An extremely long-lived singlet 4,4-dimethoxy-3,5-diphenylpyrazolidine-3,5-diyl derivative: a notable nitrogen-atom effect on intra- and intermolecular reactivity.
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Biomedical subjects
Manabu Abe
Publications and source records attributed to Manabu Abe.
A matrix isolation study of 2-isopropylidenecyclopentane-1,3-diyl (Berson-type diradical).
The photodenitrogenation of diazene 5 in an argon matrix at 10 K permitted the first observation of an IR spectrum of 2-isopropylidenecyclopentane-1,3-diyl 2 (a Berson-type diradical). A comparison of the IR spectrum with a vibrational simulation at the B3LYP/6-31G(d) level of theory revealed that the diradical 2 has a planar structure. The oxygen-trapping reaction of 2 produced regioselectively fused peroxide 6 in an oxygen-doped argon matrix at 10 K. Irradiation of the diradical 2 afforded enyne 8 in an argon matrix at 10 K.
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Experimental probe for hyperconjugative resonance contribution in stabilizing the singlet state of 2,2-dialkoxy-1,3-diyls: Regioselective 1,2-oxygen migration.
A detailed study of the regioselectivity of 1,2-oxygen migration was conducted using the unsymmetrically substituted singlet 2,2-dialkoxy-1,3-diarylcyclopentane-1,3-diyls 5. The alkoxy group selectively migrates to the electron-donating p-methoxyphenyl-substituted carbon. The regioselective migration of oxygen clearly indicates a hyperconjugative resonance structure, that is, zwitterionic characteristics, in singlet 2,2-dialkoxy-1,3-diyls. This represents the first attempt to experimentally probe the contribution of hyperconjugation to stabilizing the singlet state.
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Abundant distribution of TARP gamma-8 in synaptic and extrasynaptic surface of hippocampal neurons and its major role in AMPA receptor expression on spines and dendrites.
Transmembrane alpha-amino-3-hydroxyl-5-isoxazolepropionate (AMPA) receptor regulatory proteins (TARPs) play pivotal roles in AMPA receptor trafficking and gating. Here we examined cellular and subcellular distribution of TARP gamma-8 in the mouse brain. Immunoblot and immunofluorescence revealed the highest concentration of gamma-8 in the hippocampus. Immunogold electron microscopy demonstrated dense distribution of gamma-8 on the synaptic and extrasynaptic surface of hippocampal neurons with very low intracellular labeling. Of the neuronal surface, gamma-8 was distributed at the highest level on asymmetrical synapses of pyramidal cells and interneurons, whereas their symmetrical synapses selectively lacked immunogold labeling. Then, the role of gamma-8 in AMPA receptor expression was pursued in the hippocampus using mutant mice defective in the gamma-8 gene. In the mutant cornu ammonis (CA)1 region, synaptic and extrasynaptic AMPA receptors on dendrites and spines were severely reduced to 35-37% of control levels, whereas reduction was mild for extrasynaptic receptors on somata (74%) and no significant decrease was seen for intracellular receptors within spines. In the mutant CA3 region, synaptic AMPA receptors were reduced mildly at asymmetrical synapses in the stratum radiatum (67% of control level), and showed no significant decrease at mossy fiber-CA3 synapses. Therefore, gamma-8 is abundantly distributed on hippocampal excitatory synapses and extrasynaptic membranes, and plays an important role in increasing the number of synaptic and extrasynaptic AMPA receptors on dendrites and spines, particularly, in the CA1 region. Variable degrees of reduction further suggest that other TARPs may also mediate this function at different potencies depending on hippocampal subregions, input sources and neuronal compartments.
Animals↗
Novel substituent effects on the mechanism of the thermal denitrogenation of 2,3-diazabicyclo[2.2.1]hept-2-ene derivatives, stepwise versus concerted.
