Effect of phenolic-hydroxy-group incorporation on the biological activity of a simplified aplysiatoxin analog with an (R)-(-)-carvone-based core.

We synthesized a phenolic hydroxy group-bearing version (1) of a simplified analog of aplysiatoxin comprising a carvone-based conformation-controlling unit. Thereafter, we evaluated its antiproliferative activity against human cancer cell lines and its binding affinity to protein kinase C (PKC) isozymes. The antiproliferative activity and PKC-binding ability increased with the introduction of the phenolic hydroxy group. The results of molecular dynamics simulations and subsequent relative binding free-energy calculations conducted using an alchemical transformation procedure showed that the phenolic hydroxy group in 1 could form a hydrogen bond with a phospholipid and the PKC. The former hydrogen bonding formation facilitated the partitioning of the compound from water to the phospholipid membrane and the latter compensated for the loss of hydrogen bond with the phospholipid upon binding to the PKC. This information may facilitate the development of rational design methods for PKC ligands with additional hydrogen bonding groups.

Design, synthesis, and biological activity of a synthetically accessible analog of aplysiatoxin with an (R)-(-)-carvone-based conformation-controlling unit.

Simplified analogs of aplysiatoxin (ATX) such as 10-Me-aplog-1 exhibit potent antiproliferative activity toward human cancer cell lines by activating protein kinase C (PKC). However, the synthesis of 10-Me-aplog-1 involved a 23-step longest linear sequence (LLS). Therefore, we have been working toward the development of a more synthetically accessible analog of ATX. In this study, we designed a new analog of ATX wherein a cyclic ketal moiety derived from (R)-(-)-carvone replaced the spiroketal moiety in 18-deoxy-aplog-1. The new analog's synthesis proceeded in an 8-step LLS. Although the configuration at position 3 of the cyclic ketal in the (R)-(-)-carvone-based analog was opposite to those of ATX and 18-deoxy-aplog-1, the antiproliferative activity toward human cancer cell lines of the carvone-based analog was comparable with that of 18-deoxy-aplog-1. The obtained results indicate the potential of the carvone-based analog as a basis for discovering PKC-targeting molecules requiring a decreased number of synthetic steps.

Nematocidal activity of 6-O-octanoyl- and 6-O-octyl-d-allose against larvae of Caenorhabditis elegans.

The nematocidal activities of the fatty acid esters of d-allose were examined using the larvae of C. elegans. Among the fatty acid esters, 6-O-octanoyl-d-allose (3) showed significant activity. 6-O-octanoyl-d-glucose (5) showed no activity, indicating that the D-allose moiety is essential for the nematocidal activity of 3. A nonhydrolyzable alkoxy analog 6-O-octyl-d-allose (6) also showed activity equivalent to that of 3.

Synthesis and inhibitory activity of deoxy-d-allose amide derivative against plant growth.

1,2,6-Trideoxy-6-amido-d-allose derivative was synthesized and found to exhibit higher growth-inhibitory activity against plants than the corresponding deoxy-d-allose ester, which indicates that an amide group at C-6 of the deoxy-d-allose amide enhances inhibitory activity. In addition, the mode of action of the deoxy-d-allose amide was significantly different from that of d-allose which inhibits gibberellin signaling. Co-addition of gibberellin GA3 restored the growth of rice seedlings inhibited by the deoxy-d-allose amide, suggesting that it might inhibit biosynthesis of gibberellins in plants to induce growth inhibition.

Practical Enantioselective Reduction of Ketones Using Oxazaborolidine Catalysts Generated In Situ from Chiral Lactam Alcohols.

Oxazaborolidine catalyst (CBS catalyst) has been extensively used for catalytic borane reduction with a predictable absolute stereochemistry and high enantioselectivity. However, the use of isolated CBS catalyst sometimes has the drawback of low reproducibility due to the aging of the CBS catalyst during storage. Therefore, we investigated a more reliable and practical method for the reduction of a variety of ketones including challenging substrates, primary aliphatic ketones, α,ß-enones, and trifluoromethyl ketones. This review surveys the developments in borane reduction using oxazaborolidine catalysts generated in situ from chiral lactam alcohols and borane.

