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Ascertaining the absorption, distribution, metabolism, and excretion (ADME) profile of drugs is one of the most crucial factors in the process of drug discovery. Since it is important to combine water solubility and cell permeability within the compound to achieve the desired ADME properties, an appropriate balance between lipophilicity and hydrophilicity is required. It is often necessary to facilitate hydrophilicity of very hydrophobic candidates, because quite lipophobic molecules are rarely hit as positive in molecular-targeted or cell-based screenings. For that purpose, it has been popular to conjugate hydrophobic molecules with polyethylene glycol (PEG). However, PEG is a polymer, and PEG-conjugated molecules are not uniform. Besides, the dosage should be much increased compared with the original molecule due to the increase in molecular weight. Therefore we have been developing alternative ways to endow hydrophobic compounds with extra hydrophilicity by conjugating with symmetrically branched glycerol oligomers. This technology is versatile and easily applicable to various hydrophobic compounds. Water-solubility of fenofibrate, one of the most hydrophobic medicines in clinical use, was facilitated by a factor of more than 2000, and its lipid-lowering effect in vivo improved more than ten-fold, by simply conjugating with branched glycerol trimer, for instance. Here we will briefly introduce the basic concepts and our successful experiences of applying branched glycerol oligomers including antitumor agents in terms of water-solubility, pharmacological effects, and pharmacokinetics, and merits and current issues will be discussed in this review.

Symmetrically branched glyceryl oligomers possessing thiol at the apex were synthesized. After treatment of the surface of a silver-plated metal piece, its water contact angle was significantly dec...

8-Prenylnaringenin (8-PN) is a prenylflavonoid that originates from hop extracts and is thought to help prevent disuse muscle atrophy. We hypothesized that 8-PN affects muscle plasticity by promoting muscle recovery under disuse muscle atrophy. To test the promoting effect of 8-PN on muscle recovery, we administered an 8-PN mixed diet to mice that had been immobilized with a cast to one leg for 14 days. Intake of the 8-PN mixed diet accelerated recovery from muscle atrophy, and prevented reductions in Akt phosphorylation. Studies on cell cultures of mouse myotubes in vitro demonstrated that 8-PN activated the PI3K/Akt/P70S6K1 pathway at physiological concentrations. A cell-culture study using an inhibitor of estrogen receptors and an in vivo experiment with ovariectomized mice suggested that the estrogenic activity of 8-PN contributed to recovery from disuse muscle atrophy through activation of an Akt phosphorylation pathway. These data strongly suggest that 8-PN is a naturally occurring compound that could be used as a nutritional supplement to aid recovery from disuse muscle atrophy.

Histamine H1 receptor (H1R) gene is upregulated in patients with allergic rhinitis (AR), and its expression level is strongly correlated with the severity of allergic symptoms. We previously reported isolation of the putative anti-allergic compound, 4-methoxybenzofuran-5-carboxamide (MBCA) from Tephrosia purpurea and its chemical synthesis (Shill et al., Bioorg Med Chem 2015;23:6869-6874). However, the mechanism underlying its anti-allergic activity remains to be elucidated. Here, we report the mechanism of MBCA on phorbol 12-myristate-13-acetate (PMA)- or histamine-induced upregulation of H1R gene expression in HeLa cells, and in vivo effects of MBCA were also determined in toluene-2,4-diisocyanate (TDI)-sensitized rats. MBCA suppressed PMA- and histamine-induced upregulation of H1R expression at both mRNA and protein levels and inhibited PMA-induced phosphorylation of PKCδ at Tyr(311) and subsequent translocation to the Golgi. Furthermore, MBCA ameliorated allergic symptoms and suppressed the elevation of H1R and helper T cell type 2 (Th2) cytokine mRNAs in TDI-sensitized rats. Data suggest that MBCA alleviates nasal symptoms in TDI-sensitized rats through the inhibition of H1R and Th2 cytokine gene expression. The mechanism of its H1R gene suppression underlies the inhibition of PKCδ activation.

