In Vitro and in Vivo antitumor activity and the mechanism of siphonodictyal B in human colon cancer cells.

Liphagal, isolated from the marine sponge Aka coralliphaga, exhibits phosphatidylinositol 3-kinase alpha (PI3Kα) inhibitory activity and cytotoxic effects in human cancer cells. Siphonodictyal B, the biogenetic precursor of liphagal, also has PI3K inhibitory activity. However, its cytotoxic or antitumor activities have not been evaluated.

A novel approach to oxazole-containing diterpenoid synthesis from plant roots: salviamines E and F.

In this study, salviamines E and F, which are structurally unique abietane-type diterpene alkaloids containing an oxazole ring, were efficiently synthesized from a known molecule, 5,7,8-trimethoxy-1-naphthol. The synthetic sequence involves the following crucial steps: (i) the assembly of a carbon skeleton by coupling a six-carbon homoprenyl unit with a naphthalene moiety (Kumada-Tamao-Corriu coupling); (ii) the construction of a tricyclic phenanthrene ring by acid-induced cyclization of a naphthalene derivative with a homoprenyl side chain; (iii) the formation of an oxazole ring by nucleophilic ring closure of a 2-aminophenylene-1,4-diyl-diformate or -diacetate moiety and (iv) Friedel-Crafts acetylation at the C13 position of the tetracyclic intermediates to obtain the two target molecules, salviamines E and F. To the best of our knowledge, salviamine synthesis is reported here for the first time.

A novel approach to sesquiterpenoid benzoxazole synthesis from marine sponges: nakijinols A, B and E-G.

Nakijinols A, B and analogues E through G, which are structurally unique and biologically significant sesquiterpenoid benzoxazoles, can be efficiently obtained in a highly unified manner from the sesquiterpenoid quinone, smenospongine. The starting material is accessible from the (+)-5-methyl Wieland-Miescher ketone. The synthetic method features strategic construction of the requisite dihydroxylated benzoxazole substructure via the ring closure of the N-(2-hydroxyphenyl)-formamide or -acetamide moiety.

Antitumor activity and pharmacologic characterization of the depsipeptide analog as a novel histone deacetylase/ phosphatidylinositol 3-kinase dual inhibitor.

Histone deacetylase (HDAC)/phosphatidylinositol 3-kinase (PI3K) dual inhibition is a promising strategy for the treatment of intractable cancers because of the advantages of overcoming potential resistance and showing synergistic effects. Therefore, development of an HDAC/PI3K dual inhibitor is reasonably attractive. Romidepsin (FK228, depsipeptide) is a potent HDAC inhibitor.

Total Synthesis of Thailandepsin B, a Potent HDAC Inhibitor Isolated from a Microorganism.

Thailandepsin B, a bicyclic depsipeptide histone deacetylase inhibitor, was efficiently synthesized in 51% overall yield in eight steps, starting from commercially available D-norleucine methyl ester and known (S,E)-3-(4-methoxybenzyloxy)-7-(tritylthio)hept-4-enoic acid. The method features a convergent approach in which the corresponding seco-acid, a key precursor in macrolactonization, is directly assembled through the condensation of a D-allo-isoleucine-D-cysteine-containing segment with a D-norleucine-containing segment.

Synthesis and biological evaluation of novel FK228 analogues as potential isoform selective HDAC inhibitors.

Novel C4- and C7-modified FK228 analogues were efficiently synthesized in a highly convergent and unified manner. This synthesis features the amide condensation of glycine-d-cysteine-containing segments with d-valine-containing segments for the direct assembly of the corresponding seco-acids, which are key precursors of macrolactones. The HDAC inhibition assay and cell-growth inhibition analysis of the synthesized analogues revealed novel aspects of their structure-activity relationship.

Low-dose spiruchostatin-B, a potent histone deacetylase inhibitor enhances radiation-induced apoptosis in human lymphoma U937 cells via modulation of redox signaling.