Binding mode prediction of aplysiatoxin, a potent agonist of protein kinase C, through molecular simulation and structure-activity study on simplified analogs of the receptor-recognition domain.

Aplysiatoxin (ATX) is a naturally occurring tumor promoter isolated from a sea hare and cyanobacteria. ATX binds to, and activates, protein kinase C (PKC) isozymes and shows anti-proliferative activity against human cancer cell lines. Recently, ATX has attracted attention as a lead compound for the development of novel anticancer drugs. In order to predict the binding mode between ATX and protein kinase Cδ (PKCδ) C1B domain, we carried out molecular docking simulation, atomistic molecular dynamics simulation in phospholipid membrane environment, and structure-activity study on a simple acyclic analog of ATX. These studies provided the binding model where the carbonyl group at position 27, the hydroxyl group at position 30, and the phenolic hydroxyl group at position 20 of ATX were involved in intermolecular hydrogen bonding with the PKCδ C1B domain, which would be useful for the rational design of ATX derivatives as anticancer lead compounds.

Syntheses and biological activities of deoxy-d-allose fatty acid ester analogs.

We describe the syntheses of three different deoxy-D-allose analogs [2-deoxy-d-allose (2-DOAll), 1,2-dideoxy-d-allose (1,2-DOAll), and 1,2-didehydro-1,2-dideoxy-d-allose (1,2-DHAll)] and their fatty acid esters via regioselective lipase-catalyzed transesterification. Among them, 2-DOAll and its decanoate (2-DOAll-C10) showed higher inhibitory activity on plant growth, which is similar to d-allose (All) [corrected] and its decanoate (All-C10). Bioassay results of deoxy-All-C10 on four plant species suggest that the hydroxy group at the C-1 position might be important showing growth inhibitory activity. In addition, co-addition of gibberellin (GA3) with 1,2-DHAll-C10 and 2-DOAll-C10 recovered plant growth, suggesting that they might mainly inhibit biosynthesis of gibberellin.

Anti-proliferative activity of 6-O-acyl-D-allose against the human leukemia MOLT-4F cell line.

The anti-proliferative activities of the 6-O-acyl derivatives of D-allose against the human leukemia MOLT-4F cell line were examined. The activity of the 6-O-dodecanoyl derivative (3) was approximately 30 times stronger than that of D-allose. An evaluation of the derivatives of 3 that occurred in a furanose form revealed the pyranose forms of 3 to be important for the anti-proliferative activity.

Retarding activity of 6-O-acyl-D-alloses against plant growth.

The retarding activity of 6-O-dodecanoyl-D-allose against rice growth was higher than that of the octanoate and the decanoate. The activities of 6-O-dodecanoyl-D-glucose, -D-mannose, and -D-galactose against rice seedlings were examined. 6-O-Dodecanoyl-D-allose exhibited the highest activity, suggesting the importance of the alpha-axial hydroxy group at C-3 of D-allose.

Development of a d-allose-6-phosphate derivative with anti-proliferative activity against a human leukemia MOLT-4F cell line.

d-Allose, a C-3 epimer of d-glucose, is a naturally occurring rare monosaccharide that shows anti-proliferative activity against several human cancer cell lines. However, d-allose requires a relatively high concentration for the activity to be observed. Thus, developing more potent derivatives is needed for application. In cells, d-allose is converted to d-allose-6-phosphate (A6P), which is responsible for the anti-proliferative activity of d-allose. In this study, we synthesized A6P derivative 1 with biodegradable protecting groups, which showed higher anti-proliferative activity than A6P against a MOLT-4F human leukemia cell line. Similarly protected derivative of d-glucose-6-phosphate (G6P) (2) and tetraacetyl-A6P (3) showed weaker and less activity compared with 1, respectively, suggesting that both A6P moiety and the protecting group on the phosphate group are responsible for the activity. In addition, significantly weaker induction of thioredoxin-interacting protein (TXNIP) expression by 1 compared with d-allose suggests that 1 exhibited cytotoxicity through the synergetic effect of inducing TXNIP expression and other mechanisms.