The histamine H1 receptor (H1R) gene is an allergic disease sensitive gene, and its expression level is strongly correlated with the severity of allergic symptoms. (-)-Maackiain was identified as a Kujin-derived anti-allergic compound that suppresses the up-regulation of the H1R gene. However, the underlying mechanism of H1R gene suppression remains unknown. Here, we sought to identify a target protein of (-)-maackiain and investigate its mechanism of action. A fluorescence quenching assay and immunoblot analysis identified heat shock protein 90 (Hsp90) as a target protein of (-)-maackiain. A pull-down assay revealed that (-)-maackiain disrupted the interaction of Hsp90 with PKCδ, resulting in the suppression of phorbol 12-myristate 13-acetate (PMA)-induced up-regulation of H1R gene expression in HeLa cells. Additional Hsp90 inhibitors, including 17-(allylamino)-17-demethoxygeldanamycin, celastrol, and novobiocin also suppressed PMA-induced H1R gene up-regulation. 17-(Allylamino)-17-demethoxygeldanamycin inhibited PKCδ translocation to the Golgi and phosphorylation of Tyr(311) on PKCδ. These data suggest that (-)-maackiain is a novel Hsp90 pathway inhibitor. The underlying mechanism of the suppression of PMA-induced up-regulation of H1R gene expression by (-)-maackiain and Hsp90 inhibitors is the inhibition of PKCδ activation through the disruption of Hsp90-PKCδ interaction. Involvement of Hsp90 in H1R gene up-regulation suggests that suppression of the Hsp90 pathway could be a novel therapeutic strategy for allergic rhinitis.

An environmentally friendly coating method of lipophilic thiols on metal surface is described. Lipophilic thiols were chemically modified to a water-soluble derivative, prepared from lipophilic thiol, succinic linker, and symmetrically branched oligoglycerol. Due to the chemical modification, water was used as a solute of coating reagent. The anticorrosive effect of metal piece with the water-soluble derivative in water was as high as with lipophilic thiol in organic solvent.

A DGpYMP peptide mimetic of tyrosine(608)-phosphorylated insulin receptor substrate-1 (IRS-1), named Cblin, was previously shown to significantly inhibit Cbl-b-mediated IRS-1 ubiquitination. In the present study, we developed N-myristoylated Cblin and investigated whether it was effective in preventing glucocorticoid-induced muscle atrophy. Using HEK293 cells overexpressing Cbl-b, IRS-1 and ubiquitin, we showed that the 50% inhibitory concentrations of Cbl-b-mediated IRS-1 ubiquitination by N-myristoylated Cblin and Cblin were 30 and 120 μM, respectively. Regarding the DEX-induced atrophy of C2C12 myotubes, N-myristoylated Cblin was more effective than Cblin for inhibiting the DEX-induced decreases in C2C12 myotube diameter and IRS-1 degradation. The inhibitory efficacy of N-myristoylated Cblin on IRS-1 ubiquitination in C2C12 myotubes was approximately fourfold larger than that of Cblin. Furthermore, N-myristoylation increased the incorporation of Cblin into HEK293 cells approximately 10-folds. Finally, we demonstrated that N-myristoylated Cblin prevented the wet weight loss, IRS-1 degradation, and MAFbx/atrogin-1 and MuRF-1 expression in gastrocnemius muscle of DEX-treated mice approximately fourfold more effectively than Cblin. Taken together, these results suggest that N-myristoylated Cblin prevents DEX-induced skeletal muscle atrophy in vitro and in vivo, and that N-myristoylated Cblin more effectively prevents muscle atrophy than unmodified Cblin.

The upregulation mechanism of histamine H

The first synthesis of uralenol, 5′-prenylated quercetin, is described. The key step is a palladium-catalyzed O-1,1-dimethylallylation reaction, with concurrent acetyl migration to afford the desired intermediate as a major isomer, which was purified by recrystallization. Finally, Claisen rearrangement, followed by deprotection of all phenolic protecting groups, afforded uralenol in excellent yield.

Prenyl flavonoids are widely distributed in plant foods and have attracted appreciable attention in relation to their potential benefits for human health. Prenylation may enhance the biological functions of flavonoids by introducing hydrophobic properties in their basic structures. Previously, we found that 8-prenyl naringenin exerted a greater preventive effect on muscle atrophy than nonprenylated naringenin in a mouse model. Here, we aimed to estimate the effect of prenylation on the bioavailability of dietary quercetin (Q). The cellular uptake of 8-prenyl quercetin (PQ) and Q in Caco-2 cells and C2C12 myotube cells was examined. Prenylation significantly enhanced the cellular uptake by increasing the lipophilicity in both cell types. In Caco-2 cells, efflux of PQ to the basolateral side was

Highly regio- and stereoselective carbon–carbon bond formation reaction of vinylaziridines using a masked acyl cyanide reagent possessing a tert-butyldimethylsilyl group occurred in the presence of a catalytic amount of palladium complex in excellent yield. It is considered that these excellent selectivities are the result of three simultaneous conditions, strained leaving group, small nucleophile, and ligand with small cone-angle.

