Asymmetric Entry into 10b-aza-Analogues of Amaryllidaceae Alkaloids Reveals a Pronounced Electronic Effect on Antiviral Activity.

Development of a chiral pool-based synthesis of 10b-aza-analogues of biologically active Amaryllidaceae alkaloids is described, involving a concise reductive amination and condensation sequence, leading to ring-B/C-modified, fully functionalized ring-C derivatives. Differentiated anticancer and antiviral activities of these analogues are presented. Despite complete conformational and functional group overlap, the 10b-aza-analogues have diminished anticancer activity and no antiviral activity. These unprecedented electronic effects suggest a possible role for π-type secondary orbital interactions with the biological target.

Synthesis of the cyanobacterial metabolite nostodione A, structural studies and potent antiparasitic activity against Toxoplasma gondii.

A total synthesis of the cyanobacterial natural product nostodione A is reported involving a convergent, diversity-oriented route, enabling the assembly of a mini-library of structural analogues. The first single crystal X-ray structural determination on a member of this series is reported along with SAR studies identifying potent inhibitors of invasion and replication of the parasitic protozoan Toxoplasma gondii.

Substituent effects on dynamics at conical intersections: cycloheptatrienes.

Using selective methyl substitution, we study the effects of vibrational dynamics at conical intersections in unsaturated hydrocarbons. Here, we investigate the excited state nonadiabatic dynamics of cycloheptatriene (CHT) and its relation to dynamics in other polyenes by comparing CHT with 7-methyl CHT, 7-ethyl CHT, and perdeuterated CHT using time-resolved photoelectron spectroscopy and photoelectron anisotropy. Our results suggest that, upon ππ*-excitation to the bright 2A" state, we observe an early intersection with the dark 2A' state close to the Franck-Condon region with evidence of wavepacket bifurcation. This indicates that the wavepacket evolves on both states, likely along a planarization coordinate, with the majority of the flux undergoing nonadiabatic transition via conical intersections within 100 fs following light absorption. In CHT, large amplitude motion along the planarization coordinate improves the intra-ring π-overlap, yielding a delocalized electronic density. However, substitutions in 7 position, chosen to modify the inertia of the planarization motion, did not markedly alter the first step in the sequential kinetic scheme. This suggests that there is a crossing of potential energy surfaces before planarization is achieved and, thus, nonadiabatic transition likely takes place far away from a local minimum.

Effects of Cu ions and explicit water molecules on the copper binding domain of amyloid precursor protein APP(131-189): a molecular dynamics study.

Amyloid precursor protein (APP) is a cell-surface trans-membrane glycoprotein that appears to play an important role in in vivo Cu ion homeostasis. This protein includes a copper-binding-domain (CuBD) fragment consisting of residues 124-189, of which His147, His151, Tyr168, and possibly Met170 comprise the explicit Cu-binding site (CuBS). Molecular dynamics (MD) simulations are carried out on Cu-free and Cu-bound APP models, based on crystal structures including residues 131-189 obtained from the Protein Data Bank, to confirm the site of Cu-ion binding and to elucidate the effects of the oxidation state of the Cu ions (default GROMACS parameters modeled only the electrostatic binding to the Cu ions at the CuBS) and explicit water molecules on the conformational properties of the 131-189 residue portion of the CuBD. MD trajectory analysis demonstrated a conformational change of Met170. The sulfur atom of Met170 moves closer to the Cu(II) ion and away from Cu(I), and this change may play an important role in the reduction of Cu(II) and the release of Cu(I). Two explicit water molecules were included in the MD simulations. These water molecules that bind strongly to the Cu ions via their lone pair electrons result in a significant modification of the binding interactions with the other residues at the CuBS.

QTAIM study on the degenerate cope rearrangements of 1,5-hexadiene and semibullvalene.

Using the homotropylium cation (1) as an archetypal example of a homoaromatic molecule, we carried out a quantum theory of atoms-in-molecules (QTAIM) computational study--at DFT (density functional theory), CCSD (coupled cluster with singles and doubles), and CASSCF (complete active space self-consistent field) levels--on 1 and the degenerate Cope rearrangements of 1,5-hexadiene (2) and semibullvalene (3) including the evaluation of delocalization indexes and a visualization of atomic basins. This study yielded new insights into the factors determining the reaction barriers and the bonding of the ground and transitions states of 2 and 3. Contrary to conclusions reached in earlier studies, we found that the transition state for the degenerate rearrangement of 2 is not aromatic and that the driving force for the very facile Cope rearrangement of semibullvalene is caused by the stabilization of individual atoms as well as electronic delocalization, not by the release of strain in the three-membered ring.

