Stereoselective synthesis of scyphostatin hydrophilic moiety

A stereoselective synthesis of scyphostatin hydrophilic moiety was accomplished. Substrate- and reagent-controlled dihydroxylation of tri- and monosubstituted alkenes afforded desired diols, respectively. Chemo- and stereoselective allylation of α-(methoxycarbonyl)cyclohexanone provided allylcyclohexanol. Oxidative cleavage of glycol and subsequent β-elimination of siloxycyclohexanone furnished the desired epoxycyclohexenone.     

BASHD‐J‐resolved‐HMBC,an efficient method for measuring proton–proton and heteronuclear long‐range coupling constants

Natural products often possess various spin systems consisting of a methine group directly bonded to a methyl group (e.g. –CH_a–CH_b(CH₃)–CH_c–). The methine proton H_b splits into a broadened multiplet by coupling with several vicinal protons, rendering analysis difficult of ⁿJ_C–H with respect to H_b in the J‐resolved HMBC‐1. In purpose of the reliable and easy measurements of ⁿJ_C–H and ⁿJ_H–H in the aforesaid spin system, we have developed a new technique, named BASHD‐J‐resolved‐HMBC. This method incorporates band selective homo decoupled pulse and J‐scaling pulse into HMBC. In this method, high resolution cross peaks can be observed along the F₁ axis by J‐scaling pulse, and band selective homo decoupled pulse simplified multiplet signals. Determinations of ⁿJ_C–H and ⁿJ_H–H of multiplet signals can easily be performed using the proposed pulse sequence. Copyright © 2013 John Wiley & Sons, Ltd.     

Second-generation total synthesis of haterumalide NA using B-alkyl Suzuki-Miyaura coupling

Second-generation total synthesis of haterumalide NA, a potent cytotoxic marine macrolide, was achieved by using B-alkyl Suzuki-Miyaura coupling and Nozaki-Hiyama-Kishi coupling as key steps (1.2% in 33 steps). Compared to our first-generation approach, the second-generation synthesis is much improved in the yield of key intermediate.     

Formal total synthesis of fostriecin via 1,4-asymmetric induction using cobalt-alkyne complex

The synthesis of a protected dephosphofostriecin, and thereby a formal synthesis of fostriecin, has been accomplished. Two of the four chiral centers are controlled by an external chiral auxiliary and the other two are synthesized stereoselectively, one by a novel 1,4-asymmetric induction using cobalt-alkyne complex, and the other by 1,3-asymmetric induction.     

Photosensitized breakage and damage of DNA by CdSe-ZnS quantum dots

Strand breakages and nucleobase damages in plasmid DNA (pDNA) by CdSe-ZnS quantum dots (QDs) are investigated under different conditions of photoactivation. Here, streptavidin functionalized CdSe-ZnS QDs are conjugated to biotinylated pDNA, and photosensitized strand breakages and nucleobase damages in the conjugates are investigated using atomic force microscopy (AFM) imaging, gel electrophoreses analyses, and assay of reactive oxygen intermediates (ROI). Also, reactions of photoactivated pDNA-QD conjugates with base excision repair enzymes such as formamidopyrimidine glycosylase (Fpg) and endonuclease III (Endo III) show damages of purine and pyrimidine bases. The base excision repair enzymes recognize and remove the damaged bases. The base excision reactions of photoactivated pDNA-QD conjugates resulted in pDNA strand breakages, which appeared as sheared bands in agarose gel images. On the basis of AFM imaging, reactions of Fpg and Endo III with damaged pDNA, ROI assay, and literature reports, we attribute the breakage and damage of pDNA to its reactions with ROI. The production of ROI by photoactivated QDs is confirmed by nitroblue tetrazolium (NBT) assay. The current work shows that photoactivation of QD-conjugated nucleic acids for an extended period of time is not favorable for their stability. On the other hand, photoinduced production of ROI by QDs is an emerging research area with potential applications in the photodynamic therapy of cancer. In this regard, photosensitized damage of pDNA observed in the current work shows possibilities of QDs in nucleus-targeted photodynamic therapy.     

Novel hierarchical classification and visualization method for multiobjective optimization of drug properties: application to structure-activity relationship analysis of cytochrome P450 metabolism

In the lead optimization process, medicinal chemists must consider various chemical properties of active compounds, including ADME/Tox properties, and find the best compromise among these. This study presents a novel data mining method for multiobjective optimization of chemical properties, which consists of the hierarchical classification and visualization of multidimensional data. A hierarchical classification tree model is generated by an extension of recursive partitioning that utilizes averaged information gains for multiple objective variables as a quality-of-split criterion. All the hierarchically structured data objects are represented using a large-scale data visualization technique. The technique is an extension of HeiankyoView, which displays data objects as colored icons and group nodes as rectangular borders. Each icon is divided into subregions with different colors, so that it can present multidimensional data according to brightness of the colors. The proposed method was applied to the structure-activity relationship analysis for cytochrome P450 (CYP) substrates. The substrate specificity of six CYP isoforms was successfully delineated: e.g., CYP2C9 substrates are anionic compounds, while CYP2D6 substrates are cationic; and CYP2E1 substrates are smaller compounds, while CYP3A4 substrates are larger compounds.     