Spiruchostatin B (SP-B), is a potent histone deacetylase (HDAC) inhibitor, in addition to HDAC inhibition, the pharmacological effects of SP-B are also attributed to its ability to produce intracellular reactive oxygen species (ROS), particularly H2O2. In this study, we investigated the effects of low dose (non-toxic) SP-B on radiation-induced apoptosis in human lymphoma U937 cells in vitro. The treatment of cells with low-dose SP-B induced the acetylation of histones, however, does not induce apoptosis.

Clinical effect of biapenem on nursing and healthcare-associated pneumonia (NHCAP).

The clinical effect of Biapenem (BIPM) on Nursing and Healthcare-associated pneumonia (NHCAP) was evaluated. One hundred and three NHCAP patients (Group B: 52 patients, Group C: 51 patients) to whom BIPM was administered were included in this study. Clinical effect, bacteriological effect, and adverse events were examined.

Biochemical, biological and structural properties of romidepsin (FK228) and its analogs as novel HDAC/PI3K dual inhibitors.

Romidepsin (FK228, depsipeptide) is a potent histone deacetylase (HDAC) inhibitor that has FDA approval for the treatment of cutaneous and peripheral T-cell lymphomas. We have previously reported that FK228 and its analogs have an additional activity as phosphatidylinositol 3-kinase (PI3K) inhibitors, and are defined as HDAC/PI3K dual inhibitors. Because a combination of an HDAC inhibitor and a PI3K inhibitor induces apoptosis in human cancer cells in a synergistic manner, development of an HDAC/PI3K dual inhibitor will provide an attractive novel drug for cancer therapy.

Predicting the structures of complexes between phosphoinositide 3-kinase (PI3K) and romidepsin-related compounds for the drug design of PI3K/histone deacetylase dual inhibitors using computational docking and the ligand-based drug design approach.

Predictions of the three-dimensional (3D) structures of the complexes between phosphoinositide 3-kinase (PI3K) and two inhibitors were conducted using computational docking and the ligand-based drug design approach. The obtained structures were refined by structural optimizations and molecular dynamics (MD) simulations. The ligands were located deep inside the ligand binding pocket of the p110α subunit of PI3K, and the hydrogen bond formations and hydrophobic effects of the surrounding amino acids were predicted.

Spiruchostatin A and B, novel histone deacetylase inhibitors, induce apoptosis through reactive oxygen species-mitochondria pathway in human lymphoma U937 cells.

Spiruchostatin A (SP-A) and spiruchostatin B (SP-B) are the potent histone deacetylase inhibitors (HDACi), that has the potential for chemotherapy of leukemia but the exact mechanism of these compounds remains unclear. In the present study, the role of reactive oxygen species (ROS) production and the mechanism involved in the apoptosis was investigated in human lymphoma U937 cell. When the U937 cells were treated with SP-A and SP-B for 24h at different concentrations, evidence of apoptotic features, including increase in DNA fragmentation and changes in nuclear morphology, were obtained.

Total synthesis of burkholdacs A and B and 5,6,20-tri-epi-burkholdac A: HDAC inhibition and antiproliferative activity.

The bicyclic depsipeptide histone deacetylase (HDAC) inhibitors burkholdacs A and B were efficiently synthesized in a highly convergent and unified manner. The synthesis features the amide coupling of a D-valine-D-cysteine- or D-allo-isoleucine-D-cysteine-containing segment with a D-methionine-containing segment to directly assemble the corresponding seco-acids, key precursors for macrolactonization. Using the same methodology, 5,6,20-tri-epi-burkholdac A was also synthesized.

Enantioselective total synthesis of dysidavarone A, a novel sesquiterpenoid quinone from the marine sponge Dysidea avara.

Dysidavarone A, a structurally unprecedented sesquiterpenoid quinone, was synthesized in 30 % overall yield in a longest liner sequence of 13 steps from commercially available o-vanillin. A highly strained and bridged eight-membered carbocyclic core was established by the C7-C21 carbon bond formation through a copper enolate mediated Michael addition to the internal quinone ring.

