Monofunctional inducers

Moreover, the induction of phase 2 enzymes by curcumin is independent on AhR or CYP1A1, thus curcumin is classified as a monofunctional inducer [Dinkova-Kostova and Talalay, 1999]. 

Recently, it has been found that, in addition to its detoxification function and its function as a biomarker for up-regulation of other phase II enzymes, up-regulation of quinone reductase by monofunctional inducers may play a role in the stabilization of p53, the protein product of a tumor suppressor gene, which induces growth arrest and apoptosis. Sulforaphane has also been shown to mediate growth arrest and induce cell cycle arrest and apoptosis in many cancer cell lines, including those of human prostate, colon, and T-cell leukemia origin. - The exact mechanisms, and whether all the bioactivities of sulforaphane involve the ARE, are not yet understood. 

Figure 1 Transcriptional regulation of the rat GSTA2 and NQOl genes by bifunctional and mono functional inducers. The bifunctional inducers and the dioxin TCDD bind to and activate the AhR, which then translocates into the nucleus and associates with ARNT to activate transcription through the XRE. The bifunctional inducers can also activate transcription through the ARE via a separate pathway following their biotransformation into reactive metabolites that have characteristics of the monofunctional inducers. The monofunctional inducers can only act through the ARE-mediatedpathway. 3-MC, 3-methylcholanthrene B(a)P, benzo(a)pyrene TCDD, 2,3,7,8-tetrachlorodibenzo-/>-dioxin.

Monofunctional inducers share certain common chemical properties. They are electrophilic compounds that are capable of reacting with sulfhydryl groups in addition, certain compounds can also undergo oxidation-reduction reactions (28). The bifunctional inducers acquire these properties following oxidative metabolism. Compounds such as the isothiocyanates and diethyl maleate do not require metabolism and can directly react with sulfhydryl groups, oxidizing cysteine... 

Withanolides 26 and 27 isolated by Minguzzi and co-workers from A. arborescens were very potent as monofunctional inducers of quinone reductase (CD value), but their selectivity (Cl value) was marginal [22],... 

Nylon resins are made by numerous methods (53) ranging from ester amidation (54) to the Schotten-Baumann synthesis (55). The most commonly used method for making nylon-6,6 and related resins is the heat-induced condensation of monomeric salt complexes (56). In this process, stoichiometric amounts of diacid and diamine react in water to form salts. Water is removed and further heating converts the carboxylate functions to amide linkages. Chain lengths are controlled by small amounts of monofunctional reagents. The molten finished nylon resin can be dkectly extmded to pellets. 

Secondly, the interaction of hindered amines with hydroperoxides was examined. At room temperature, using different monofunctional model hydroperoxides, a direct hydroperoxide decomposition by TMP derivatives was not seen. On the other hand, a marked inhibitory effect of certain hindered amines on the formation of hydroperoxides in the induced photooxidation of hydrocarbons was observed. Additional spectroscopic and analytical evidence is given for complex formation between TMP derivatives and tert.-butyl hydroperoxide. From these results, a possible mechanism for the reaction between hindered amines and the oxidizing species was proposed. 

Further experiments focused therefore on [RuCl(en)(r 6-tha)]+ (12) and [RuCl(rj6-p-cym)(en)]+ (22), which represent the two different classes, and their conformational distortion of short oligonucleotide duplexes. Chemical probes demonstrated that the induced distortion extended over at least seven base pairs for [RuCl(rj6-p-cym)(en)]+ (22), whereas the distortion was less extensive for [RuCl(en)(rj6-tha)]+ (12). Isothermal titration calorimetry also showed that the thermodynamic destabilization of the duplex was more pronounced for [RuCl(r 6-p-cym)(en)]+ (22) (89). DNA polymerization was markedly more strongly inhibited by the monofunctional Ru(II) adducts than by monofunctional Pt(II) compounds. The lack of recognition of the DNA monofunctional adducts by HMGB1, an interaction that shields cisplatin-DNA adducts from repair, points to a different mechanism of antitumor activity for the ruthenium-arenes. DNA repair activity by a repair-proficient HeLa cell-free extract (CFE) showed a considerably lower level of damage-induced DNA repair synthesis (about six times) for [RuCl(en)(rj6-tha)] + compared to cisplatin. This enhanced persistence of the adduct is consistent with the higher cytotoxicity of this compound (89). 

Natarajan, A.T., Simons, J.W.I.M., Vogel, E.W. van Zeeland, A.A. (1984) Relationship between cell killing, chromosomal aberrations, sister-chromatid exchanges and point mutations induced by monofunctional alkylating agents in Chinese hamster cells. A correlation with different ethylation products in DNA. Mutat. Res., 128, 31-40... 

Prochaska HJ, Talalay P. 1988. Regulatory mechanisms of monofunctional and bifunctional anticarcinogenic enzyme inducers in murine liver. Cancer Res 48 4776-4782. 

The monofunctional tryptase inhibitor APC-366 (Axys Pharmaceuticals) reduces the acute airway response and histamine release to allergen in a pig model of allergen-induced asthma [19]. APC-366 is also effective in a sheep model of allergen-induced asthma but was only poorly effective in asthma patients (proof-of-principle) [8], The compound was in clinical development phase II for asthma (inhalative). Although highly selective for tryptase over plasmin and plasma kal-likrein, APC-366 was not selective against thrombin and trypsin [13], Another monofunctional tryptase inhibitor is bis(5-amidino-2-benzimidazol-yl)methane (BABIM) which has been shown to be effective in the sheep. Further development of the compound was, however, discontinued, maybe because of the lack of selectivity over trypsin [13, 16, 17] (Figure 3.2.2). 

From these experiments it can be concluded that the closure of the monofunctional adducts depends upon the presence of other adducts in its vicinity. Although a systematic study has not yet been done, the interference between two or more adducts is expected to be a function of several parameters, such as the nature and the number of base pairs between the adducts, the DNA supercoiling, the local environment of the DNA, in addition to the distortions of the DNA double helix induced by the adducts, which are also function of these parameters. DNA has to be platinated at a low drug-to-nucleotide residue ratio when in vitro and in vivo experiments are compared. This holds also for cisplatin-modified DNA, but is masked by the preferential binding of cisplatin to runs of guanine residues and the ability of the monofunctional adducts to react with the adjacent residues. 

Fleer R, Brendel M. 1982. Toxicity, interstrand cross-links and DNA fragmentation induced by activated cyclophosphamide in yeast Comparative studies on 4-hydroxyperoxy-cyclophosphamide, its monofunctional analogue, acrolein, phosphoramide mustard, and nor-nitrogen mustard. Chem Biol Interact 39 1-15. 

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