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Biomedical subjects

Josef Michl

Publications and source records attributed to Josef Michl.

At least 37 records · Page 2Linked to original sources
PubMed2004

A new type of intermediate, C+(BCH3)11- <--> C(BCH3)11, in a Grob fragmentation coupled with intramolecular hydride transfer. A nonclassical carbocation ylide or a carbenoid?

In solvolysis of alkyl halides Hal-(CH(2))(n)-C(BCH(3))(11)(-) (n = 2, 5, 6, but not 3, 4, or 7) and protonation of alkenes CH(2)=CH-(CH(2))(n)(-)(2)-C(BCH(3))(11)(-) (n = 3, 6, 7, but not 4 or 5) carrying the icosahedral electrofuge -C(BCH(3))(11)(-) attached through its cage carbon atom, generation of incipient positive charge on C(alpha) (as shown in Scheme 1 in the article) leads to simultaneous cleavage of the C(beta)-C(BCH(3))(11)(-) bond. The products are a C(alpha)=C(beta) alkene and a postulated intermediate C(+)(BCH(3))(11)(-) <--> C(BCH(3))(11), trapped as the adduct Nu-C(BCH(3))(11)(-) by one of the nucleophiles (Nu(-)) present. The reaction kinetics is E1, first order in the haloalkylcarborane and zero order in [Nu(-)], and the elimination appears to be concerted, as in the usual E2 mechanism. The process is best viewed as a Grob fragmentation. The loss of the longer chains involves intrachain hydride transfer from the C(alpha)-H bond to an incipient carbocation on C(delta)(') or C(epsilon)(') via a five- or six-membered cyclic transition state, respectively. The electronic structure of the postulated intermediate is believed to lie between those of a nonclassical carbonium ylide C(+)(BCH(3))(11)(-) and a carbenoid C(BCH(3))(11) whose electronic ground state resembles the S(2) state of ordinary carbenes.

Journal Article↗
PubMed2004

A multichannel electron energy loss spectrometer for low-temperature condensed films.

We describe a wide-gap multichannel cylindrical deflection electron energy analyzer suitable for measuring the weak signals characteristic of electronically inelastic electron energy loss spectra. The analyzer has nearly ideal fringing field termination, and its resolution and energy dispersion were characterized as a function of energy by solving numerically the equation of motion of electrons in an ideal cylindrical electric field. The numerical results for the radial location of the electrons at the detector as a function of the entrance location, angle, and energy are closely approximated by a second order polynomial, and match closely with those observed. The detection efficiency of the analyzer is 100-150 times better than that of an equivalent single-channel instrument, but limited energy transmission of the zoom lens system used in our case reduced it by a factor of about 2. The performance of the new instrument was demonstrated by measuring the (3)E(1u) electronic spectrum of benzene in only 2 min and the spectrum of endo-benzotricyclo[4.2.1.0(2.5)]nonane.

Crystallization↗
PubMed2004

Joint experimental and theoretical study of vibrationally inelastic electron scattering on propane.

Vibrational electron energy loss spectra were measured for propane at incident energies of 3, 6, 10, 15, 20, and 25 eV at scattering angles of 40 degrees, 55 degrees, 70 degrees, 85 degrees, and 100 degrees . The spectra are compared with the results of ab initio calculations using a recently developed two-channel discrete momentum representation method. Good agreement between theory and experiment was found for large scattering angles and energies above the resonant region.

Computer Simulation↗
PubMed2004

Metal cation-methyl interactions in CB11Me12(-) salts of Me3Ge+, Me3Sn+, and Me3Pb+.

