyssa. Their structures were elucidated based on the results of spectroscopic analysis and chemical conversion. Epidioxysterol 2 was found to show significant growth inhibitory effects against human cancer cell lines.

Bioassay-directed fractionation of the lipophilic extract of the marine sponge Mycale izuensis led to the isolation of cytotoxic mycalolides including a new compound, 30,32-dihydroxymycalolide A (1). Its structure including absolute stereochemistry was deduced by spectroscopic and chemical methods. Compound 1 was cytotoxic against HeLa cells with an IC(50) value of 2.6 ng/mL.

Four new alkaloids (1-4) were isolated from the marine sponge Axinella brevistyla, and their structures were determined on the basis of spectroscopic analysis. The alkaloids 1-4 were antifungal against the yeast Saccharomyces cerevisiae at <1.0, <1.0, 30, and 100 microg/disk, respectively. Compounds 1-3 also exhibited cytotoxicity against L1210 cells with IC(50) values of 1.1, 0.66, and 2.5 microg/mL, respectively.

Two new cytotoxic bromotyrosine alkaloids, suberedamines A (1) and B (2), have been isolated from an Okinawan marine sponge Suberea sp. The structures were elucidated on the basis of spectroscopic data and chemical means.

A new pentacyclic steroid, xestobergsterol C [1], possessing a cis C/D ring junction, has been isolated together with two known compounds, xestobergsterols A [2] and B [3], from the Okinawan marine sponge Ircinia sp., and the structure determined on the basis of spectral data. Reexamination of the nmr data of xestobergsterols A [2] and B [3] resulted in revision of the configuration at C-23 and of the conformation of ring D in 2 and 3. The absolute stereochemistry of xestobergsterol A [2] was established by the cd exciton chirality method.

Following the characterization of altohyrtin A (1), altohyrtins B (2) and C (3) and 5-desacetylaltohyrtin A (4) have been isolated from the Okinawan marine sponge Hyrtios altum and their plane structures and parts of their relative configurations elucidated. Three congeneric macrolides (2, 3, and 4) exhibit extremely potent cytotoxicities similar to those of 1 against KB cells with IC50 values of 0.02, 0.4, and 0.3 ng/ml, respectively.