First synthesis and anticancer activity of phosmidosine and its related compounds

This paper describes the first synthesis of phosmidosine and phosmidosine B, i.e., nucleotide antibiotics composed of 8-oxoadenosine and L-proline which are connected via a unique N-acyl phosphoramidate linkage. Phosmidosine has a yet-undetermined chiral center at the phosphorus atom of the N-acyl phosphoramidate linkage. Phosmidosine B is a demethylated phosmidosine derivative with no chirality on the phosphorus. Phosmidosine B was successfully synthesized by the reaction of an N-acetyl-8-oxoadenosine 5'-O-phosphoramidite derivative with an N-protected prolinamide in the presence of 5-(3,5-dinitrophenyl)-1H-tetrazole. The successful synthesis of phosmidosine was achieved by use of a tert-butoxycarbonyl (Boc) group, which was found to be selectively introduced into the 7-NH function of 8-oxoadenosine and to serve as a pseudo-protecting group due to its steric effect in such manner that the unmasked 6-amino group was not phosphitylated. Final coupling reaction of the 8-oxoadenosine 5'-phosphoramidite derivative with N-tritylprolinamide followed by full deprotection gave a mixture of phosmidosine and its diastereoisomer. The (13)C NMR spectra of the diastereomers suggest that the slow-eluted diastereomer 1b is the naturally occurring phosmidosine. The growth inhibitory activity of phosmidosine 1b, its diastereomer 1a, and phosmidosine B in various tumor cell lines was evaluated by the MTT assay. As the result, phosmidosine B showed high anticancer activities and both the diastereomers 1a and 1b of phosmidosine isolated were found to have similar but approximately 10 times higher anticancer activities than phosmidosine B. Moreover, it turned out that these phosmidosine derivatives showed characteristic inhibitory activities against cancer cells independent of their p53 phenotypes. These results suggest that phosmidosine and its related compounds would be promising as a new type of anticancer agents having a wide range of inhibitory activities against tumor cells.     

Prostaglandins and their cyclodextrin complexes

Generally, prostaglandins (PG) are unstable and insoluble in water, though they exhibit strong biological activities in minute amount. The most difficult problem in developing PG preparations is how to stabilize and solubilize PG without loss of their activities. We have successfully developed the pharmaceutical preparations contaning PG complexes with cyclodextrins (CD). These preparations are already on the market, namely PGE₂ ·-CD Tablet and PGE₁ ·-CD Injection. Moreover, PG and PGI₂ derivatives are now under development as a form of CD complex.     

Preparation and characterization of new cycloplatinated carbene complexes

Reaction of iodotrimethylplatinum(IV) tetramer with bis(1,3-diphenyl-2-imidazolidinylidene) [(Hdpim)₂] gave a new dinuclear carbene complex, [{Pt(dpim)I}₂](dpim  1,3-diphenyl-2-imidazolidinylidenato-2-C,2′-C), III, in 84% yield, which contains a cycloplatinated carbene structure. Some mononuclear derivatives, [Pt(dpim)(acac)], [Pt(dpim)I{P(OCHMe₂)₃}], [Pt(dpim)-(NCCH₃)₂]ClO₄, and [Pt(dpim)(COD)]ClO₄ were prepared from III and characterized by means of elemental analysis, IR and NMR spectroscopy, and molar conductivity. An intermediate species, [{PtMeI(Hdpim)}₂], leading to III is discussed also.     

Suppression of the Rayleigh-Taylor instability due to self-radiation in a multiablation target

A scheme to suppress the Rayleigh-Taylor instability has been investigated for a direct-drive inertial fusion target. In a high-Z doped-plastic target, two ablation surfaces are formed separately-one driven by thermal radiation and the other driven by electron conduction. The growth of the Rayleigh-Taylor instability is significantly suppressed on the radiation-driven ablation surface inside the target due to the large ablation velocity and long density scale length. A significant reduction of the growth rate was observed in simulations and experiments using a brominated plastic target. A new direct-drive pellet was designed using this scheme.     