Enantioselective total synthesis of otteliones A and B, novel and powerful antitumor agents from the freshwater plant Ottelia alismoides.

Otteliones A and B, isolated from the freshwater plant Ottelia alismoides, have attracted significant attention because of their potential as novel anticancer agents. In this review, four independent enantioselective total syntheses and one formal synthesis of these natural products are presented with particular focus on their methodology and strategy.

Total synthesis of bicyclic depsipeptides spiruchostatins C and D and investigation of their histone deacetylase inhibitory and antiproliferative activities.

The bicyclic depsipeptide histone deacetylase (HDAC) inhibitors spiruchostatins C and D were synthesized for the first time in a highly convergent and unified manner. The method features the amide coupling of a D-leucine-D-cysteine- or D-valine-D-cysteine-containing segment with a D-alanine- or D-valine-containing segment to directly assemble the corresponding seco-acids, key precursors of macrolactonization. The HDAC inhibitory assay and cell-growth inhibition analysis of the synthesized depsipeptides determined the order of potency of spiruchostatins A-D in comparison with the clinically approved depsipeptide FK228 (romidepsin).

Romidepsin (FK228) and its analogs directly inhibit phosphatidylinositol 3-kinase activity and potently induce apoptosis as histone deacetylase/phosphatidylinositol 3-kinase dual inhibitors.

Activation of phosphatidylinositol 3-kinase (PI3K) signaling is involved in carcinogenesis and cancer progression. The PI3K inhibitors are considered candidate drugs for cancer treatment. Here, we describe a drug screening system for novel PI3K inhibitors using Saccharomyces cerevisiae strains with deleterious mutations in the ATP-binding cassette transporter genes, because wild-type S.

Characterization of cells resistant to the potent histone deacetylase inhibitor spiruchostatin B (SP-B) and effect of overexpressed p21waf1/cip1 on the SP-B resistance or susceptibility of human leukemia cells.

We previously showed that the B cell leukemia cell line NALM-6 had the highest susceptibility among a number of leukemia cell lines to spiruchostatin B (SP-B), a potent histone deacetylase (HDAC) inhibitor. We also showed that SP-B-induced cytotoxicity depended on induction of apoptosis that was mediated by p21waf1/cip1 expression. In the present study, we generated and characterized a stable, SP-B-resistant NALM-6 cell line (NALM-6/SP-B) by continuous exposure to SP-B, starting with a low SP-B concentration.

Involvement of p21waf1/cip1 expression in the cytotoxicity of the potent histone deacetylase inhibitor spiruchostatin B towards susceptible NALM-6 human B cell leukemia cells.

Spiruchostatin B (SP-B) is a potent histone deacetylase (HDAC) inhibitor that has potential for the chemotherapy of leukemia. The aim of this study was to study the susceptibility of human leukemia cell lines to SP-B. We found that NALM-6 human B cell leukemia cells are the most susceptible to SP-B.

Total synthesis of (+)-stachyflin: a potential anti-influenza A virus agent.

The first enantioselective total synthesis of (+)-stachyflin, a potential anti-influenza A virus agent, was achieved; the method features a BF(3).Et(2)O-induced domino epoxide-opening/rearrangement/cyclization reaction to stereoselectively form the requisite pentacyclic ring system in one step.

Trends in antimicrobial susceptibility of Streptococcus pneumoniae in the Tohoku district of Japan: a longitudinal analysis from 1998 to 2007.

Streptococcus pneumoniae is a common cause of respiratory tract infections (RTIs). The prevalence of Streptococcus pneumoniae strains with reduced susceptibility to antimicrobial agents has dramatically increased worldwide. Susceptibility to nine antimicrobial agents and serotypes were determined among 1,644 Streptococcus pneumoniae strains isolated from patients with RTIs in the Tohoku district of Japan from October to December every year from 1998 to 2007.

