Ab initio quantum dynamical study of the multi-state nonadiabatic photodissociation of pyrrole.

There has been a substantial amount of theoretical investigations on the photodynamics of pyrrole, often relying on surface hopping techniques or, if fully quantal, confining the study to the lowest two or three singlet states. In this study we extend ab initio based quantum dynamical investigations to cover simultaneously the lowest five singlet states, two π-σ∗ and two π-π∗ excited states. The underlying potential energy surfaces are obtained from large-scale MRCI ab initio computations. These are used to extract linear and quadratic vibronic coupling constants employing the corresponding coupling models. For the N-H stretching mode Q(24) an anharmonic treatment is necessary and also adopted. The results reveal a sub-picosecond internal conversion from the S(4) (π-π∗) state, corresponding to the strongly dipole-allowed transition, to the S(1) and S(2) (π-σ∗) states and, hence, to the ground state of pyrrole. The significance of the various vibrational modes and coupling terms is assessed. Results are also presented for the dissociation probabilities on the three lowest electronic states.

Electron ionisation induced fragmentation of fused norbornene analogues containing SiMe2 or GeMe2 and oxygen bridges. Migration of SiMe2 and GeMe2 groups.

The main electron ionisation induced fragmentation processes of fused norbornene analogues containing SiMe2 or GeMe2 and oxygen bridges, as well as their dependence on substitution, were investigated using mass (MS) and tandem mass (MS/MS) spectrometric analysis. Formation of the rearrangement ions of m/z 176 in the mass spectra of fused norbornene analogues containing SiMe2 and m/z 222 in the mass spectrum of norbornene analogues containing GeMe2 provides firm evidence for the migration of a SiMe2 and GeMe2 bridge, respectively.

Benzocyclobutene: The Impact of Fusing a Strained Ring onto Benzene.

The gas-phase acidities of the two aromatic sites in benzocyclobutene were measured in a Fourier transform mass spectrometer using a kinetic technique (i.e., the DePuy method). Fusion of a cyclobutane ring onto benzene is found to have a slight acidifying effect at the alpha-position (3.2 +/- 1.7 kcal mol(-)(1)) and little, if any, influence on the beta-site (0.8 +/- 1.9 kcal mol(-)(1)). Energetic data (DeltaH degrees (acid) = 386.2 +/- 3.0 kcal mol(-)(1), EA = 0.84 +/- 0.11 eV, and C-H BDE = 92 +/- 4 kcal mol(-)(1)) for the benzylic position were obtained via the bracketing technique and application of a thermodynamic cycle. Differences in the reactivities of the three conjugate bases also were explored. Ab initio and density functional theory calculations were carried out to provide geometries, energies, and insights into the carbanions' electronic structures.

Effect of cisplatin and 6-bromo-6-deoxy-L-ascorbic acid on some biochemical and functional parameters in mice.

The results of the present study demonstrate that 6-bromo-6-deoxy-L-ascorbic acid (6-BrAA), an antioxidative derivative of ascorbic acid, is capable of lowering the toxicity of cisplatin, cis-diaminedichloroplatinum (cis-DDP), an anticancerogenic drug. The biological aspects and pharmacological significance of a combined treatment of these two substances were investigated in a mouse model. The results indicate that the effectiveness of 6-BrAA on biological response(s) is strongly dependent on the dose of cis-DDP. Injection of 10 mg/kg body weight (bw) of cis-DDP following pretreatment with 6-BrAA (480 mg/kg bw) enhances the tissue-protecting effect of 6-BrAA and reduces, to some extent, the ensuing nephro-, liver and spleen toxicity. On the other hand, 6-BrAA in animals treated with a higher dose of cis-DDP (15 mg/kg bw) leads to exacerbation of the toxic cis-DDP effect and concurrent loss of the protective potential of 6-BrAA with respect to tissue damage. The exact mechanism(s) of 6-BrAA protection and exacerbation of the toxic cis-DDP effect is unclear, although scavenging or generating of free radicals may play an important role. The results obtained may be of importance in planning the rational use of cis-DDP and 6-BrAA administration in the potential treatment of cancer.

Growth suppression of malignant leukemia cell line in vitro by ascorbic acid (vitamin C) and its derivatives.

In recent years there has been a growing interest in the therapeutic application of L-ascorbic acid (AA) and its derivatives as anticancer agents. AA is a gamma-crotonolactone derivative with reactive hydroxyl groups at the 2- and 3-positions and an ethylene glycol substitution at the 4-position. Despite the various reports on AA toxicity, no work has been reported underlying the critical chemical structural features for its activity. The present study addresses this question. We tested in vivo, using malignant leukemia cell line P388D1, (i) L-AA and its isomers, (ii) substitution at the 2-position: -PO4, -SO4, O-Me, O-octadecyl, (iii) substitution at the 6-position: -PO4, -SO4, -palmitate, -stearate, (iv) substitution at the 2,6-position: dipalmitate, (v) 6-deoxy derivative: -Cl, -Br, -NH2 and (vi) dihydroxy gamma-crotonolactone with substitutions at the 4-position: -H, -CH3, -CH2-CH3 and -CH=CH2. L-AA and its isomers were very cytotoxic even at very low concentration. All 6-substituted and 6-deoxy derivatives were as toxic as AA. However, 2-substituted and 2,6-disubstituted AA derivatives were non-toxic. Interestingly, dihydroxy gamma-crotonolactone with or without substitution at the 5-position also exhibited toxicity. These results suggest that the underlying criterion for AA toxicity resides in dihydroxy gamma-crotonolactone moiety. Either substitution in the hydroxy groups or saturating the double bond render the molecule inactive.

