高橋 孝志

We have achieved a total synthesis of telomestatin, and its absolute configuration was determined to be (R). Coupling of cysteine-containing trisoxazole amine and serine-containing trisoxazole carboxylic acid, followed by macrocyclization, provided a 24-membered diamide. The seventh oxazole ring was formed by a Shin's procedure via dehydroamide. Cyclodehydration of a modified (R)-cysteine-(S-Bu-t) moiety using Kelly's method (PPh3(O)-Tf2O) with anisole furnished (R)-telomestatin, whose CD spectrum was in good agreement with that of the natural product.

A 24-member combinatorial library based on the structure of aeruginosin 298-A (1a) was synthesized utilizing solid-phase, and their inhibitory activity against trypsin was evaluated. Among the library, we found that D-Hpla-D-Leu-L-Choi-Agma (1h) is 300 times more potent than the parent natural product 1a.

Although the idea of homogeneous electrochemical immunoassay using antibody and an electroactive modified antigen as a probe looks to be very useful for high-throughput drug screening, there have been few reports. One reason for this is the difficulty experienced making an electroactive probe, because the introduction of electroactive compounds to antigens often interferes with the antigen-antibody interaction. To apply a homogeneous electrochemical assay to drug screening, we have designed new probes referring to the information of immobilization on beads which could identify the drug receptor. FK506 (also called Tacrolimus), immunosuppressive agent is modified with ferrocene derivatives as an electron mediator between glucose oxidase and an electrode. at a non-obstructing part. One of the probes still indicated the electrochemical activity as a mediator and had the specific binding capability for FKBP12 (FK506 binding protein). The current decrease in response to the additional FKBP 12, detected with constant voltage amperometry using the probe, was observed within 5 min. Then, free FK506 as a leader drug, rapamycin and cyclosporine A as unknown drugs were used as a model for drug screening. Since the order of response currents at the same concentration of each drug reflected their binding constants, it was shown that binding capacity of an unknown drug candidate could be estimated by comparison of response currents between the leader drug and the unknown drug candidate. Thus, this glucose oxidase assisted homogeneous electrochemical drug-receptor binding assay has been proved to be a useful tool for drug screening. (c) 2005 Elsevier B.V. All rights reserved.

[GRAPHICS] We have achieved a total synthesis of apratoxin A in which thiazoline formation was accomplished from the moCys containing amide 4 using PPh3(0)/Tf2O. Deprotection of the Troc and allyl ester in 17, coupling with tripeptide 3, and deprotection of the allyl ester and the Fmoc, followed by macrolactamization provided apratoxin A (1).

We achieved the total synthesis of the histone deacetylase inhibitor spiruchostatin A, as the prelude to the preparation of a combinatorial library of its analogues. Two key reactions were an asymmetric acetate aldol reaction using a Zr-enolate and macrolactonization Using the Shiina method. (c) 2005 Published by Elsevier Ltd.

A unique two-dimensional (2D) long-range structure has been observed in a low-temperature phase X-1 for a banana molecule having bromine atom substituted on the central core using synchrotron radiation (SR) x-ray scattering measurements. The X-1 phase is formed from the B-2 phase with the SmCAPA structure upon cooling and then shows multiple reflections around the first layer line, which are interpreted as a peculiar frustrated structure with long-range layer modulation order. Furthermore, the observation of a well-defined (100) reflection with a spacing of 171 angstrom means that there is the electron density modulation along the layers. By coupling these reflections, a 2D lattice with a=173 angstrom, c=53.4 angstrom, and beta=81.1 degrees is determined where the a axis is parallel to the original layer of the B-2 phase. This unique structure with modulation can be interpreted as an undulated layer structure and suggested to be the result from deformation with polarization splay defects periodically occurring along the layer. The angle, beta=81.1 degrees, between a and c axes indicates that the position of splay defects in one layer is staggered from that in the neighboring layer. In other words, the splay defect lines run in a direction tilted by roughly 80 degrees with respect to the a axis.

