Secondary-Rim γ-Cyclodextrin Functionalization to Conjugate with C60 : Improved Efficacy as a Photosensitizer.

DIBAL-H-mediated demethylation provides a novel method to access secondary-rim functionalized γ-cyclodextrin. 2A ,3B -Dihydroxyl-per-O-methylated-γ-cyclodextrin has been obtained, whose conjugation with C60 allows access to the most water-soluble C60 conjugate described so far. The water solubility of 0.12 m (550 mg mL-1 ) is 150 times higher than that of the native γ-CD/C60 complex. Its singlet oxygen (1 O2 ) quantum yield is 0.39, an increase of one to two orders of magnitude compared to that of α(ß)CD-C60 conjugates.

Electron affinity of tricyclic, bicyclic, and monocyclic compounds containing cyanoenones correlates with their potency as inducers of a cytoprotective enzyme.

UNLABELLED: Tricyclic, bicyclic, and monocyclic compounds containing cyanoenones induce various anti-inflammatory and cytoprotective enzymes through activation of the Keap1/Nrf2/ARE (antioxidant response element) pathway. The potency of these compounds as Nrf2 activators was determined using a prototypic cytoprotective enzyme NAD(P)H: quinone oxidoreductase 1 (NQO1) in Hepa1c1c7 murine hepatoma cells. The electron affinity (EA) of the compounds, expressed as the energy of their lowest unoccupied molecular orbital [E (LUMO)], was evaluated using two types of quantum mechanical calculations: the semiempirical (AM1) and the density functional theory (DFT) methods. We observed striking linear correlations [r=0.897 (AM1) and 0.936 (DFT)] between NQO1 inducer potency of these compounds and their E (LUMO) regardless of the molecule size. Importantly and interestingly, this finding demonstrates that the EA is the essentially important factor that determines the reactivity of the cyanoenones with Keap1.

Correlation between electron-donating ability of a series of 3-nitroflavones and their efficacy to inhibit the onset and progression of aberrant crypt foci in the rat colon.

A series of five 3-nitroflavones were tested for their ability to inhibit the formation of colon aberrant crypt foci (ACF) induced by a s.c. injection of azoxymethane (C2H6N2O) in rats. Our aim was to relate the electron-donating effects of the 3-nitroflavones as characterized by their Hammett substitution constants with their efficacy in inhibiting ACF. In a first assay (initiation, protocol A) the 3-nitroflavone as well as the 4'-substituted nitro-, methoxy-, fluoro-, and hydroxy-3-nitroflavones were continuously present in the diet. In a second assay (postinitiation, protocol B) they were given for a period of 4 weeks after the last azoxymethane injection. The different substituents of the 3-nitroflavones at the 4'-position spanned a spectrum of Hammett constants (sigma(p+)), going from +0.79 for the electron-withdrawing group, NO2, to -0.92 for the electron-donating group, OH. For both protocols the percentages of inhibition plotted versus the Hammett substitution constants showed a linear correlation, the most efficacious ACF inhibition being produced by the molecules with the most electron-donating substituents. Moreover, the nitroflavones were not only chemoprotective during initiation of the ACF, but also therapeutic in the postinitiation progression assay. The above correlations may be of predictive value in the search for new chemoprotective agents. The overall molecular mechanism of the inhibition of ACF by the 3-nitroflavones under study appears to involve redox reactions.

Redox ranking of inducers of a cancer-protective enzyme via the energy of their highest occupied molecular orbital.

Induction of phase 2 enzymes is a major strategy in chemoprotection against cancer. Inducers belong to nine different chemical classes. In this study we found that a measure of the tendency of 30 plant phenylpropenoids and synthetic analogs to release electrons correlates linearly with their potency in inducing the activity of NAD(P)H:quinone reductase (NQO1), a prototypic phase 2 cancer-protective enzyme. The tendency to release electrons was determined by the energy of the highest occupied molecular orbital (E(HOMO)), calculated by simple quantum-mechanical methods. The correlations observed establish a clear conclusion: the smaller the absolute E(HOMO) of an agent, A, i.e., the lower its reduction potential, E(A*+/A), the stronger is its electron donor property and the greater its inducer potency. The finding of this redox ranking of the inducers demonstrates the possibility of controlling and predicting the genetic expression of an enzymatic defense against cancer by xenobiotics via one physicochemical parameter, the reduction potential, E(A*+/A).

Potency of inhibition of human DNA topoisomerase I by flavones assessed through physicochemical parameters.