The substituent effect on the thermal denitrogenation mechanism of 7,7-disubstituted 2,3-diazabicyclo[2.2.1]hept-2-enes, concerted versus stepwise, has been investigated in detail. Unrestricted DFT calculations at the B3LYP/6-31G(d) level of theory suggest that azoalkanes that possess electron-withdrawing substituents at C(7) prefer to expel the nitrogen molecule in a stepwise manner. The activation energy is calculated to be ca. 36 kcal/mol for the dihydroxy-substituted azoalkane. In contrast, the preferred mechanism of the concerted denitrogenation is predicted for azoalkanes that possess electron-donating substituents at C(7). The activation energy is computed to be ca. 28 kcal/mol for the silyl-substituted azoalkane. The theoretical prediction of the substituent effects on the mechanistic change is supported by analyzing the activation parameters of the azoalkane decompositions. The activation enthalpy for the decomposition of the 7,7-diethoxy-substituted azoalkane is determined to be 39.1 kcal/mol, which is 13.1 kcal/mol higher in energy for the denitrogenation of the 7-silyl-substituted azoalkane. These dramatic substituent effects can be reasonably explained by the preferred electronic configuration of the lowest singlet state of the cyclopentane-1,3-diyls produced during the denitrogenation of the azoalkanes.
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Theoretical calculations of the effects of 2-heavier group 14 element and substituents on the singlet-triplet energy gap in cyclopentane-1,3-diyls and computational prediction of the reactivity of singlet 2-silacyclopentane-1,3-diyls.
UDFT and CASSCF calculations with the 6-31G(d) basis set were performed to investigate the heavier group 14 element (M) effect on the ground-state spin multiplicity of cyclopentane-1,3-diyls and their reactivity. The calculations find that 2-metallacyclopentane-1,3-diyls (M = Si, Ge) that possess a variety of substituents (X = H, Me, F, OR, SiH(3)) at M(2) are singlet ground-state molecules. The energies of the 1,3-diphenyl-substituted singlet 2-silacyclopentane-1,3-diyls are calculated to be ca. 5 kcal/mol lower than those of the intramolecular ring-closure products, i.e., 1,4-diphenyl-5-silabicyclo[2.1.0]pentanes, at the B3LYP/6-31G(d) level of theory. The energy barrier for the disrotatory ring closure of singlet 2,2-dimethyl-1,3-diphenyl-2-silacyclopentane-1,3-diyl (lambda(calcd) = 757 nm, f = 1.01 at RCIS/6-31G(d)) to the corresponding 5-silabicyclo[2.1.0]pentane is computed to be 11.6 kcal/mol, which is 13.1 kcal/mol lower in energy than that for the conrotatory ring-opening to a 3-silapenta-1,4-diene. The computational work predicts that singlet 1,3-diaryl-2-silacyclopentane-1,3-diyls are persistent molecules under conditions without trapping agents.
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2-Silyl group effect on the reactivity of cyclopentane-1,3-diyls. Intramolecular ring-closure versus silyl migration.
Generation of singlet and triplet 2-silylcyclopentane-1,3-diyls and their reactivity have been investigated in the thermal and photochemical denitrogenation of 2,3-diaza-7-silylbicyclo[2.2.1]hept-2-ene. 5-Silylcyclopentene (silyl migration product) is quantitatively obtained, while 5-silylbicyclo[2.1.0]pentane (intramolecular ring-closure product) is not detected in the denitrogenation reactions. Deuterium labeling studies clarify that 5-silylcyclopentene is formed by a suprafacial [1,2] silyl migration in singlet 2-silylcyclopentane-1,3-diyl. UDFT calculations closely reproduce the observed reactivity of the singlet diradical: The enthalpic barriers of the intramolecular ring-closure are calculated to be DeltaH++exo468 = 5.8 kcal/mol and DeltaH++endo468 = 6.7 kcal/mol, which are much higher than the energy barrier for the [1,2] silyl migration, DeltaH++468 = 2.7 kcal/mol. The notable effect of the silyl group on raising the energy barrier of the intramolecular cyclization is rationalized by an electronic configuration of the lowest singlet state of 2-silylcyclopentane-1,3-diyls.
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NMDA receptor GluRepsilon/NR2 subunits are essential for postsynaptic localization and protein stability of GluRzeta1/NR1 subunit.
