Total Synthesis and Biological Evaluation of Siladenoserinol A and its Analogues

The total synthesis of siladenoserinol A, an inhibitor of the p53–Hdm2 interaction, has been achieved. AuCl₃‐catalyzed hydroalkoxylation of an alkynoate derivative smoothly and regioselectively proceeded to afford a bicycloketal in excellent yield. A glycerophosphocholine moiety was successfully introduced through the Horner–Wadsworth–Emmons reaction using an originally developed phosphonoacetate derivative. Finally, removal of the acid‐labile protecting groups, followed by regioselective sulfamate formation of the serinol moiety afforded the desired siladenoserinol A, and benzoyl and desulfamated analogues were also successfully synthesized. Biological evaluation showed that the sulfamate is essential for biological activity, and modification of the acyl group on the bicycloketal can improve the inhibitory activity against the p53–Hdm2 interaction.     

Ultrafast photoinduced intramolecular charge separation and recombination processes in the oligothiophene-substituted benzene dyads with an amide spacer

Photoinduced intramolecular charge separation (CS) and recombination (CR) processes of the tetrathiophene-substituted benzene dyads with an amide spacer (4T-PhR, R = 4-H (1), 4-CN (2), 3,4-(CN)2 (3), 4-NO2 (4), 3,5-(NO2)2 (5)) in solvents of different polarities were investigated using various fast spectroscopies. It was revealed that the CS rates depend on the ability of the acceptor and solvent polarity. Ultrafast CS with the rate of 5 x 10(12) s(-1) was revealed for 5 in PhCN and MeCN. The ultrafast CS can be attributed to the large electronic coupling matrix element between the donor and the acceptor despite the relative long donor-acceptor distance. The existence of the state with large electron density on the spacer between 14T*-PhR and LUMO should facilitate the CS process in the present dyad system. It was also revealed that the CR rates in these dyads were rather fast because of the enhanced superexchange interaction through the amide spacer.     

Synthesis of chiral nonracemic 1-(2-pyridinyl)ethylamines: stereospecific introduction of amino function onto the 2-pyridinylmethyl carbon center

Stereospecific substitutions of optically pure 1-(pyridinyl)ethyl methanesulfonates with various amines are described. The reaction of (R)- or (S)-1-(2-pyridinyl)ethyl methanesulfonate with primary amines, including amino acid esters, gives N-substituted (S)- or (R)-1-(2-pyridinyl)ethylamines (4) with inversion of the configuration. Secondary cyclic amines are also reacted with (R)-2 to give the corresponding substituted amines (5) in excellent yields. Optically pure and meso triamine ligands having two pyridine rings, (S,S)-4f and meso-4f, (S,S)-9e, (S,R)-9e, and (S,S)-9f, have been prepared in stereochemically pure form by this method. Not only the substitution reaction of optically active 2 but also that of 1-(4-pyridinyl)ethyl and 1-(3-pyridinyl)ethyl methanesulfonates 11 and 14 take place stereospecifcally with inversion of the chiral center.     

Stereocontrolled synthesis of steroid side chain; stereoselective syntheses of cholesterol and 25-hydroxycholesterol

Novel stereoselective method to introduce side chain onto 17-oxosteroids has been deviced, and using the method cholesterol and 25-hydroxycholesterol are synthesized.     

Interaction of heptakis (2,3,6-tri-O-methyl)-beta-cyclodextrin with cholesterol in aqueous solution

The interaction of cholesterol with heptakis (2,3,6-tri-O-methyl)-beta-cyclodextrin (TOM-beta-CyD) was investigated in water using solubility method. It was found that TOM-beta-CyD forms two kinds of soluble complexes, with molar ratios of 1:1 and 1:2 (cholesterol:TOM-beta-CyD). The thermodynamic parameters for 1:1 and 1:2 complex formation of cholesterol with TOM-beta-CyD were: DeltaG0(1:1)=-11.0 kJ/mol at 25 degrees C (K1:1=7.70 x 10 M(-1)); DeltaH0(1:1)=-1.28 kJ/mol; TDeltaS0(1:1)=9.48 kJ/mol; DeltaG0(1:2)=-27.8 kJ/mol at 25 degrees C (K1:2)=7.55 x 10(4) M(-1)); DeltaH0(1:2)=-0.57 kJ/mol; TDeltaS0(1:1)=27.3 kJ/mol. The formation of the 1:2 complex occurred much more easily than that of the 1:1 complex. The driving force for 1:1 and 1:2 complex formation was suggested to be exclusively hydrophobic interaction. Based on the measurements of proton nuclear magnetic resonance spectra and studies with Corey-Pauling-Koltun atomic models, the probable structures of the 1:2 complex were estimated. In addition, the interaction of TOM-beta-CyD with cholesterol was compared with that of heptakis (2,6-di-O-methyl)-beta-CyD (DOM-beta-CyD). The interaction of TOM-beta-CyD is more hydrophobic than that of DOM-beta-CyD, and the life time of the complexed TOM-beta-CyD is sufficiently long to give separated signals, at the NMR time scale, which differs from that of complexed DOM-beta-CyD.     