Methotrexate (MTX) is the anticancer and antirheumatoid drug that is believed to block nucleotide synthesis and cell cycle by inhibiting dihydrofolate reductase activity. We have developed novel affinity matrices, termed SG beads, that are easy to manipulate and are compatible with surface functionalization. Using the matrices, here we present evidence that deoxycytidine kinase (dCK), an enzyme that acts in the salvage pathway of nucleotide biosynthesis, is another target of MTX. MTX modulates dCK activity differentially depending on substrate concentrations. 1-β-D- Arabinofuranosylcytosine (ara-C), a chemotherapy agent often used in combination with MTX, is a nucleoside analog whose incorporation into chromosome requires prior phosphorylation by dCK. We show that, remarkably, MTX enhances incorporation and cytotoxicity of ara-C through regulation of dCK activity in Burkitt's lymphoma cells. Thus, this study provides new insight into the mechanisms underlying MTX actions and demonstrates the usefulness of the SG beads. Copyright © 2006 The American Society for Pharmacology and Experimental Therapeutics.

Three types of latex nanoparticles carrying naltrindole (NTI) derivatives were synthesized as probes for the affinity isolation of their binding proteins including the δ-opioid receptor. The effect of the attachment of NTI to different positions on the linker was investigated. Only latex nanoparticles in which the NTI derivative was linked through the phenol group were useful for isolating the recombinant δ-opioid receptor solubilized from CHO cell membrane. These latex nanoparticles could be a useful tool for investigations of the pharmacological activity of NTI. © 2005 Elsevier Ltd. All rights reserved.

A unique two-dimensional (2D) long-range structure has been observed in a low-temperature phase X1 for a banana molecule having bromine atom substituted on the central core using synchrotron radiation (SR) x-ray scattering measurements. The X1 phase is formed from the B2 phase with the Sm CA PA structure upon cooling and then shows multiple reflections around the first layer line, which are interpreted as a peculiar frustrated structure with long-range layer modulation order. Furthermore, the observation of a well-defined (100) reflection with a spacing of 171 means that there is the electron density modulation along the layers. By coupling these reflections, a 2D lattice with a=173 , c=53.4 , and β=81.1° is determined where the a axis is parallel to the original layer of the B2 phase. This unique structure with modulation can be interpreted as an undulated layer structure and suggested to be the result from deformation with polarization splay defects periodically occurring along the layer. The angle, β=81.1°, between a and c axes indicates that the position of splay defects in one layer is staggered from that in the neighboring layer. In other words, the splay defect lines run in a direction tilted by roughly 80° with respect to the a axis. © 2006 The American Physical Society.

Three types of latex nanoparticles carrying naltrindole (NTI) derivatives were synthesized as probes for the affinity isolation of their binding proteins including the delta-opioid receptor. The effect of the attachment of NTI to different positions on the linker was investigated. Only latex nanoparticles in which the NTI derivative was linked through the phenol group were useful for isolating the recombinant delta-opioid receptor solubilized from CHO cell membrane. These latex nanoparticles could be a useful tool for investigations of the pharmacological activity of NTI. (c) 2005 Elsevier Ltd. All rights reserved.

An effective approach for the synthesis of oligo-α(2,8) sialosides using N-Troc sialyl donors is described. Glycosylation of N-Troc sialoside with N-Troc sialyl N-phenyltrifluoroimidate and phosphites smoothly proceeded to provide α(2,8) disialosides in good yield and selectivity. © 2006 The Japan Institute of Heterocyclic Chemistry All rights reserved.

Synthesis of beauveriolide III (1b), which is an inhibitor of lipid droplet accumulation in macrophages, was achieved by solid-phase assembly of linear depsipeptide using a 2-chlorotrityl linker followed by solutionphase cyclization. On the basis of this strategy, a combinatorial library of beauveriolide analogues was carried out by radio frequency-encoded combinatorial chemistry. After automated purification using preparative reversed-phase HPLC, the library was tested for inhibitory activity of CE synthesis in macrophages to determine structure-activity relationships of beauveriolides. Among them, we found that diphenyl derivative 7{9,1} is 10 times more potent than 1b.