The upregulation mechanism of histamine H1 receptor through the activation of protein kinase C-δ (PKCδ) and the receptor gene expression was discovered. Levels of histamine H1 receptor mRNA and IL-4 mRNA in nasal mucosa were elevated by the provocation of nasal hypersensitivity model rats. Pretreatment with antihistamines suppressed the elevation of mRNA levels. Scores of nasal symptoms were correlatively alleviated to the suppression level of mRNAs above. A correlation between scores of nasal symptoms and levels of histamine H1 receptor mRNA in the nasal mucosa was observed in patients with pollinosis. Both scores of nasal symptoms and the level of histamine H1 receptor mRNA were improved by prophylactic treatment of antihistamines. Similar to the antihistamines, pretreatment with antiallergic natural medicines showed alleviation of nasal symptoms with correlative suppression of gene expression in nasal hypersensitivity model rats through the suppression of PKCδ. Similar effects of antihistamines and antiallergic natural medicines support that histamine H1 receptor-mediated activation of histamine H1 receptor gene expression is an important signaling pathway for the symptoms of allergic diseases. Antihistamines with inverse agonist activity showed the suppression of constitutive histamine H1 receptor gene expression, suggesting the advantage of therapeutic effect.

Quercetin, a typical dietary flavonoid, is thought to exert antidepressant effects by inhibiting the monoamine oxidase-A (MAO-A) reaction, which is responsible for regulation of the metabolism of the neurotransmitter 5-hydroxytryptamine (5-HT) in the brain. This study compared the MAO-A inhibitory activity of quercetin with those of O-methylated quercetin (isorhamnetin, tamarixetin), luteolin, and green tea catechins ((-)-epicatechin, (-)-epicatechin gallate, (-)-epigallocatechin, and (-)-epigallocatechin gallate) by measuring the formation of the oxidative deamination product of 5-HT, 5-hydroxyindole aldehyde (5-HIAL), in mouse brain mitochondria. Quercetin was inferior to luteolin in the inhibition of MAO-A activity, whereas isorhamnetin, tamarixetin, and tea catechins scarcely exerted inhibitory activity. Quercetin did not affect MAO-A activity in mouse intestinal mitochondria, indicating that it does not evoke side effects on the metabolism of dietary monoamines in the gut. These data suggest that quercetin is a weak (but safe) MAO-A inhibitor in the modulation of 5-HT levels in the brain.

Acid-catalyzed equilibrium of a mixture of 1,2- and 1,3-methyleneglycerol in 1,4-dioxane affords predominantly the 1,3-isomer via bridged acetal exchange. The minor 1,2-isomer is removed via sequential pivaloylation and tritylation to afford the desired 1,3-isomer in >99.5% purity. A symmetrically branched triglycerol is efficiently synthesized starting from the purified 1,3-isomer.

Liposomes are recognized as potentially useful drug carriers but many problems preclude practical medical application. Liposomes bind with serum proteins (opsonization) and are captured by the reticuloendothelial system cells in the liver and spleen, which limits their ability to deliver drugs to other target sites. Modification of lipids with flexible, hydrophilic polymers such as poly(ethylene glycol) (PEG) to yield sterically stabilized liposomes is one approach to improve liposome blood circulation and tissue distribution properties. In this study, we examined liposomes prepared using lipids modified with a new branched oligoglycerol (BGL) moiety for steric stabilization. This novel BGL comprised 14 glycerol units (termed BGL014) connected with flexible ether linkages, resulting in a branched cascade-like structure that is highly expanded in aqueous solution. BGL014 was coupled to 1,2-distearoylphosphatidylethanolamine to yield BGL014-modified lipids. Incorporation of BGL014 into liposomes (BGL014L) resulted in long blood circulation times, despite a much thinner fixed aqueous layer thickness compared to PEG formulations. BGL014 produced a liposome surface coating that appears to function through steric inhibition of non-specific protein binding without strong interference of specific protein-binding reactions. Liposome structure and functionality was maintained following BGL014-modification, as the incorporation ratio of drug remained high. These results suggest that the BGL014 modification of liposomes is a promising approach to produce stable and long circulating drug carriers capable of selective binding to specific proteins.