Development of a Chemical Methodology for the Preparation of Peptide Thioesters Applicable to Naturally Occurring Peptides Using a Sequential Quadruple Acyl Transfer System

Peptide thioesters are very useful in protein chemistry, and chemistry- and biochemistry-based protocols are used for the preparation of thioesters. Among such protocols, only a few biochemistry-based approaches have been use for naturally occurring peptide sequences. The development of chemistry-based protocols applicable to natural sequences remains a challenge, and the development of such methods would be a major contribution to protein science. Here, we describe the preparation of peptide thioesters using innovative methodology that features nickel(II)-mediated alcoholysis of a naturally occurring peptide sequence, followed by O−N and N−S acyl transfers. This protocol involves sequential quadruple acyl transfer, termed SQAT. Notably, the SQAT system consists of sequential chemical reactions that allow naturally occurring peptide sequences to be converted to thioesters without requiring an artificial chemical unit.     

Fluorescent pyrimidopyrimidoindole nucleosides: control of photophysical characterizations by substituent effects

10-(2-Deoxy-beta-D-ribofuranosyl)pyrimido[4',5':4,5]pyrimido[1,6-a]indole-6,9(7H)-dione (dCPPI) and its derivatives were synthesized via the Suzuki-Miyaura coupling reaction of 5-iododeoxycytidine with 5-substituted N-Boc-indole-2-borates and characterized by UV-vis and fluorescence spectroscopy. The new fluorescent nucleosides showed rather large Stokes shifts (116-139 nm) in an aqueous buffer. The fluorescent intensities were dependent on the nature of the substituents on the indole rings. The electron-withdrawing groups increased the fluorescent intensity while the electron-donating groups having lone pairs decreased it. Among the substituted dCPPI derivatives tested, the trimethylammonium derivative of dCPPI was found to emit the brightest fluorescent light. The solvatochromism of dCPPI and its derivatives was also studied. Some of the dCPPI derivatives showed interesting solvent-dependent fluorescence enhancement and could be useful as new fluorescent structural probes for nucleic acids. The Lippert-Mataga analyses of the Stokes shift were also carried out to obtain estimated values of the dipole moment of the excited states of some of the derivatives.     

Photoelectrode characteristics of an organic bilayer in water phase containing a redox molecule

We have recently reported that the organic bilayer of 3,4,9,10-perylenetetracarboxyl-bisbenzimidazole (PTCBI, n-type semiconductor) and 29H,31H-phthalocyanine (H₂Pc, p-type semiconductor), which is a part of a photovoltaic cell, acts as a photoanode in the water phase (Abe et al., ChemPhysChem 5:716, [2004]); in that case, the generation of the photocurrent involving an irreversible thiol oxidation at the H₂Pc/water interface took place to be coupled with hole conduction through the H₂Pc layer, based on the photophysical character of the bilayer. In the present work, the photoelectrode characteristics of the bilayer were investigated in the water phase containing a redox molecule , where the photo-induced oxidation and reduction for the couple were found to take place at the bilayer. The photoanodic current involving the oxidation efficiently occurred at the interface of H₂Pc/water, similar to the previous example. In the view of the voltammograms obtained, it was noted that there are pin-holes in the H₂Pc layer of the bilayer, leading to a cathodic reaction with at the PTCBI surface especially in the dark; that is, the band bending at the PTCBI/water interface can essentially be reduced by applying a negative potential [e.g., < ∼ 0 V (vs Ag/AgCl)] to the PTCBI, when the cathodic reaction may take place through the conduction band of the PTCBI. Moreover, under that applied potential condition of irradiation, the photogenerated electron carrier part can move to the PTCBI surface, thus enhancing the reduction of .     

Synthesis of a well-defined glycopolymer by atom transfer radical polymerization

Controlled free radical polymerization of sugar-carrying methacrylate, 3-O-methacryloyl-1,2 : 5,6-di-O-isopropylidene-d-glucofuranose (MAIpGlc) was achieved by the atom transfer radical polymerization (ATRP) technique with an alkyl halide/copper-complex system in veratrole at 80°C. The time–conversion first-order plot was linear and the number-average molecular weight increased in direct proportion to the ratio of the monomer conversion to the initial initiator concentration, providing PMAIpGlc with a low polydispersity. The sequential addition of the two monomers styrene (S) and MAIpGlc afforded a block copolymer of the type PS-b-PMAIpGlc. The acidolysis of the homo- and block copolymers gave well-defined glucose-carrying water-soluble polymers PMAGlc and PS-b-PMAGlc, respectively. The amphiphilic PS-b-PMAGlc block copolymer exhibited a microdomain surface morphology with spherical PS domains in a PMAGlc matrix. © 1998 John Wiley & Sons, Inc. J. Polym. Sci. A Polym. Chem. 36: 2473–2481, 1998