Two chiral bent-core mesogens Pn-O-PIMB(n - 2)* (n = 9 and 10) and their oxygen analogues Pn-O-PIMB(n - 2)*-(n - 4)0 (n = 8, 9, and 10) with omega-[(S)-amyloxy]alkoxy terminal groups were prepared, and their phase structures were investigated by means of electro-optic, polarization reversal current and second harmonic generation measurements in order to clarify the effect of the interlayer steric interaction on the emergence of polar orderings. The odd-even behavior for the alternative appearance of ferroelectricity and antiferroelectricity was observed in two homologous series; the bent-core mesogens P10-O-PIMB8*, P8-O-PIMB6*-4O, and P10-O-PIMB8*-6O in addition to the previously reported P6-O-PIMB4* and P8-O-PIMB6*, where the length of chains n is even, exhibited ferroelectric phases. On the contrary, the mesogens P7-O-PIMB5*, P9-O-PIMB7*, and P9-O-PIMB7*-5O, where n is odd, showed antiferroelectric phases. It is obvious that the interlayer steric interaction plays a major role for the emergence of a variety of phase structures.

An effective method for the synthesis of aryl hydrazines by amination of anilines using the solid-supported phenylsufonyl-hydroxylamine was described. Treatment of aniline with the solid-supported aminating agent, followed by removal of the resin, provided the corresponding hydrazine in 21% yield. The resulting hydrazines were directly adapted to the solid-phase synthesis of indoles, providing nine naltrindole derivatives varying the substituents on the aromatic rings.

We have developed a practical synthetic route to construct C-aromatic taxane derivatives as three-dimension templates by way of intramolecular alkylation. The usefulness of synthesized compounds as the core template was evaluated by using a newly developed screening system for P-glycoprotein. (c) 2005 Elsevier Ltd. All rights reserved.

We describe an efficient synthesis of H type 1 and 2 trisaccharides by one-pot glycosylation involving glycosidation of glycal epoxide. Copyright © 2005 The Chemical Society of Japan.

An efficient synthesis of a protected dimeric Lewis X epitope by two sequential one-pot glycosylations is described. Combinatorial synthesis of the dimeric Lewis X epitope derivatives by the one-pot glycosylation was accomplished utilizing an automated synthesizer to provide 12-protected oligosaccharides.

The stereoselective formation of the C ring was accomplished by nitrile oxide [3+2] cycloaddition of an intermediate with the A ring already constructed. We found that stereoelectronic effect to a 1,1-substituted alkene moiety is important in the reaction.

1,3-Dipolar cycloaddition of azomethine imines to the polymer-supported vinylsulfone was achieved. Pyrazole derivatives bearing various aryl groups were synthesized regioselectively.

New unsymmetrical banana-shaped molecular series having C different lengths of alkyl flexible chain on both side wings designated by "P-(n(1), n(2))-OPIMB", are studied comparing with the symmetric banana molecules in P-n-O-PIMB homologues.

The efficient and elegant synthesis of N-glycosides by N-glycosylation of asparagine-containing peptides is described. Glycosylation of primary amides with glycosyl N-phenyltrifluoroimidates in the presence of a catalytic amount of TMSOTf in nitromethane smoothly proceeded to provide the corresponding N-glycosyl amino acids in excellent yields. This coupling method was adaptable to the coupling of various glycosyl donors with amino acids and peptides. Copyright © 2005 American Chemical Society.

The Asp-Thr tethered Diels-Alder reaction of 1a was accomplished to provide 2a exclusively in a regio- and stereoselective manner.