Indium(III) acetate-catalyzed intermolecular radical addition of organic iodides to electron-deficient alkenes

In the presence of phenylsilane and a catalytic amount of indium(III) acetate, organic iodides added to electron-deficient alkenes in ethanol at room temperature. Both simple and functionalized organic iodides were applicable to this reaction. A plausible reaction mechanism involves the formation of indium hydride species by hydride transfer from silicon to indium and an indium hydride-mediated radical chain process.     

C-H activation on a diphosphine and hydrido-bridged diiridium complex: generation and detection of an active IrII-IrII species [(Cp*Ir)2(micro-dmpm)(micro-H)]+

Reaction of [Cp*Ir(micro-H)](2) (5) (Cp* = eta(5)-C(5)Me(5)) with bis(dimethylphosphino)methane (dmpm) gives a new neutral diiridium complex [(Cp*Ir)(2)(micro-dmpm)(micro-H)(2)] (3). Treatment of 3 with methyl triflate at -30 degrees C results in the formation of [(Cp*Ir)(H)(micro-dmpm)(micro-H)(Me)(IrCp*)][OTf] (6). Warming a solution of above 0 degrees C brings about predominant generation of 32e(-) Ir(II)-Ir(II) species [(Cp*Ir)(micro-dmpm)(micro-H)(IrCp*)][OTf] (7). Further heating of the solution of 7 up to 30 degrees C for 14 h leads to quantitative formation of a new complex [(Cp*Ir)(H)(micro-Me(2)PCH(2)PMeCH(2))(micro-H)(IrCp*)][OTf] (8), which is formed by intramolecular oxidative addition of the methyl C-H bond of the dmpm ligand. Intermolecular C-H bond activation reactions with 7 are also examined. Reactions of 7 with aromatic molecules (benzene, toluene, furan, and pyridine) at room temperature result in the smooth sp(2) C-H activation to give [(Cp*Ir)(H)(micro-dmpm)(micro-H)(Ar)(IrCp*)][OTf] (Ar = Ph (9); Ar = m-Tol (10a) or p-Tol (10b); Ar = 2-Fur (11)) and [(Cp*Ir)(H)(micro-dmpm)(micro-C(5)H(4)N)(H)(IrCp*)][OTf] (12), respectively. Complex also reacts with cyclopentene at 0 degrees C to give [(Cp*Ir)(H)(micro-dmpm)(micro-H)(1-cyclopentenyl)(IrCp*)][OTf] (13). Structures of 3, 8 and 12 have been confirmed by X-ray analysis.     

HELFIT: Helix fitting by a total least squares method

The problem of fitting a helix to data arises in analysis of protein structure, in nuclear physics, and in engineering. A continuous helix is described by five parameters: helix axis, helix radius, and helix pitch. One of these helix parameters is frequently predefined in the helix fitting. Other algorithms find only the helix axis or determine separately the helix axis, the helix radius, or the helix pitch. Here we describe a total least squares method, HELFIT, for helix fitting. HELFIT enables one to calculate simultaneously all five of the helix parameters with high accuracy. The minimum number of data points required for the analysis is only four. HELFIT is very insensitive to noise even in short helices. HELFIT also calculates a parameter, p = rmsd/(N − 1)^1/2, which estimates the regularity of helical structures independent of the number of data points, where rmsd is the root mean square distance from the best-fit helix to data points and N is the number of data points. It should become a basic tool of structural bioinformatics.     

Controlled deposition of calcium carbonate particles on porous membranes by using alternating current system

The deposition of calcium carbonate particles in the absence of additives was performed through the application of an alternating current. Solutions of calcium chloride and sodium carbonate were filled in glass cells, and a porous polymer membrane was interposed between the glass cells. An alternating current with a sine waveform (frequency: 10 Hz) was applied by using a platinum electrode. In this process, the reciprocal migration of calcium and carbonate ions toward the interface of the pores on the membrane takes place. Moreover, ion mixing occurs to a small extent at the interface of the pores. An alternating current was applied for 30 min during which the ion mixing continued. When observed using a scanning electron microscope, a majority of the formed calcium carbonate particles was found to exhibit a spheroidal vaterite crystal structure. This crystal structure was confirmed to be vaterite after characterization by X-ray diffraction. In the absence of an alternating current, only calcite was formed on the porous polymer membrane. Taking this result into account, it was concluded that the alternating current could induce reciprocal ion migration through the pores of the membrane, and vaterite deposition can be achieved. This is one of the methods employed for the calcium carbonate formation on the porous membrane by using an alternating current system.