In NMDA receptors, GluRepsilon/NR2 subunits strictly require the GluRzeta1/NR1 subunit to exit from endoplasmic reticulum (ER) to the cell surface in vitro and to the postsynapse in vivo, whereas C terminus-dependent self-surface delivery has been demonstrated for the GluRzeta1 subunit in vitro. To test whether this leads to C terminus-dependent self-postsynaptic expression in neurons in vivo, we investigated the GluRzeta1 subunit in cerebellar granule cells lacking two major GluRepsilon subunits, GluRepsilon1/NR2A and GluRepsilon3/NR2C. In the mutant cerebellum, synaptic labeling for the GluRzeta1 subunit containing the C2 (GluRzeta1-C2) or C2' (GluRzeta1-C2') cassette was reduced at mossy fiber-granule cell synapses to the extrasynaptic level. The loss was not accompanied by decreased transcription and translation levels, increased extrasynaptic labeling, or ER accumulation. Quantitative immunoblot revealed substantial reductions in the mutant cerebellum of GluRzeta1-C2 and GluRzeta1-C2'. The most severe deficit was observed in the postsynaptic density (PSD) fraction: mutant levels relative to the wild-type level were 12.3 +/- 3.3% for GluRzeta1-C2 and 17.0 +/- 4.6% for GluRzeta1-C2'. The GluRzeta1 subunit carrying the C1 cassette (GluRzeta1-C1) was, although low in cerebellar content, also reduced to 12.7 +/- 3.5% in the mutant PSD fraction. Considering a trace amount of other GluRepsilon subunits in the mutant cerebellum, the severe reductions thus represent that the GluRzeta1 subunit, by itself, is virtually unable to accumulate at postsynaptic sites, regardless of C-terminal forms. By protein turnover analysis, the degradation of the GluRzeta1 subunit was accelerated in the mutant cerebellum, being particularly rapid for that carrying the C2 cassette. Therefore, accompanying expression of GluRepsilon subunits is essential for postsynaptic localization and protein stability of the GluRzeta1 subunit.
Animals↗
Mechanism of stereo- and regioselectivity in the Paternò-Büchi reaction of furan derivatives with aromatic carbonyl compounds: importance of the conformational distribution in the intermediary triplet 1,4-diradicals.
Temperature and substituent effects on the stereo- and regioselectivity have been investigated in the photochemical [2 + 2] cycloaddition reaction, the so-called Paternò-Büchi (PB) reaction, of unsymmetrically substituted furans 2a,b (2-methyl- and 3-methylfuran) with aromatic carbonyl compounds 1a,b (benzaldehyde and benzophenone). The regio-random but stereoselective (exo/endo > 97/3) formation of lower substituted oxetane 3a and higher substituted oxetane 4a is found in the reaction with benzaldehyde (1a). The exclusive stereoselectivity is not dependent on the position of methyl substituent on the furan ring and the reaction temperature. The double-bond selection (3a versus 4a) is slightly dependent on the reaction temperature (3a/4a = 55/45 to 40/60). The Eyring plots of the regioselectivity are linear. Contrastively, in the reaction with benzophenone (1b), the double-bond selection (3b versus 4b) largely depends on the reaction temperature. The Eyring plots are not linear, but the inflection points are observed. The transient absorption spectroscopic analyses (picosecond time scale) clarify the intervention of triplet 2-oxabutane-1,4-diyls in the photochemical processes. Computational studies reveal the equilibrium structures of the triplet diradicals, energy barriers between the conformers, and the equilibrium constants. A rational mechanism is herein proposed by the support of both experimental and computational investigations to account for not only the exclusive formation of the exo-configured oxetanes 3a and 4a but also the nonlinear Eyring plots observed in the reaction with 1b.
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Effects of spiroconjugation on the calculated singlet-triplet energy gap in 2,2-dialkoxycyclopentane-1,3-diyls and on the experimental electronic absorption spectra of singlet 1,3-diphenyl derivatives. Assignment of the lowest-energy electronic transition of singlet cyclopentane-1,3-diyls.