A Novel Protoilludane Sesquiterpene from the Wood of Xanthoceras sorbifolia

In the course of our searching for anti-HIV agents from natural sources, we have isolated a triterpene and a doubly linked proanthocyanidin dimer as HIV-1 protease inhibitors from the wood of Xanthoceras sorbifolia Bunge (Sapindaceae)1. Further investigation of this plant has led to the isolation of a protoilludane sesquiterpene (1). The present paper describes the isolation and structural determination of this novel sesquiterpene. The EtOH eluate of a MeOH extract of the wood of X. so…     

Loop-contraction mutagenesis of type 1 copper sites

The shortest known type 1 copper binding loop (that of amicyanin, Ami) has been introduced into three different cupredoxin beta-barrel scaffolds. All of the loop-contraction variants possess copper centers with authentic type 1 properties and are redox active. The Cu(II) and Co(II) sites experience only small structural alterations upon loop contraction with the largest changes in the azurin variant (AzAmi), which can be ascribed to the removal of a hydrogen bond to the coordinating thiolate sulfur of the Cys ligand. In all cases, loop contraction leads to an increase in the pK(a) of the His ligand found on the loop in the reduced proteins, and in the pseudoazurin (Paz) and plastocyanin (Pc) variants the values are almost identical to that of Ami ( approximately 6.7). Thus, in Paz, Pc, and Ami, the length of this loop tunes the pK(a) of the His ligand. In the AzAmi variant, the pK(a) is 5.5, which is considerably higher than the estimated value for Az (<2), and other controlling factors, along with loop length, are involved. The reduction potentials of the loop-contraction variants are all lower than those of the wild-type proteins by approximately 30-60 mV, and thus this property of a type 1 copper site is fine-tuned by the C-terminal loop. The electron self-exchange rate constant of Paz is significantly diminished by the introduction of a shorter loop. However, in PcAmi only a 2-fold decrease is observed and in AzAmi there is no effect, and thus in these two cupredoxins loop contraction does not significantly influence electron-transfer reactivity. Loop contraction provides an active site environment in all of the cupredoxins which is preferable for Cu(II), whereas previous loop elongation experiments always favored the cuprous site. Thus, the ligand-containing loop plays an important role in tuning the entatic nature of a type 1 copper center.     

Evaluation of the efficiency of the photocatalytic one-electron oxidation reaction of aromatic compounds adsorbed on a TiO2 surface

The TiO2 photocatalytic one-electron oxidation mechanism of aromatic sulfides with a methylene bridging group (-(CH2)n-, n=0-4) between the 4-(methylthio)phenyl chromophore and the carboxylate binding group on the surface of a TiO2 powder slurried in acetonitrile (MeCN) has been investigated by time-resolved diffuse reflectance (TDR) spectroscopy. The electronic coupling element (H(DA)) between the hole donor and acceptor, which was estimated from the spectroscopic characteristics of the charge transfer (CT) complexes of the substrates (S) and the TiO2 surface, exhibited an exponential decline with the increasing of the methylene number of S. The determined decay factor (beta) of 9 nm(-1) also supports the fact that the 4-(methylthio)phenyl chromophore is separated from the TiO2 surface. The efficiency of the one-electron oxidation of S adsorbed on the TiO2 surface, which was determined from the relationship between the amount of adsorbates and the concentration of the generated radical cations, significantly depended on the H(DA) value, but not on the oxidation potential of S determined in homogeneous solution.     

pH-dependence of 31P-NMR spectroscopic parameters of monofluorophosphate, phosphate, hypophosphate, phosphonate, phosphinate and their dimers and trimers

³¹P-NMR chemical shifts and coupling constants of nine inorganic phosphorus compounds composed of different structural units or oxidation numbers P^V, P^IV, P^III, and P^I were measured in the pH-range 3 11. A concise map of NMR data providing the pH-dependence of the chemical shift (-pH map) was set up to be used for identifying phosphorus compounds under varying pH-conditions. Chemical shifts of monofluorophosphate, as well as most phosphorus compounds of oxidation numbers 5 and 4, were greatly dependent on pH, in contrast to the less or negligible pH-dependence of phosphorus compounds of oxidation numbers 1 and 3. Monofluorophosphate gave the parameters: =+1.3±0.2 ppm and ¹J_PF=870±0.2 Hz, that remained unchanged at pH>6, but varied at pH<6. The practical use of the -pH map was shown with a few kinetic experiments in which monofluorophosphate was enzymatically hydrolyzed by alkaline phosphatase (EC3.1.3.1) at pH 7.2 and non-enzymatically at pH 3.