Ascorbic acid and 6-deoxy-6-chloro-ascorbic acid: potential anticancer drugs.

The role of ascorbic acid (AA) in prevention and suppression of carcinogenesis has been known for a long time. It was also found that AA may inhibit the growth of some tumor cells in vitro and in vivo. We examined the influence of ascorbic acid and 6-chloro-6-deoxy ascorbic acid (6-Cl-AA) on the growth of various human cell lines: lung fibroblasts (Hef), ovarian adenocarcinoma (OVCAR), colon adenocarcinoma (HT-29), laryngeal carcinoma (HEp2) cells, HEp2 cells resistant to vincristine (HEp2VA3), cervical carcinoma (HeLa) cells, HeLa cells resistant to cisplatin (Helacis), breast adenocarcinoma (SK-BR-3) cells, and SK-BR-3 resistant to doxorubicin (SK-BR-3-Dox), as well as mouse fibroblasts L929, mouse melanoma B16 (Mel B16) cells and Chinese hamster fibroblasts (V79). Both drugs arrested the growth of: HeLa, SK-BR-3, SK-BR-3-Dox, L929, and Mel B16 cells, but did not influence the growth of others: Hef, OVCAR, HEp2, HEp2VA3 and V79. 6-Cl-AA suppressed more the proliferation of HeLacis, SK-BR-3-Dox and Mel B16 cells than AA, while AA was active only against HT-29 cells. Inhibitory effect of 6-Cl-AA was confirmed by the in vivo experiments on solid melanoma B16 tumors. Our results indicate that AA and 6-Cl-AA could serve as potential antitumor agents, especially against some tumor cells resistant to chemotherapy.

6-Amino-6-deoxyascorbic acid induces apoptosis in human tumor cells.

6-Amino-6-deoxyascorbic acid was found to inhibit human tumor cell growth. The antitumor effect depends on the tumor type and concentration of the acid. After cell treatment with 6-amino-6-deoxyascorbic acid, drastic morphological changes were found. Although image analysis did not show a difference in p53 and c-myc gene expression, the appearance of chromatin aggregation and DNA fragmentation points to apoptosis or programmed cell death.

One-electron oxidation and reduction reactions of vitamin C derivatives: 6-bromo- and 6-chloro-6-deoxy-ascorbic acid.

6-Bromo- and 6-chloro-6-deoxy derivatives of ascorbate anion are able to transfer an electron to the oxidizing radicals .OH, Br2.- and RS. with the same rate constants as the ascorbate anion itself. The resulting radicals also show the same kinetic stabilities and optical absorption spectra as the well-characterized ascorbate radical anion (lambda max = 360 nm; epsilon 360 = 330 m2 mol-1). This proves that there is no influence of the structural changes in the side chain on the antioxidant capacity of the ascorbate moiety. In contrast, measured reduction of the 6-halo-6-deoxy derivatives occurs significantly faster (up to one order of magnitude) than the reduction of unsubstituted ascorbate. For example, absolute rate constants of 4.6 x 10(9) and 2.2 x 10(7) dm3 mol-1 s-1 have been measured for the reactions of bromo-derivative with eaq- and (CH3)2COH respectively. These radical-induced reductions proceed via dissociative electron capture and, under cleavage of the C-halogen bond, yield C-6 carbon-centered radicals. In the presence of oxygen the corresponding peroxyl radical is readily formed. This radical is again able to oxidize the ascorbate moiety (rate constant 2 x 10(7) dm3 mol-1 s-1). Results are discussed in terms of biological relevance of the investigated compounds regarding their ability to act as efficient antioxidants and bioreductive antitumour agents simultaneously.

6-Deoxy-6-bromo-ascorbic acid inhibits growth of mouse melanoma cells.

The influence of 6-deoxy-6-bromo-ascorbic acid (6-Br-AA) and ascorbic acid (AA) on the growth of mouse melanoma cell line B16, mouse fibroblasts (L929), and human cervical carcinoma HeLa cells was examined by in vitro experiments. 6-Br-AA was added in concentrations 10(-1) to 10(-8)M and for incubation periods of 2, 18, 24 and 72 h. The present results indicate that 6-Br-AA exhibits a highly pronounced inhibiting effect on growth and DNA synthesis of melanoma cells. Inhibitory effect of 6-Br-AA was confirmed by the in vivo experiments. The tumor-suppressing effect on solid melanoma B16 was attained with 9 mg per mouse given three times daily for 16 days. Our preliminary results indicate that 6-Br-AA could serve as a potential antitumor agent.