DNA topoisomerases, enzymes involved in DNA replication and transcription, are known as targets for anticancer drugs. Among the various types of topoisomerase inhibitors, flavones (F) have been identified as promising compounds. In this study, it is shown that the potency of flavones acting as topoisomerase I inhibitors can be ranked according to their redox properties and their 3D structure. Linear correlations were observed between the topoisomerase I inhibition activity exerted by five flavones (chrysin, apigenin, kaempferol, fisetin, quercetin) and experimental and theoretical redox parameters of F. Moreover, theoretical calculations of the dihedral angle O(1)-2-1'-2' in the flavone molecules indicate the importance of their structural and steric features in their potency as topoisomerase I inhibitors. It is suggested that the flavones might interact with the DNA-topoisomerase I complex after their oxidation into quinones via autoxidation, enzymatic oxidation, or reactions with reactive oxygen species. Our investigation opens a new strategy quantitatively based on redox and 3D structural parameters in the search for the most active flavones as anticancer drug candidates inhibiting topoisomerase I.

Potency ranking of triterpenoids as inducers of a cytoprotective enzyme and as inhibitors of a cellular inflammatory response via their electron affinity and their electrophilicity index.

Electron affinity (EA) and electrophilicity index (omega) of 16 synthetic triterpenoids (TP), previously identified as inducers of cytoprotective enzymes and as inhibitors of cellular inflammatory responses, have been calculated by the molecular orbital method. Linear correlations were obtained by plotting the values of EA, as well as those of omega versus (i) the potencies of induction of NAD(P)H quinone reductase (NQO1, EC 1.6.99.2), a cytoprotective enzyme, expressed via the concentration of TP required to double the specific activity of NQO1 (CD value) and (ii) the values of their anti-inflammatory activity expressed via the IC-50 of TP for suppression of upregulation of inducible nitric oxide synthase (iNOS, EC 1.14.13.39), both previously experimentally determined. The observed correlations demonstrate quantitatively for a series of triterpenoids that their electrophilicity is a major factor determining their potency as inducers of the cytoprotective phase 2 response and as inhibitors of inflammatory processes.

Two-step mechanism of induction of the gene expression of a prototypic cancer-protective enzyme by diphenols.

Cancer-preventive activity by exogenous molecules can be mediated by enhancing the expression of cytoprotective enzymes [e.g, glutathione- S-transferase (GST) or NAD(P)H-quinone oxidoreductase 1 (NQO1)] via antioxidant-response elements (AREs) present in the promoter regions of their genes. Previously, potency of induction of NQO1 has been linearly correlated with the ability to release an electron from different classes of inducers, including diphenols, phenylpropenoids, and flavonoids. In the present work, we focus on the induction of NQO1 by diphenols, which we consider as a model underlying the mechanisms of action of other phenolic inducers such as phenylpropenoids and flavonoids. A two-step mechanism of NQO1 activation is proposed involving (i) oxidation of diphenol inducers to their quinone derivatives and (ii) oxidation of two highly reactive thiol groups by these quinones of a protein involved in NQO1 induction. These two putative routes are supported by linear correlations between the inducer potencies and the redox properties of diphenols and of their corresponding quinones. The linear correlations demonstrate the possibility to predict the enhanced gene expression of enzymatic defenses by diphenols from quantum mechanical calculations (i) of the ability of diphenols to release electrons and (ii) of the electron affinity of their corresponding quinones.

Monomeric azaheterofullerene derivatives RC59N: influence of the R moiety on spectroscopic and photophysical properties.

We have synthesised nine monomeric azaheterofullerene (AZA) derivatives, RC(59)N, with a wide variety of different side chains R and investigated their spectroscopic and photophysical properties in toluene and o-dichlorobenzene (ODCB). Measurements include their ground-state absorption spectra, molar absorption coefficient (epsilon(G)), fluorescence spectra, fluorescence quantum yields (Phi(F)), singlet-state lifetimes (tau(F)), triplet-state absorption spectra, triplet molar absorption coefficients (epsilon(T)), singlet oxygen (Phi(Delta)), and triplet state (Phi(T)) quantum yields. The replacement of a carbon by a nitrogen atom in the C(60) sphere strongly affects most of the spectroscopic and photophysical properties. The chemical nature of the R moiety has definite effects on these properties in contrast with minor effects on the chemical nature of the addends in [6,6]-ring bridged monoadduct methano[60]fullerene derivatives. These effects concern properties of the ground state, singlet excited state, and triplet states of our nine RC(59)N derivatives and in particular the values of photophysical parameters epsilon(G), epsilon(T), Phi(Delta), and Phi(T), which are significantly lower than those of analogous monoadduct [6,6]-ring bridged methano[60]fullerene derivatives.