The effect of a 2,2-ethylene-ketal functionality on the singlet-triplet energy gap (Delta E(ST)) and on the first electronic transition in singlet cyclopentane-1,3-diyls (1) has been investigated. UDFT calculations predict a significant increase in the preference for a singlet ground state in the diradical with the cyclic ketal at C2 (1g; Delta E(ST) = -6.6 kcal/mol in C(2) symmetry and -7.6 kcal/mol in C(2v) symmetry), compared to the 2,2-dihydroxy- and 2,2-dimethoxy-disubstituted diradicals (1d, Delta E(ST) = -3.6 kcal/mol in C(2) symmetry, and 1e, Delta E(ST) = -3.4 kcal/mol in C(2) symmetry). Spiroconjugation is shown to be responsible for the larger calculated value of absolute value Delta E(ST) in 1g, relative to 1d and 1e. A strong correlation between the calculated values of Delta E(ST) and the computed electronic excitation energies of the singlet diradicals is found for diradicals 1d, 1e, and 1g and for 2,2-difluorocyclopentane-1,3-diyl (1c). A similar correlation between Delta E(ST) and lambda(calcd) is predicted for the corresponding 1,3-diphenylcyclopentane-1,3-diyls 3, and the predicted blue shift in the spectrum of 3g, relative to 3e, has been confirmed by experimental comparisons of the electronic absorption spectra of the annelated derivatives 2c, 2e, and 2g in a glass at 77 K. The wavelength of the first absorption band in the singlet diradicals decreases in the order 2e (lambda(onset) = 650 nm) > 2g (lambda(onset) = 590 nm) > 2c (lambda(onset) = 580 nm). The combination of these computational and experimental results provides a sound basis for reassignment of the first electronic absorption band in singlet diradicals 2c, 2e, and 2g to the excitation of an electron from the HOMO to the LUMO of these 2,2-disubstituted derivatives of cyclopentane-1,3-diyl.
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Selectivity control in electron spin inversion processes: regio- and stereochemistry of Paternò-Büchi photocycloadditions as a powerful tool for mapping intersystem crossing processes.
Regio- and stereoselectivity in ene-carbonyl photocycloadditions depend on the spin multiplicity of the excited carbonyl state, although both singlet and triplet states produce the cycloadducts with comparable chemoselectivity. The correlation between selectivity and spin state was evaluated by concentration, temperature, and solvent viscosity studies. The higher selectivity observed for triplet reactions is rationalized by the optimal conformations of the intermediate 2-oxabutane-1,4-diyls for intersystem crossing (ISC) to the singlet manifold, controlled preferentially by spin-orbit coupling. This weak interaction connected with ISC can lead to substantial control of regio- and stereoselectivity. The role of hyperfine coupling is demonstrated by magnetic isotope effects.
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DFT calculations on the effects of para substituents on the energy differences between singlet and triplet states of 2,2-difluoro-1,3-diphenylcyclopentane-1,3-diyls.
UB3LYP/6-31g* calculations have been performed on a series of para-substituted 2,2-difluoro-1,3-diphenylcyclopentane-1,3-diyls (4). The singlet is computed to be the ground state for each of the diradicals, regardless of the nature of the para substituents, which range from strongly pi-electron-donating (amino) to strongly pi-electron-withdrawing (nitro). In the symmetrically para-disubstituted diradicals, the size of the singlet-triplet energy gap (Delta E(ST)) increases with the pi-electron-donating ability of the substituents, but in the unsymmetrically substituted diradicals, large values of Delta E(ST) are calculated even when one of the substituents is a pi electron acceptor. The origins of the competitive and cooperative substituent effects, predicted for diradical 4, are discussed in light of the calculated effects of the same substituents on the singlet and triplet states of diradical 6, which lacks the geminal fluorines at C-2 that are present in 4.
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Synthesis of antimalarial yingzhaosu A analogues by the peroxidation of dienes with Co(II)/O2/Et3SiH.
Co(II)-catalyzed peroxidation of dienes including (S)-limonene in the presence of molecular oxygen and triethylsilane provided in each case the corresponding 2,3-dioxabicyclo[3.3.1]nonane derivatives via the intramolecular cyclization of the unsaturated peroxy radical intermediates. The product composition was remarkably influenced by the structure of the dienes, the nature of the solvents, and the concentration of the substrates and the catalyst. Some of the yingzhaosu A analogues obtained in this study showed notable antimalarial activities in vitro.
Alkadienes↗
Mechanism of an alcohol-trapping reaction in the direct and benzophenone-sensitized photodenitrogenation of a spiroepoxy-substituted azoalkane: solvent effects and stereochemical deuterium labeling.