Oxidation of Me(6)M(2) (M = Ge, Sn) and Me(4)Pb with the CB(11)Me(12)(*) radical in alkane solvents produced the insoluble salts Me(3)M(+)CB(11)Me(12)(-), characterized by CP-MAS NMR and EXAFS. The cations interact with methyl groups of CB(11)Me(12)(-) with coordination strength increasing from Pb to Ge. Density functional theory (DFT) calculations for the isolated ion pairs, Me(3)M(+)CB(11)Me(12)(-) (M = Ge, Sn), revealed three isomers with the cation above methyl 2, 7, or 12, and not above a BB edge or a BBB triangle. The interaction has a considerable covalent component, with the cation attempting to perform a backside S(E)2 substitution on the methyl carbon. In a fourth less favorable isomer the cation is near methyl 1, inclined toward methyl 2, and interacts with hydrogens. DFT atomic charge distributions and plots of the electrostatic potential on the surface of spheres centered at the CB(11)H(12)(-) and CB(11)Me(12)(-) icosahedra display the effects of uneven charge distribution within the anion and contradict the common belief that the negative charge of the cage anion is concentrated primarily on the cage boron atoms 7-12; in CB(11)Me(12)(-), roughly half is on the cage carbon and the rest on methyls 7-12.

Boron Compounds↗
PubMed2004

Magnetic circular dichroism of peralkylated tetrasilane conformers.

Magnetic circular dichroism (MCD) of five peralkylated tetrasilanes (1-5) conformationally constrained to angles ranging from nearly 0 degrees to 180 degrees and of the open chain tetrasilane Si(4)Me(10) (6) shows a clear conformational dependence and permits the detection of previously hidden transitions. In the tetrasilane CH(2)Si(4)Me(8) (1), with the smallest dihedral angle, comparison of MCD with absorption spectra reveals four low-energy electronic transitions. In the tetrasilanes 2-4, three distinct transitions are apparent. In tetrasilanes 5 and 6, MCD reveals the very weak transition that has been predicted to be buried under the first intense peak and to which the anomalous thermochromism of 6 and other short-chain oligosilanes has been attributed.

Journal Article↗
PubMed2004

Toward self-assembled surface-mounted prismatic altitudinal rotors. A test case: molecular rectangle.

[structure: see text] A self-assembly path toward prismatic molecular rotors based on transversely reactive terminally metalated molecular rods and pyridine-terminated star connectors is outlined. The concept is tested on the assembly of the biphenyl rod [Ph(2)P(CH(2))(3)PPh(2)Pt(+)-C(6)H(4)-C(6)H(4)-Pt(+)[Ph(2)P(CH(2))(3)PPh(2)] and 4,4'-bipyridyl into a molecular rectangle, fully characterized by NMR and MS, including diffusion-ordered NMR and collision-induced dissociation MS.

Journal Article↗
PubMed2004

Dipolar and nonpolar altitudinal molecular rotors mounted on an Au(111) surface.

We describe the preparation of a compound whose molecules consist of two metal sandwich stands carrying tentacles with affinity to metal surfaces and holding an axle that carries a dipolar or a nonpolar rotator. The dipolar rotor exists as three pairs of enantiomers, rapidly interconverting at room temperature. When mounted on a gold surface, each molecule represents a chiral altitudinal rotor, with the rotator axle parallel to the surface. The surface-mounted rotor molecules are characterized by several spectroscopic and imaging techniques. At any one time, in about one-third of the dipolar rotors the rotator is free to turn and the direction of its dipole can be flipped by the electric field applied by an STM tip, as revealed by differential barrier height imaging. Molecular dynamics calculations suggest that electric field normal to the surface causes members of one pair of enantiomers to rotate unidirectionally.

Journal Article↗
PubMed2004

Li+ -induced sigma-bond metathesis: aryl for methyl exchange on boron in a methylated monocarbadodecaborate anion.

At 190 degrees C, formal sigma-bond metathesis between the B-CH3 bond in position 12 of the lithium monocarbadodecaborate derivative 1a and the C-Si(CH3)3 bond in p-bromophenyltrimethylsilane occurs and produces Si(CH3)4 and a salt of the arylated carborate anion 2, whose X-ray structure has been determined. The reaction requires the presence of active Li+ cations and does not occur with the cesium salt 1b or when 12-crown-4 is added to 1a. Possible mechanisms are briefly discussed.