Synthesis of C8-prenylated flavonols and flavanones via the palladium-catalyzed 7-O-1,1-dimethylprop-2-enylation, followed by Claisen rearrangement is described. Two regioselectivities (carbon–carbon bond formation at either the tail or head of the prenyl group and carbon–carbon bond formation at either C8 or C6) were efficiently improved when acetic anhydride was used as a solvent instead of N,N-dimethylformamide.

Synthesis of a symmetrically branched diglycerol (BGL002, involving one iminodiacetic residue) as a G2 dendron, and the tetradecaglycerol (BGL014, involving one iminodiacetic residue) as a G4 dendron, is described. Several members of the BGL family of G2-G4 dendrons were assembled, with G2 bearing four hydroxyl groups at the terminus region, G3 bearing eight, and G4 bearing sixteen. It is noteworthy that triglycerol (BGL003, including no iminodiacetic residue), has a water-solubility ten times higher than BGL002, and the liposome surrounded by BGL014 has a duration period in blood vessel roughly two times longer than the liposome surrounded by dodecaglycerol (BGL012, including three iminodiacetic residues).

A highly selective mono-C-allylation of pentaethyl diethylenetriaminepentaacetate was achieved with allyl bromide and potassium carbonate via a newly developed elaborate procedure based on Stevens rearrangement. It is contrastive that the conservative one-pot procedure gave a complicated mixture.

We examined the effect on drug delivery of liposomes with surfaces that were modified with branched oligoglycerols (BGLs) and explored possible formulation advantages to increase drug exposure. BGL012 is a branched oligoglycerol derivative with a cascade-like structure of 12 glycerol units, characterized as a widely spread structure in aqueous solution. We prepared BGL-phospholipid derivatives (BGL-PEs), including BGL012, by coupling 1,2-distearoylphosphatidylethanolamine to BGLs. BGL012-PE modification of the liposomes (BGL012L) achieved a long circulation time after intravenous injection in rats. The circulation lifetime of BGL012L was almost the same as that of polyethylene glycol (PEG)-modified liposomes. The surface of BGL012L induced the formation of a fixed aqueous layer and reduced protein adsorption on the liposome surface, without strong interference with the binding reaction on the liposome. Thus, the newly synthesized branched oligoglycerol derivatives are considered to have useful hydrophilic and physical properties for modifying the liposome surface to increase drug exposure.

α-Acetoxy esters or amides were synthesized directly and in one portion from aldehydes and alcohols or amines by one-carbon homologation using a masked acyl cyanide reagent bearing an acetyl group.

Synthesis of α-siloxy esters via a one-pot reaction from various aldehydes and alcohols using a masked acyl cyanide (MAC) reagent bearing tert-butyldimethylsilyl group is described.

A one-pot method for synthesizing alpha-siloxy-Weinreb amides from aldehydes was developed with use of N,O-dimethylhydroxylamine and a masked acyl cyanide reagent bearing a tert-butyldimethylsilyl group avoiding the competitive reaction toward N-methoxy-N-methyl-2-amino-1-siloxymalononitrile.

( R)-6-Heptyltetrahydropyran-2-one and its S-enantiomer were synthesized via chiral resolution of (±)-1-undecen-4-ol by ( R)-3a-allyl-3,3a,4,5-tetrahydro-2 H-cyclopenta[ B]furan (CPF). The R-enantiomer has sophisticated strong, fruity flavor, while the -flavor of the S-enantiomer is soft and sweet, similar to apricot.

A large series of branched oligoglycerols, BGL07 -(heptamer) with cyclic protecting groups, was synthesized.

Water solubility and partition-coefficient measurements have been conducted on already known monobenzoylated octamethylenediamine-containing branched oligoglycerols. A new oligoglycerol, a hexamer bearing eight primary hydroxy groups, has also been prepared and its properties examined. Water solubility was found to increase in an approximately geometric progression with the number of hydroxy groups and the water solubility of the hexamer derivative was atleast half a million times greater than that of the propanamide derivative. (© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2007)

Addition reactions of dicyanomethyl tert -butyldimethylsilyl ether (H–MAC–TBS) to optically active tert -butanesulfinimides afforded α-amino acid precursors in excellent yields and with high diastereoselectivities.