The spin-state-dependent reactivity, singlet versus triplet, of the 2-spiroepoxy-1,3-cyclopentane-1,3-diyl DR2 has been assessed through alcohol-trapping reactions for which the effect of solvent acidity on the product distribution of the alcohol trapping products 2 versus 3 + 4 and stereochemical deuterium-labeling studies have been performed. The proposed mechanism for the solvent effect on the product ratio (2/3 + 4) reveals the importance of the hydrogen-bonded intermediates I1 and I2 in the trapping reactions; the stereochemical deuterium-labeling results clarify the dipole structure trapped by the alcohol. The dipoles DP1 and DP2, in which the configuration between the epoxide oxygen and the deuterium atoms is retained, are inferred for the direct photodenitrogenation reactions (singlet state), whereas for the benzophenone-sensitized photoreactions (triplet state), after ISC, the ring-opened dipole DP3 is implied as the intermediate that is trapped by the alcohol.
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DFT prediction of ground-state spin multiplicity of cyclobutane-1,3-diyls: notable effects of two sets of through-bond interactions.
DFT calculations (UB3LYP/6-31+G**) have been performed to predict the substituent effect on the ground-state spin-multiplicity and the singlet-triplet energy gap in cyclobutane-1,3-diyls, CB-DR. The ground state is calculated to be largely dependent on the substituents (X, Y) at the C2 and C4 positions. The substituent effects can be reasonably explained by the two sets of through-bond (TB) interactions which result from the coupling between the symmetric nonbonding molecular orbital (Psi(S)) and the C-X (Y) sigma and sigma* orbitals.
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Multifunctional anti-angiogenic activity of the cyclic peroxide ANO-2 with antitumor activity.
Our focus was to develop an anti-angiogenic drug possessing the inhibitory activity of urokinase-type plasminogen activator (u-PA) production. During preliminary screening, the effects of 13 ozonides on the inhibition of u-PA production in human fibrosarcoma HT-1080 cells and on the inhibition of angiogenesis on chicken embryonic chorioallantoic membranes were determined. Of the ozonides tested, 9 inhibited in vitro u-PA production of HT-1080 cells and 7 of these 9 exhibited strong anti-angiogenic activity. Interestingly, 6 of the 13 ozonides also inhibited cathepsin B activity. 1-Phenyl-1, 4-epoxy-1H,4H-naphtho[1,8-de][1, 2]dioxepin (ANO-2) potently inhibited cathepsin B (IC(50) = 0.47 microM) as well as u-PA production. Consequently, ANO-2 was selected for further study. ANO-2 inhibited tube formation by human umbilical vein endothelial cells cultured on Matrigel while exhibiting no cytotoxicity. Additionally, in vivo administration of ANO-2 inhibited angiogenesis induced by mouse Sarcoma-180 cells tested using the mouse dorsal air sac assay. Moreover, ANO-2 also suppressed primary tumor growth and reduced the number of pulmonary metastases caused by Lewis lung carcinoma cells in mice. These in vitro and in vivo activities indicate that ANO-2 has considerable potential as a new and potent anti-angiogenic drug that inhibits both u-PA production and enzymatic activity of cathepsins, indicating that ANO-2 may be a multifunctional inhibitor of angiogenesis.
Air Sacs↗
On the electronic character of localized singlet 2,2-dimethoxycyclopentane-1,3-diyl diradicals: substituent effects on the lifetime.
Photodenitrogenation of the diazenes 4 affords exclusively the housanes 5 through intramolecular cyclization of the spectrally detected and characterized singlet diradicals 3. The lifetime of singlet diradical 3, determined by transient absorption measurements, depends on the Y and Z substituents at the para position of the phenyl ring and has the following order: Y, Z = OMe, OMe > OMe, CN > CN, CN > OMe, H > Cl, Cl approximately CN, H approximately Me, Me > H, H. This unprecedented substituent effect reveals stabilization of the singlet 2,2-dimethoxycyclopentane-1,3-diyl diradicals 3 through radical, zwitterionic, pi-bonding, and hyperconjugative structures.
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Notable Substituent Electronic Effects on the Regioselectivity of an Oxygen-Atom Abstraction in the Reaction of Unsymmetrically Substituted Monocyclic 1,2-Dioxolanes with Triphenylphosphine.
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