Journal Article↗
PubMed2004

NMR solution structure of a peptide from the mdm-2 binding domain of the p53 protein that is selectively cytotoxic to cancer cells.

We have recently found that a peptide from the mdm-2 binding domain of the p53 protein induced rapid membranolytic necrosis of a variety of different human cancer cell lines. To determine the role of solution structure in this peptide's selective and rapid tumor membrane disruptive behavior, we have performed two-dimensional NMR on a 32-residue sequence called PNC-27, in both an aqueous cytosolic-like and a mixed organic membrane-mimetic solution environment. In an aqueous milieu, PNC-27 contains three alpha-helical domains connected by loop structures, forming an S shape, and another similar structure with less helical structure. In a solution environment simulating a membrane, the helical domains found in water increase in length, forming three classes of structures, all of which form a U-shaped helix-coil-helix ensemble. In both solvent systems, this peptide forms amphipathic structures such that its hydrophobic residues coalesce on one face while the polar residues aggregate on the opposite face. The ability to form these unique structures in these two solution environments may allow the PNC-27 peptide to selectively and rapidly disrupt cancer cell membranes.

Amino Acid Motifs↗
PubMed2003

Molecular dynamics simulation of an electric field driven dipolar molecular rotor attached to a quartz glass surface.

Molecular dynamics simulations of the response of a dipolar azimuthal 3-chloroprop-1-ynyl rotor mounted on the surface of quartz glass to a rotating electric field were performed. The rotor motion was classified as synchronous, asynchronous, random, or hindered, based on the value of the average lag of the rotor behind the field and a comparison of the intrinsic rotational barrier V(b) with kT. A phase diagram of rotor behavior was deduced at 10, 300, and 500 K as a function of field strength and frequency. A simple model for the rotor motion was developed, containing the driving force, the temperature, the height of the torsional barrier, and the friction constant of the rotor. Defining E(bo) to be the electric field strength necessary to get rotational response from the rotor ("breakoff field") and mu to be the rotor dipole moment component in the plane of rotation, we find that E(bo) is frequency independent when 2 microE(bo) is less than either V(b) or kT (the driving force needs to overcome the more important of the two, the intrinsic barrier or random thermal motion). At higher frequencies, E(bo) is a quadratic function of the frequency and the driving force fights friction, which is dictated by intramolecular vibrational redistribution (IVR) from the pumped rotational mode to all others. Fitting the simple model to simulation data, we derived a friction constant of 0.26 ps eV x (nu - 0.5)/THz between 500 and 1000 GHz.

Journal Article↗
PubMed2003

Peptides designed from molecular modeling studies of the ras-p21 protein induce phenotypic reversion of a pancreatic carcinoma cell line but have no effect on normal pancreatic acinar cell growth.

PURPOSE: From molecular modeling studies we found that two ras-p21 peptides, corresponding to p21 residues 35-47 (PNC-7) and 96-110 (PNC-2), selectively block oncogenic (Val 12-p21), but not insulin-activated wild-type, p21-induced oocyte maturation. Our purpose was to determine if these peptides block the growth of mammalian cancer cells but not their normal counterpart cells. METHODS: Since oncogenic ras has been implicated as a causative factor in over 90% of human pancreatic cancers, we have established a normal pancreatic acinar cell line (BMRPA1) and the corresponding ras-transformed pancreatic cancer cell line (TUC-3). We treated both cell lines with PNC-7 and PNC-2 and the unrelated negative control peptide, X13, attached to the penetratin sequence that allows membrane penetration and also transfected these cell lines with plasmids encoding all three peptides. RESULTS: Treatment of TUC-3 cells with each peptide resulted in their complete phenotypic reversion to the untransformed phenotype as revealed by the lack of tumor formation of these revertant cells implanted in the peritoneal cavities of nude mice. In contrast, treatment with X13-leader resulted in no inhibition of cell growth. Identical results were obtained when TUC-3 cells were transfected with plasmids expressing PNC-2, PNC-7 and X13. None of these peptides affected the normal growth of BMRPA1 cells. CONCLUSIONS: PNC-2 and PNC-7 peptides induce phenotypic reversion of ras-induced pancreatic cancer cells and have no effect on normal pancreatic cell growth. Since the plasmid encoding PNC-2 without penetratin also had the same effect on the TUC-3 cell line, we conclude that the penetratin sequence has no effect on the activity of this peptide. Since X13 attached to penetratin had no effect on TUC-3 cells, the effect is specific for PNC-2 and PNC-7 and further confirms that the effect is not caused by the penetratin sequence. PNC-2- and PNC-7-penetratin may therefore be useful in the treatment of ras-induced pancreatic carcinomas.