Discovery of the apoptosis-inducing activity and high accumulation of the butenolides, menisdaurilide and aquilegiolide in Dicentra spectabilis.

The occurrence of two butenolides, menisdaurilide and aquilegiolide, in commercial specimens of Dicentra spectabilis is reported for the first time; a rapid and direct isolation protocol is described. The ability of these lactones to induce apoptosis in human tumour cell lines at 10 microM concentration is also described. The high abundance and apoptosis-inducing activity reported here indicates that these constituents play a more significant role than the hormonal action previously attributed to them.

Correlation effects in EOM-CCSD for the excited states: evaluated by AIM localization index (LI) and delocalization index (DI).

We have extended the evaluation and interpretation of QTAIM (quantum theory of atoms in molecules) localization and delocalization indices lambda (LI) and delta (DI) to electronic excited states by studying ground states (at HF and CCSD levels) and excited states (at CIS and EOM-CCSD) of H2C=CH2, HCCH, H2C=O, H2C=S, CO2, CS2, and SO2. These molecules undergo extensive geometrical changes upon the excitation to the valence adiabatic excited singlet state. The importance of Coulomb correlation effects was demonstrated by comparing the LIs and DIs at none-correlated levels (HF and CIS) and those at correlated levels (CCSD and EOM-CCSD). In interpreting the changes in the magnitudes of the LIs and DIs, we made use of simple molecular orbital and Walsh-diagram analyses. Coulomb correlation is important in determining the magnitude of the LIs and DIs and obtaining geometries that are close to experiment.

7-Norbornyl Cation [Formula: see text] Fact or Fiction? A QTAIM-DI-VISAB Computational Study.

QTAIM-DI-VISAB analyses were used to characterize the bonding of the 'nonclassical' 7-norbornyl cation and its rearrangement transitions states. These analyses involved obtaining QTAIM molecular graphs and delocalization indexes (DIs) that were correlated with the proximities of atomic basins (VISAB). This study showed that the so-called 7-norbornyl cation actually exhibits the molecular graph of the bicyclo[3.2.0]heptyl cation at its equilibrium geometry. Dynamical aspects of its molecular graph/density were explored with QTAIM by analyzing the nuclear motions of the 206 cm(-)(1) normal mode. This study cements the QTAIM-DI-VISAB analysis as a method of choice for establishing the nature of the bonding in so-called nonclassical carbocations while obviating the need for dotted-line representations of bonding.

Protonolysis of the Hg-C bond of chloromethylmercury and dimethylmercury. A DFT and QTAIM study.

Possible mechanisms for degrading chloromethylmercury (CH(3)HgCl) and dimethylmercury [(CH3)2Hg] involving thiol and ammonium residues were investigated by DFT and atoms-in-molecules (QTAIM) calculations. Using H2S and HS- as models for thiol and thiolate groups RSH and RS-, respectively, we obtained transition states and energy barriers for possible decomposition routes to Hg(SH)2 based on a model proposed by Moore and Pitts (Moore, M. J.; Distefano, M. D.; Zydowsky, L. D.; Cummings, R. T.; Walsh, C. T. Acc. Chem. Res. 1990, 23, 301. Pitts, K. E.; Summers, A. O. Biochemistry 2002, 41, 10287). Demethylation was found to be a multistep process that involved initial substitution of Cl- by RS-. We found that successive coordination of Hg with thiolates leads to increased negative charge on the methyl group and facilitates the protonolysis of the Hg-C bond by H-SH. This was also found to be the case for (CH3)2Hg. We found that NH4(+) readily protonolyzes the Hg-C bond of these thiolate complexes, suggesting that ammonium residues of protonated amino acids might also act as effective proton donors.

Displacement of Cu(II) by Ag(I) in solvated metal sulfides. A DFT and AIM computational study.