Total synthesis of the bicyclic depsipeptide HDAC inhibitors spiruchostatins A and B, 5''-epi-spiruchostatin B, FK228 (FR901228) and preliminary evaluation of their biological activity.

The bicyclic depsipeptide histone deacetylase (HDAC) inhibitors spiruchostatins A and B, 5''-epi-spiruchostatin B and FK228 were efficiently synthesized in a convergent and unified manner. The synthetic method involved the following crucial steps: i) a Julia-Kocienski olefination of a 1,3-propanediol-derived sulfone and a L- or D-malic acid-derived aldehyde to access the most synthetically challenging unit, (3S or 3R,4E)-3-hydroxy-7-mercaptohept-4-enoic acid, present in a D-alanine- or D-valine-containing segment; ii) a condensation of a D-valine-D-cysteine- or D-allo-isoleucine-D-cysteine-containing segment with a D-alanine- or D-valine-containing segment to directly assemble the corresponding seco-acids; and iii) a macrocyclization of a seco-acid using the Shiina method or the Mitsunobu method to construct the requisite 15- or 16-membered macrolactone. The present synthesis has established the C5'' stereochemistry of spiruchostatin B.

Ir-catalyzed oxidative desymmetrization of meso-diols.

The catalytic oxidative desymmetrization of meso-diols was realized using a chiral iridium catalyst. In particular, the reaction is effective for the cyclic diols to give the corresponding hydroxy ketones in high chemical yields with high ee's. With this reaction as a key step, a short-step synthesis of common intermediate of ottelione and scyphostatin was achieved.

Enantioselective total synthesis of (-)-candelalides A, B and C: potential Kv1.3 blocking immunosuppressive agents.

Novel Kv1.3 blocking immunosuppressants, (-)-candelalides A, B and C, were efficiently synthesized for the first time in a convergent and unified manner starting from (+)-5-methyl-Wieland-Miescher ketone. The synthetic method involved the following key steps: i) a strategic [2,3]-Wittig rearrangement of a stannylmethyl ether to install the stereogenic center at C9 and the exo-methylene function at C8 present in the decalin portion; ii) a straightforward coupling of a trans-decalin portion (BC ring) and a gamma-pyrone moiety through the C16-C3' bond to assemble the requisite carbon framework; and iii) a construction of a characteristic di or tetrahydropyran ring (A ring) by internal nucleophilic ring closure of a hydroxy aldehyde or a hydroxy epoxide.

Total synthesis of spiruchostatin B, a potent histone deacetylase inhibitor, from a microorganism.

The first total synthesis of spiruchostatin B, a potent histone deacetylase inhibitor, was achieved in a convergent manner; the synthesis established stereochemistry at the C5'' position.

Highly efficient total synthesis of the marine natural products (+)-avarone, (+)-avarol, (-)-neoavarone, (-)-neoavarol and (+)-aureol.

Biologically important and structurally unique marine natural products avarone (1), avarol (2), neoavarone (3), neoavarol (4) and aureol (5), were efficiently synthesized in a unified manner starting from (+)-5-methyl-Wieland-Miescher ketone 10. The synthesis involved the following crucial steps: i) Sequential BF(3)Et(2)O-induced rearrangement/cyclization reaction of 2 and 4 to produce 5 with complete stereoselectivity in high yield (2 --> 5 and 4 --> 5); ii) strategic salcomine oxidation of the phenolic compounds 6 and 8 to derive the corresponding quinones 1 and 3 (6 --> 1 and 8 --> 3); and iii) Birch reductive alkylation of 10 with bromide 11 to construct the requisite carbon framework 12 (10 + 11 --> 12). An in vitro cytotoxicity assay of compounds 1-5 against human histiocytic lymphoma cells U937 determined the order of cytotoxic potency (3 > 1 > 5 > 2 > 4) and some novel aspects of structure-activity relationships.