Base Sequence↗
PubMed2003

Preferential induction of necrosis in human breast cancer cells by a p53 peptide derived from the MDM2 binding site.

p53 is the most frequently altered gene in human cancer and therefore represents an ideal target for cancer therapy. Several amino terminal p53-derived synthetic peptides were tested for their antiproliferative effects on breast cancer cell lines MDA-MB-468 (mutant p53), MCF-7 (overexpressed wild-type p53), and MDA-MB-157 (null p53). p53(15)Ant peptide representing the majority of the mouse double minute clone 2 binding site on p53 (amino acids 12-26) fused to the Drosophila carrier protein Antennapedia was the most effective. p53(15)Ant peptide induced rapid, nonapoptotic cell death resembling necrosis in all breast cancer cells; however, minimal cytotoxicity was observed in the nonmalignant breast epithelial cells MCF-10-2A and MCF-10F. Bioinformatic/biophysical analysis utilizing hydrophobic moment and secondary structure predictions as well as circular dichroism spectroscopy revealed an alpha-helical hydrophobic peptide structure with membrane disruptive potential. Based on these findings, p53(15)Ant peptide may be a novel peptide cancer therapeutic because it induces necrotic cell death and not apoptosis, which is uncommon in traditional cancer therapy.

Amino Acid Chloromethyl Ketones↗
PubMed2003

Time-dependent density functional theory treatment of the first UV absorption band in all-transoid permethyloligosilanes SinMe2n + 2 (n = 2-8, 10).

The TD B3LYP/6-311G(d,p) method slightly overestimates the excitation energies of the first UV absorption band of the all-transoid conformers of SinMe2n + 2 (n = 2-8, 10), deduced from temperature-dependent measurements on conformer mixtures in hydrocarbon solvents, by a nearly constant amount (approximately 2000 cm-1). The TD B3LYP/6-31G(d) results are less satisfactory. The first band is calculated to be due to a sigma pi * excitation in Si2Me6 and to a superposition of overlapping sigma sigma * and sigma pi * excitations in the longer oligosilanes. The sigma pi * excitation is calculated to lie a little below the sigma sigma * excitation up to Si4Me10, the two transitions are nearly degenerate in Si5Me12, and the sigma sigma * excitation drops increasingly below the sigma pi * as the chain length is extended. The dipole strength of the sigma sigma * excitation grows by 4.8 D2 (D = debye) per added SiSi bond (more slowly up to n = 5) and the calculation overestimates it by a factor of about three. The sigma pi * excitation is computed to carry no or almost no oscillator strength, but as noted earlier by others, its presence is critical for the interpretation of the observed thermochromism. Upon cooling below room temperature, the first absorption maximum is blue-shifted in short chains and red-shifted in long chains. Unlike the prior investigators, we attribute the blue shift to the disappearance of hot bands built on the sigma pi * origin using intensity borrowing sigma-pi mixing vibrations (b1 in Si3Me8). As usual, the red shift is attributed to the disappearance of twisted conformers, which have higher calculated sigma sigma * excitation energies.

