Self-assembly of chemically linked rod-disc mesogenic liquid crystals

A series of new molecular discs (RDn, here n is the number of carbon atoms between the rod and disc mesogens) was synthesized via the chemical attachment of six cyanobiphenyl calamitic (rod) mesogens (R) linked to the triphenyl discotic (disc) mesogen (D) with a series of six alkyl chain linkages (n = 6-12). In this study, phase structures, transitions, and liquid crystalline (LC) behavior of the RD12 compound with 12 carbon atoms in each alkyl chain linkage between the rod and disc mesogens were investigated. Differential scanning calorimetry, polarized light microscopy, wide-angle X-ray diffraction (WAXD), and selected area electron diffraction (SAED) allowed us to identify three ordered phases below the isotropization temperature: nematic (N) LC and K1 and K2 crystalline phases. On the basis of the structural results obtained via 2D WAXD experiments on oriented samples and SAED experiments on single crystals, the K1 crystalline unit cell was determined to be triclinic with the dimensions of a = 1.36 nm, b = 1.45 nm, c = 2.11 nm, alpha = 85 degrees, beta = 100 degrees, and gamma = 50 degrees. The K2 phase was metastable with respect to the K1 phase. It also possessed a triclinic unit cell with a = 1.40 nm, b = 1.51 nm, c = 1.92 nm, alpha = 87 degrees, beta = 117 degrees, and gamma = 62 degrees. Molecular packing models for the crystalline phases were proposed on the basis of the diffraction results. In the whole range of ordered structures, it was found that RD12 molecular discs are intercalated. Both triphenyl discotic mesogens and cyanobiphenyl calamitic mesogens are completely interdigitated.     

Fluorescence properties and photophysics of the sulfoindocyanine Cy3 linked covalently to DNA

The sulfoindocyanine Cy3 is one of the most commonly used fluorescent dyes in the investigation of the structure and dynamics of nucleic acids by means of fluorescence methods. In this work, we report the fluorescence and photophysical properties of Cy3 attached covalently to single-stranded and duplex DNA. Steady-state and time-resolved fluorescence techniques were used to determine fluorescence quantum yields, emission lifetimes, and fluorescence anisotropy decays. The existence of a transient photoisomer was investigated by means of transient absorption techniques. The fluorescence quantum yield of Cy3 is highest when attached to the 5' terminus of single-stranded DNA (Cy3-5' ssDNA), and decreases by a factor of 2.4 when the complementary strand is annealed to form duplex DNA (Cy3-5' dsDNA). Substantial differences were also observed between the 5'-modified strands and strands modified through an internal amino-modified deoxy uridine. The fluorescence decay of Cy3 became multiexponential upon conjugation to DNA. The longest lifetime was observed for Cy3-5' ssDNA, where about 50% of the decay is dominated by a 2.0-ns lifetime. This value is more than 10 times larger than the fluorescence lifetime of the free dye in solution. These observations are interpreted in terms of a model where the molecule undergoes a trans-cis isomerization reaction from the first excited state. We observed that the activation energy for photoisomerization depends strongly on the microenvironment in which the dye is located. The unusually high activation energy measured for Cy3-5' ssDNA is an indication of dye-ssDNA interactions. In fact, the time-resolved fluorescence anisotropy decay of this sample is dominated by a 2.5-ns rotational correlation time, which evidences the lack of rotational freedom of the dye around the linker that separates it from the terminal 5' phosphate. The remarkable variations in the photophysical properties of Cy3-DNA constructs demonstrate that caution should be used when Cy3 is used in studies employing DNA conjugates.     

An ultrafast study of phenyl azide: the direct observation of phenylnitrenium ion

Ultrafast photolysis (lambda(ex) = 308 nm) of phenyl azide in 100% formic acid produces a broadly absorbing transient within the instrument time resolution (300 fs), which is assigned to an excited state of the azide. The azide excited state fragments within 300 fs to form singlet phenylnitrene. The decay of the nitrene (tau = 12.0 ps) produces a new species with absorption centered at 500 nm, which is assigned to phenylnitrenium ion. The lifetime of phenylnitrenium ion is 110 ps in 100% formic acid. This is the first spectroscopic observation of phenylnitrenium ion.     

Total synthesis of isoprekinamycin: structural evidence for enhanced diazonium ion character and growth inhibitory activity toward cancer cells

The structurally novel diazobenzo[a]fluorene antibiotic isoprekinamycin (IPK) has been synthesized for the first time employing a Suzuki coupling of a brominated AB ring synthon with a boronate ester representing the D ring, followed by anionic cyclization and appropriate functional group manipulations. The first indication that the diazobenzo[a]fluorene system exhibits in vitro anticancer activity is provided and X-ray crystallographic evidence for enhancement of diazonium ion character as a consequence of intramolecular H-bonding is described.     

A concise synthesis of quinazolinone TGF-β RI inhibitor through one-pot three-component Suzuki-Miyaura/etherification and imidate-amide rearrangement reactions

A simple and efficient synthesis of dihydropyrrolopyrazole boronic acid intermediate (5) has been developed. Utilization of a three-component Suzuki-Miyaura/etherification with microwave heating led to advanced compound 11 in high yield and with easy purification. Reaction of compound 11 with methanesulfonyl chloride at room temperature furnished the 1,3 O-N rearranged product (12), which is postulated to proceed via an intramolecular mechanism. The outlined synthesis provides a highly efficient and high-yielding route that is amenable to rapid analog synthesis.     