Evaluation of the Anti-Proliferative Activity of Rare Aldohexoses against MOLT-4F and DU-145 Human Cancer Cell Line and Structure-Activity Relationship of D-Idose.

D-Allose (D-All), a C-3 epimer of D-glucose (D-Glc), is a naturally rare monosaccharide, which shows anti-proliferative activity against several human cancer cell lines. Unlike conventional anticancer drugs, D-All targets glucose metabolism and is non-toxic to normal cells. Therefore, it has attracted attention as a unique "seed" compound for anticancer agents. However, the anti-proliferative activities of the other rare aldohexoses have not been examined yet. In this study, we evaluated the anti-proliferative activity of rare aldohexoses against human leukemia MOLT-4F and human prostate cancer DU-145 cell lines. We found that D-All and D-idose (D-Ido) at 5 mM inhibited cell proliferation of MOLT-4F cells by 46 % and 60 %, respectively. On the other hand, the rare aldohexoses at 5 mM did not show specific anti-proliferative activity against DU-145 cells. To explore the structure-activity relationship of D-Ido, we evaluated the anti-proliferative activity of D-sorbose (D-Sor), 6-deoxy-D-Ido, and L-xylose (L-Xyl) against MOLT-4F cells and found that D-Sor, 6-deoxy-D-Ido, and L-Xyl showed no inhibitory activity at 5 mM, suggesting that the aldose structure and the C-6 hydroxy group of D-Ido are important for its activity. Cellular glucose uptake assay and western blotting analysis of thioredoxin-interacting protein (TXNIP) expression suggested that the anti-proliferative activity of D-Ido is induced by inhibition of glucose uptake via TXNIP-independent pathway.

2-Geranyl-1,4-naphthoquinone, a possible intermediate of anthraquinones in a Sesamum indicum hairy root culture.

2-Geranyl-1,4-naphthoquinone was isolated from the hairy root culture of Sesamum indicum. The structure was determined to be 2-[(E)-3,7-dimethylocta-2,6-dienyl]-1,4-naphthoquinone on the basis of spectroscopic evidence and chemical synthesis. The production of anthrasesamones A, B and C by the hairy root culture was also confirmed for the first time.

Practical production of 6-O-octanoyl-D-allose and its biological activity on plant growth.

The transesterification of D-allose (the C-3 epimer of D-glucose) with vinyl octanoate using Candida antarctica lipase in tetrahydrofuran proceeded with high regioselectivity to produce 6-O-octanoyl-D-allose with nearly complete conversion. The growth-inhibiting activity of 6-O-octanoyl-D-allose on lettuce seedlings was about 6-fold greater than that of D-allose.

Synthesis of D-allose fatty acid esters via lipase-catalyzed regioselective transesterification.

The acylation of the rare sugar, D-allose (the C-3 epimer of D-glucose), with fatty acid vinyl esters was successfully carried out using Candida antarctica lipase in acetonitrile at 45 degrees C to give D-allose 6-alkanoates with high regioselectivity in good yields.

Production of dihydroxy C50-carotenoid by Aureobacterium sp. FERM P-18698.

The dihydroxy C(50)-carotenoid, decaprenoxanthin, was produced by Aureobacterium sp. collected from sea water. The addition of D-psicose to the culture medium improved the growth of cells and the yield of the carotenoid. The (13)C-NMR spectrum of decaprenoxanthin, which has not previously been reported, was successfully measured.