Journal Article↗
PubMed2002

Synthesis and structure of trigonal and tetragonal connectors for a "Tinkertoy" construction set.

We describe a convergent synthesis of eight 1,3,5- and 1,2,4,5-substituted benzene derivatives with long rigid arms containing 4-pyridyl, 2,2'-bipyridyl, and 2,2'-bipyrimidyl termini, meant to be used as trigonal or tetragonal connectors for the construction of large molecular structures. The synthesis involved copper-free Pd-mediated coupling of terminal acetylenes to aryl halides. First, one of the termini of 1,3-diethynylbicyclo[1.1.1]pentane was coupled with a brominated aza heterocycle, and second, 3 equiv of the resulting extended arm were coupled with 1,3,5-triiodobenzene or 4 with 1,2,4,5-tetraiodobenzene. An improved large-scale synthesis for 1,3-diethynylbicyclo[1.1.1]pentane is described. The structures of two of the arms were determined by single-crystal X-ray analysis. Several long molecular rods with 4-pyridyl termini were obtained as byproducts, and a single-crystal X-ray structure is reported for the shortest of these.

Journal Article↗
PubMed2002

Prediction of an inverse heavy-atom effect in H-C-CH(2)Br: bromine substituent as a pi acceptor.

A comparison of spin-orbit coupling calculated [CASSCF(6,6)/(cc-pVDZ on C,H and VDZ+P on Br] for bromomethylcarbene and methylcarbene predicts a highly unusual inverse heavy-atom effect by the Br substituent, particularly at geometries near the syn conformation. This behavior is due to a vacant 4d orbital on the Br atom acting as a weak pi-electron acceptor and overwhelming the even weaker effect of the pi-symmetry lone pair donor 4p orbital, which in itself would cause a small normal heavy-atom effect.

Journal Article↗
PubMed2002

Self-assembly of a metal-ion-bound monolayer of trigonal connectors on mercury: an electrochemical Langmuir trough.

The adsorption of the trigonal connector, 1,3,5-tris[10-(3-ethylthiopropyl)dimethylsilyl-1,10-dicarba-closo-decaboran-1-yl]benzene (1), from acetonitrile/0.1 M LiClO(4) on the surface of mercury at potentials ranging from +0.3 to -1.4 V (vs. aqueous Ag/AgCl/1 M LiCl) was examined by voltammetry, Langmuir isotherms at controlled potentials, and impedance measurements. No adsorption is observed at potentials more negative than approximately -0.85 V. Physisorption is seen between approximately -0.85 and 0 V. At positive potentials, adsorbate-assisted anodic dissolution of mercury occurs and an organized surface layer is formed. Although the mercury cations are reduced at -0.10 V, the surface layer remains metastable to potentials as negative as -0.85 V. Its surface areas per molecule and per redox center are compatible with a regular structure with the connectors 1 woven into a hexagonal network by RR'S-->Hg(2)(2+)<--SRR' or RR'S-->Hg(2+)<--SRR' bridges. The structure is simulated closely by geometry optimization in the semiempirical AM1 approximation.

Acetonitriles↗
PubMed2002

An experimental test of C-N bond twisting in the TICT state: syn-anti photoisomerization in 2-(N-methyl-N-isopropylamino)-5-cyanopyridine.

A previously untested essential consequence of the "TICT" (twisted internal charge transfer) interpretation of the nature of the "anomalous" excited state of p-dimethylaminobenzonitrile (1) and related compounds has now been verified: at -90 degreesC, the dual fluorescence of a desymmetrized analogue, 2-(N-methyl-N-isopropylamino)-5-cyanopyridine (2), in methanol (MeOH) is accompanied by syn-anti isomerization around the C-N bond, whereas its ordinary fluorescence in tetrahydrofuran is not.

Journal Article↗