Hybrid molecular dynamics-quantum mechanics simulations of solute spectral properties in the condensed phase: evaluation of simulation parameters

We have explored the impact of a number of basic simulation parameters on the results of a recently developed hybrid molecular dynamics-quantum mechanics (MD-QM) method (Mercer et al., J Phys Chem B 1999, 103, 7720). The method utilizes MD simulations to explore the ground-state configuration space of the system and QM evaluation of those structures to yield the time-dependent electronic transition energy, which is transformed into the optical line-broadening function using the second-order cumulant expansion. Both linear and nonlinear optical spectra can then be generated for comparison to experiment. The dependence of the resulting spectra on the length of the MD trajectory, the QM sampling rate, and the QM model chemistry have all been examined. In particular, for the system of oxazine-4 in methanol studied here, at least 20 ps of MD trajectory are needed for qualitative convergence of linear spectral properties, and >100 ps is needed for quantitative convergence. Surprisingly, little difference is found between the 3-21G and 6-31G(d) basis sets, and the CIS and TD-B3LYP methods yield remarkably similar spectra. The semiempirical INDO/s method yields the most accurate results, reproducing the experimental Stokes shift to within 5% and the FWHM to within 20%. Nonlinear 3-pulse photon echo peak shift (3PEPS) decays have also been simulated. Decays are generally poorly reproduced, though the initial peak shift which depends on the overall coupling of motions to the solute transition energy is within 15% of experiment for all model chemistries other than those using the STO-3G basis.     

Trapping of a dopaquinone intermediate in the TPQ cofactor biogenesis in a copper-containing amine oxidase from Arthrobacter globiformis

The biogenesis of the topaquinone (TPQ) cofactor of copper amine oxidase (CAO) is self-catalyzed and requires copper and molecular oxygen. A dopaquinone intermediate has been proposed to undergo 1,4-addition of a copper-associated water molecule to form the reduced form of TPQ (TPQ(red)), followed by facile oxidation by O(2) to yield the mature TPQ (TPQ(ox)). In this study, we have incorporated a lysine residue in the active site of Arthrobacter globiformis CAO (AGAO) by site-directed mutagenesis to produce D298K-AGAO. The X-ray crystal structure of D298K-AGAO at 1.7-A resolution revealed that a covalent linkage formed between the epsilon-amino side chain of Lys298 and the C2 position of a dopaquinone derived from Tyr382, a precursor to TPQ(ox). We assigned the species as an iminoquinone tautomer (LTI) of lysine tyrosylquinone (LTQ), the organic cofactor of lysyl oxidase (LOX). The time course of the formation of LTI at pH 6.8 was followed by UV/vis and resonance Raman spectroscopies. In the early phase of the reaction, an LTQ-like intermediate was observed. This intermediate then slowly converted to LTI in an isosbestic manner. Not only is the presence of a dopaquinone intermediate in the TPQ biogenesis confirmed, but it also provides strong support for the proposed intermediacy of a dopaquinone in the biogenesis of LTQ in LOX. Further, this study indicates that the dopaquinone intermediate in AGAO is mobile and can swing from the copper site into the active-site wedge to react with Lys298.     

On the mechanism of reaction of radicals with tirapazamine

Ketyl radicals produced by photolysis of ketones or di-tert-butyl peroxide (DTBP) in alcohol solvents react rapidly with tirapazamine (TPZ). The acetone ketyl radical (ACOH) reacts with TPZ with an absolute second-order rate constant of (9.7 +/- 0.4) x 108 M-1 s-1. The reaction kinetics can be followed by monitoring the bleaching of TPZ absorption at 475 nm or the formation of a reaction product which absorbs at 320 and 410 nm. The ACOD radical reacts with TPZ in 2-propanol-OD with an absolute rate constant of (6.7 +/- 0.5) x 108 M-1 s-1, corresponding to a kinetic isotope effect (KIE) of 1.4. Deuteration of the radical on carbon (ACOH-d6) retards the reaction of the radical with TPZ even further (absolute rate constant = (4.8 +/- 0.04) x 108 M-1 s-1). This result corresponds to a KIE of 2.0. Radicals derived from dioxane and diisopropyl ether by flash photolysis of DTBP in ethereal solvent react with TPZ more slowly than do ketyl radicals. It is concluded that ketyl radicals react, in part, with TPZ in organic solvents by transfer of a hydrogen atom from the OH and CH3 groups of the ketyl radical to the oxygen atom at the N4 position of TPZ to form acetone or acetone enol and a radical derivative of TPZ (TPZH). The latter species absorbs at 320 and 405 nm, has a lifetime of hundreds of microseconds in alcohol solvents, and decays by disproportionation to form TPZ and a reduced heterocycle. The reduced heterocycle eventually forms a desoxytirapazamine by a polar mechanism. The results are supported by density functional theory calculations. It is proposed that dioxanyl radical will also react, in part, with TPZ by transfer of a hydrogen atom from the carbon adjacent to the radical center to the oxygen atom at the N4 position of TPZ. This produces the enol ether and the previously mentioned TPZH radical. It is further posited that ether radicals react a bit more slowly than ketyl radicals because they lack the second mode of hydrogen transfer (from the OH group) that is present in the ACOH radical. Our data are permissive of the possibility that ether radicals add to TPZ at a rate that is competitive with beta-hydrogen atom transfer.