The substitution of Cu2+ by Ag+ in hydrated CuIIS and (CuII)3S3 was modeled computationally by density functional theory quantum theory of atoms in molecules, and solvent field methods. The coordination, first-shell and partly second-shell molecular structures, and thermochemical data for solvated Cu2+, Ag+, CuIIS, (CuII)3S3, AgCu2S3 and their reactions were obtained. The thermochemical data showed that displacement of Cu2+ and Cu+ from CuIIS and (CuII)3S3 by Ag+, while unfavorable in the gas phase, is facilitated in an aqueous environment. Several covalently bonded species were examined as intermediates in the substitution reactions.

A QTAIM and Electron Delocalization Computational Study of tert-Butylmethylene, Trimethylsilylmethylene, and Trimethylgermylmethylene. A New Method for Unambiguously Characterizing the Bonding between Pairs of Atoms in Reaction Intermediates.

While studies on the experimental photolytic and thermolytic extrusion of nitrogen from tert-butyldiazomethane and tert-butyldiazirine and the decomposition of other precursors have shown a mixture of C-H and C-C insertion products depending on conditions, the analogous trimethylsilyldiazomethane undergoes solely Si-C insertion. Description of the singlet tert-butylmethylene intermediates potentially involved in the C-H and C-C insertion reactions and were addressed through computational means by Armstrong et al. (J. Am. Chem. Soc. 1995, 117, 3685-3689). In addition to re-examining singlet tert-butylmethylene at a higher level of theory [CCSD/6-311+G(d,p)], we have studied the silicon and germanium analogues trimethylsilylmethylene and trimethylgermylmethylene. A computational atoms-in-molecules and atomic-basin-delocalization-indices analysis established that the singlet carbenes, while exhibiting varying degrees of delocalization, are not bridged species based on the fact that none possess a pentacoordinate methyl group. In addition, from the results, we are able to make a prediction of solely a Ge-C insertion product for the extrusion of nitrogen from trimethylgermyldiazomethane. Most importantly, we demonstrated that a combination of quantum theory of atoms in molecules (QTAIM) molecular graphs, the evaluation of delocalization indices, and a visualization of the closeness of atomic basins [Formula: see text] a QTAIM-DI-VISAB analysis [Formula: see text] should be considered as the method of choice for unambiguously characterizing the bonding between pairs of atoms not only of carbenes but of other reaction intermediates such as carbocations, carbanions, and radicals.

Density functional theory and QT atoms-in-molecules study on the hydration of CuI and AgI ions and sulfides.

The hydrates of Cu+, Ag+, CuS-, AgS-, Cu2S, and Ag2S were investigated with density functional theory (DFT), solvent field, and atoms-in-molecules (QTAIM) calculations. We found that covalent bonding of the first-shell water molecules to the metals plays a significant role in the total solvation energy. Molecular graphs were obtained and the bonding characterized by analysis of the electron density and its laplacian at bond critical points. Long-range electrostatic interactions between solute and the bulk solvent, quantified by solvent-field calculations, are more important for hydrated anions CuS- and AgS- than for Cu+ and Ag+ as well as for the neutral species Cu2S and Ag2S. Computed enthalpies of formation for hydrated Cu+ and Ag+ correlated well with experimentally determined values and allowed us to characterize the structures of several hydrates studied in the gas phase. We found that the stability of the hydrates is leveled in the water solvent field. The reactions of dissociation and substitution of metal sulfides in the gas phase and in solution were compared. A decrease in the of energy of the reactions in going from the gas phase to solution is explained on the basis of the higher coordination of metal atoms in the first hydration shell.

Pyrolysis and UV photoelectron spectroscopy of bicyclo[3.2.0]hept-6-en-2-one; preparation and detection of cyclohepta-2(Z),4(E)-dien-1-one.

Flash vacuum pyrolysis of bicyclo[3.2.0]hept-6-en-2-one (1) in the source chamber of a UV photoelectron (PE) spectrometer using a CW CO2 laser as a directed heat source facilitated an electrocyclic ring expansion to yield the transient species cyclohepta-2(Z),4(E)-dien-1-one (2), the PE spectrum of which was compared to that of an authentic sample of cyclohepta-2(Z),4(Z)-dien-1-one (4) and confirmed a conrotatory ring opening of 1 that obeys the Woodward-Hoffmann rules.