The synthesis of two latex nano-particles coupled to FR901464 derivatives is described. Two FR901464 derivatives attached with an amino-alkyl group at a different position were prepared from natural occurring FR 901464. Biological activities of the two ligands were significantly different. The acylation of two amino ligands with the activated esters on latex particles smoothly proceeded to provide the corresponding latex nano-particles coupled to FR 901464 at a different position.

Novel derivative series of the well known bent-shaped P-n-O-PIMB liquid crystal mesogens, referred to as '4Br-P-n-O-PIMB', '4Cl-P-N-O-PIMB' and '5Cl-P-n-O-PIMB', having halogen atoms substituted on the phenyl ring in the central core, were synthesized by solution phase parallel synthesis based on a combinatorial approach. The mesomorphic behaviour and physical properties of all the new compounds were studied by means of optical microscopy, differential scanning calorimetry, X-ray and circular dichroism spectroscopy. We found interesting transitional behaviour for the 4Br-P-n-O-PIMB homologous series. The homologues with alkyl tails having carbon numbers of n=3-10, 12, 14 exhibit rather complicated mesomorphic behaviour, which is strongly sensitive to n. The chiral fluid smectic B2 phase with SmCAPA structure and unidentified smectic Bx phase were observed in the homologues with n = 9, 10, 12, 14 and n=3-5, respectively. Interestingly, every member exhibits frustrated and/or helical ordered phases at low temperatures, designated as X1, X2, and X3 phases, which result from a spontaneous escape from a macroscopic polarization. The mesomorphic behaviour and mesophase structures differ remarkably from those of the parent P-n-O-PIMB homologues, suggesting that substitution of the halogen atoms at the central core essentially creates a particular interaction between molecules.

Novel derivative series of the well known bent-shaped P-n-O-PIMB liquid crystal mesogens, referred to as '4Br-P-n-O-PIMB', '4Cl-P-n-O-PIMB' and '5Cl-P-n-O-PIMB', having halogen atoms substituted on the phenyl ring in the central core, were synthesized by solution phase parallel synthesis based on a combinatorial approach. The mesomorphic behaviour and physical properties of all the new compounds were studied by means of optical microscopy, differential scanning calorimetry, X-ray and circular dichroism spectroscopy. We found interesting transitional behaviour for the 4Br-P-n-O-PIMB homologous series. The homologues with alkyl tails having carbon numbers of n=3-10, 12, 14 exhibit rather complicated mesomorphic behaviour, which is strongly sensitive to n. The chiral fluid smectic B2 phase with SmCAPA structure and unidentified smectic Bx phase were observed in the homologues with n=9, 10, 12, 14 and n=3-5, respectively. Interestingly, every member exhibits frustrated and/or helical ordered phases at low temperatures, designated as X1, X2, and X3 phases, which result from a spontaneous escape from a macroscopic polarization. The mesomorphic behaviour and mesophase structures differ remarkably from those of the parent P-n-O-PIMB homologues, suggesting that substitution of the halogen atoms at the central core essentially creates a particular interaction between molecules.

Catch and release method utilizing polymer-support was investigated in the separation of 1alpha,25-(OH)(2) pre- and provitamin D-3. Polymer-supported alkyldiisopropylsityl triflate selectively captured the previtamin D-3 from a 26:74 mixture of pre- and provitamin D-3 produced by photoisomerization of provitamin D-3. (C) 2004 Elsevier Ltd. All rights reserved.

Various trialkylsilyl linked polymer supports have been prepared by reacting benzyl chloride resin and a di-Grignard reagent with CuBr.Me2S, followed by dialkylchlorosilanes. 4-Alkoxybenzyl type resin, Wang-Cl 2c and Argogel Wang-Cl 2d provided 4c and 4d at ambient temperature, whereas nonactivated resin, Merrifield 2a and Argogel-Cl 2b afforded 4a and 4b at 60degreesC. Primary and secondary alcohols 6-10 were attached to the alkyldiisopropyl-linked Wang type resin 4cA by a novel dehydrosilation with B(C6F5)(3) as well as by conventional methods. (C) 2004 Elsevier Ltd. All rights reserved.