An impact test equipment was developed. This equipment is able to produce comparatively low load rate of impact. The impact strength of the acrylic adhesive under low temperature was measured using the developed impact test equipment. By using aluminum alloy as adherend, the equipment can measure the impact strength of acrylic adhesive. The tensile strength of the adhesive under various load rate and low temperature were measured. Conventional equipments were also used for these tests. Relations between the load rate, the test temperature and the tensile strength of adhesive were investigated. As an experimental result, at any case of load rate the tensile strength of the acrylic adhesive increased once with temperature decrease. However, when the temperature decreased lower than a specific value, the strength of the adhesive decreased. The temperature that the strength of the adhesive becomes maximum rises with the increase of the load rate. The change of strength of the acrylic adhesive is influenced by the viscosity of the adhesive itself.

Cbl-b is a RING-type ubiquitin ligase. Previously, we showed that Cbl-b-mediated ubiquitination and proteosomal degradation of IRS-1 contribute to muscle atrophy caused by unloading stress. The phospho-pentapeptide DGpYMP (Cblin) mimics Tyr612-phosphorylated IRS-1 and inhibits the Cbl-b-mediated ubiquitination and degradation of IRS-1 in vitro and in vivo. In this study, we confirmed the direct interaction between Cblin and the TKB domain of Cbl-b using NMR. Moreover, we showed that the shortened tripeptide GpYM also binds to the TKB domain. To elucidate the inhibitory mechanism of Cblin, we solved the crystal structure of the TKB-Cblin complex at a resolution of 2.5 A. The pY in Cblin inserts into a positively charged pocket in the TKB domain via hydrogen-bond networks and hydrophobic interactions. Within this complex, the Cblin structure closely resembles the TKB-bound form of another substrate-derived phosphopeptide, Zap-70-derived phosphopeptide. These peptides lack the conserved intrapeptidyl hydrogen bond between pY and a conserved residue involved in TKB-domain binding. Instead of the conserved interaction, these peptides specifically interact with the TKB domain. Based on this binding mode of Cblin to the TKB domain, we can design drugs against unloading-mediated muscle atrophy.

A novel naturally occurring compound with a benzofuran skeleton was isolated from a plant, Tephrosia purpurea collected in Bangladesh. The chemical synthesis of this compound confirmed its structure, and preliminary biological results showed its suppressive activity towards histamine H1 gene expression. One isomer and four derivatives were also synthesized, and their suppression activity was investigated. Although only small quantities of this compound can be isolated from its natural source, a 10 g scale synthesis was demonstrated by the newly developed method.

An alternative method for the synthesis of cyclopenta[1,2-b]furan (CPF) derivatives, which show promise as chiral resolving agents, was developed. Various CPF derivatives, arylsubstituted at the 3a-position, can be synthesized via Suzuki-Miyaura Coupling reaction.

An impact test equipment was developed to measure the strength of adhesive resins subjected to impact loads at low temperatures. The stress wave propagating the adhesive layer and the adherend was analyzed by the one-dimensional elastic wave theory. It was confirmed that the average stress value in the adhesive layer could be evaluated by the stress value of the adherend. Therefore, the measurement method with this equipment is effective. The impact strength of an acrylic adhesive was evaluated using the developed test equipment. As a result of the impact test, the impact strength of the acrylic adhesive increased once with temperature decrease. However, when the temperature decreased lower than a specific value, the impact strength decreased. It was considered that this phenomenon occurs because the adhesive becomes brittle as the temperature decrease.

The reaction of 3a-benzhydryl-3,3a,4,5-tetrahydro-2H-cyclopenta[b]furan and various 2-alkanols in the presence of a catalytic amount of pyridinium 4-tolunesulfonate in dichloromethane gave 3a-benzhydryl-6a-(1-methyl-aloxy)-hexahydrocyclopenta[b]furan in more than 90% chemical yields. The resulting diastereomeric mixture is easily separable on silica gel chromatography because of the large ΔRf value (briefly 0.1). Absolute configuration of the 2-alkanols can be easily estimated by the chemical shifts of 1H and 13C NMR of methyne group of the benzhydryl moiety.

Polyamine–enediyne conjugates were synthesized and exhibited potent DNA damaging ability under physiological conditions. The extent of their activity was shown to depend upon the polyamine length that regulates the DNA binding affinity of the conjugates, and enhanced DNA damaging activities were observed under slightly acidic conditions.

Recent progress of the synthetic study by using Masked Acyl Cyanides (MAC reagents) is described. Various kinds of electrophiles like organohalides, aldehydes, ketons, α, β-unsaturated carbonyl compounds, 1, 3-diene monoxides, allylic carbonates and so on can be transformed to amides or esters with one-carbon homologation. Several syntheses of optically active compounds were demonstrated. Racemization of the α-position of the resulting amides and esters was effectively inhibited by the nature of MAC reagents since the resulting carbonyl group is masked as an oxymalononitrile form during the transformation steps. Highly effective one-portion reaction for the connection of three components (aldehydes or ketones, MAC reagent having silyl group, amines or alcohols) was newly developed. A new short-step preparation of MAC reagents is also introduced.

The synthesis and Myers–Saito type cycloaromatization reactions of 10-membered enediynes containing a sulfone or a sulfoxide moiety are described. These enediynes cycloaromatized smoothly under physiological conditions to generate bioactive α,3-didehydrotoluene biradicals, that showed potent DNA damaging abilities. Further, in the presence of a nucleophile such as amine or sulfide, cycloaromatization did not occur following the radical reaction pathway but ionically induced cycloaromatization took place.

The chaperone αB-crystallin (αBC) is a member of the small heat shock protein family and its point or truncated mutants cause the muscular disorder α-crystallinopathy. The illness is histologically characterized by accumulation of protein aggregates in muscle cells. Expression of the myopathy-causing R120G mutant of αBC, harboring an arginine-to-glycine mutation at position 120, results in aggregate formation. We demonstrated that tethering αBC to the endoplasmic reticulum (ER) membrane represses the protein aggregation mediated by the R120G mutant. ER-anchored αBC decreased the amount of the R120G mutant through autophagic proteolysis. In contrast, knockdown of ATG5, an E3 ligase essential for autophagy, in ER-anchored αBC-transfected cells restored the quantity of the R120G mutant. In this context, aggregate formation was still suppressed, indicating that ER-anchored αBC profoundly constrains aggregation competency of the R120G mutant separately from downregulating the abundance of the mutant. We have proposed that protein aggregation is prevented by manipulation of the ER microenvironment with αBC, and have shed light on a novel aspect of the ER as a therapeutic target.

Development of enediyne model compounds that produce dehydrotoluene diradicals under acidic media is described. The ionic character of the diradicals is shown to be avoided by the electron-withdrawing groups in the molecules both in benzene and MeOH.

Stereoselective synthesis of l- and d-phenylglycine derivatives was accomplished by the reaction of Ss-(+)-N-(benzylidene)-p-toluenesulfinamide with 2-(tert-butyldimethylsiloxy)malononitrile (H-MAC-TBS) in the presence of Lewis acids and tert-amines.

A method for the preparation of α-azido-masked acyl cyanides as synthetic equivalents of N-protected–C-activated α-amino acids was developed using carbon–carbon bond formation between aldehydes and the Masked Acyl Cyanide Reagents, followed by sulfonylation and substitution by azide anion. This method was applied to the synthesis of d -threonine and l -allo-threonine derivatives.

Stable α-alkynylacetic acid derivatives related to cis-enediyne were synthesized and the rate of decarboxylative cycloaromatization of 3,5-difluoro derivative 7c was found to be much faster than that of the corresponding phenyl derivative 7a. The cycloaromatization reaction mechanisms of 7c under various conditions were investigated.

The evaluation of the Gd-carborane complex 2 as an MR imaging and boron carrier agent was carried out in vivo using tumor-bearing Donryu rats, MRI, ICP-AES, and alpha-autoradiography. The MR imaging revealed that the carborane Gd-DTPA 2 was metabolized slower in the body than Gd-DTPA 1. The results of the ICP-AES method indicated that compound 2 was incorporated into normal tissues and metabolized quickly, whereas it was not accumulated into tumor or brain tissue. The alpha-autoradiography showed that a high level of boron was obtained in the internal organs and in the necrosis of tumor tissue.

A highly stereoselective synthesis of an alkenylated malonic diamide starting from a γ,δ-epoxy-α,β-unsaturated carboxamide was accomplished using the masked acyl cyanide (MAC: the protected hydroxymalonitrile) via palladium-catalyzed regio- and stereoselective carboncarbon bond formation.

The beta-cholestane derivatives 1a-c bearing a cascade-type polyol, were newly synthesized. The release of fluorescent marker 6-CF [5(6)-carboxyfluorescein] encapsulated in the modified liposomes prepared from 1 was dramatically faster than that in the conventional liposomes prepared from cholesterol.