Aromatic amines, structure-activity

The imidazole ring is a privileged structure in medicinal chemistry since it is found in the core structure of a wide range of pharmaceutically active compounds efficient methods for the preparation of substituted imidazole libraries are therefore of great interest. Recently, a rapid synthetic route to imidazole-4-carboxylic acids using Wang resin was reported by Henkel (Fig. 17) [64]. An excess aliphatic or aromatic amine was added to the commercially available Wang-resin-bound 3-Ar,M-(dimethylamino)isocyano-acrylate, and the mixture was heated in a sealed vial with microwave irradi-... 

Various phenallcylamines were shown to produce either DOM-like or AMPH-like stimulus effects the structure-activity requirements for these activities are different from the standpoints of aromatic substitution patterns, terminal amine substituents, and optical activity. Thus, it has been possible to formulate two distinct SARs. It should be realized, however, that phenalkylamines need not produce only one of these two types of effects certain phenallcylamines can produce pharmacological effects like neither DOM nor AMPH. Moreover, they can produce effects that are primarily peripheral, not central, in nature (Glennon 1987a). The fact that an agent produced DOM- or AMPH-like effects does not imply that it carmot produce an additional effect conversely, if an agent does not produce either DOM- or AMPH-like stimulus effects, it is not necessarily inactive. 

Shinkai s 38 is also a PET system whose fluorescence is controlled by Na" binding to a coordinatively active spacer which is a calix[4]aiene tetraester in this case. However, the through-space distance between the photoactive termini is expanded by Na complexation, thus reducing the PET efficiency. Kuhn s 39 is not dissimilar in that a PET-type quencher (a nitroaromatic unit) is held away from the lumophore by Ca binding. However a conventional lumophore-spacer-receptor is also contained within 39 as found in 24. At this point it would not be out of place to mention several important studies on the control of PET/EET by ion binding to a coordinatively active spacer between photoactive terminii." " System 36 is structurally related to Verhoewen s 40 since they both contain an aromatic lumophore and an aromatic amine with one or more interposed aliphatic amines. System 40 also displays the functional similarities that PET processes were... 

Fortunately, there is now a comprehensive body of knowledge on the metabolic reactions that produce reactive (toxic) intermediates, so the drug designer can be aware of what might occur, and take steps to circumvent the possibility. Nelson (1982) has reviewed the classes and structures of drugs whose toxicities have been linked to metabolic activation. Problem classes include aromatic and some heteroaromatic nitro compounds (which may be reduced to a reactive toxin), and aromatic amines and their N-acylated derivatives (which may be oxidized, before or after hydrolysis, to a toxic hydroxylamine or iminoquinone). These are the most common classes, but others are hydrazines and acyl-hydrazines, haloalkanes, thiols and thioureas, quinones, many alkenes and alkynes, benzenoid aromatics, fused polycyclic aromatic compounds, and electron-rich heteroaromatics such as furans, thiophenes and pyrroles. 

Discovered over a century ago, electrophilic mercuration is probably the oldest known C-H bond-activation reaction with a metal compound. The earliest examples of aromatic mercuration were reported by Volhard (mercuration of thiophene) [1], Pesci (mercuration of aromatic amines) [2], and Dimroth [3], who was the first to mercurate benzene and toluene, generalize the reaction, and assign the correct structures to the products originally observed by Pesci. Since the work of Dimroth electrophilic aromatic metalation reactions with compounds of other metals, for example Tl(III), Pb(IV), Sn(IV), Pt(IV), Au(III), Rh(III), and Pd(II), have been discovered [4], In this chapter, we will focus on intermolecular SEAr reactions involving main-group metal electrophiles and resulting in the formation of isolable metal aryls which find numerous important applications in synthesis [5], Well-known electrophilic cyclometalation reactions, for example cyclopalla-dation can be found in other chapters of this book and will not be reviewed here. 

Exposure of cells to carcinogens may result in the formation of DNA adducts varying in size from methyl groups to bulky structures, such as metabolites of polycyclic aromatic hydrocarbons and aromatic amines. In vivo, these adducts usually are removed enzymatically and at different rates from the DNA. Because the liver is the main site of activation of chemical carcinogens, the DNA of this organ usually forms more adducts. Direct detection and measurement of DNA damage are thus possible, in principle, by detection and measurement of the bound adduct. Because the number of adducts is usually extremely small, very sensitive methods cure required for their measurement. 

Benigni, R., Giuliani, A., Franke, R., and Gruska, A., Quantitative structure-activity relationships of mutagenic and carcinogenic aromatic amines, Chem. Rev., 100, 3697-3714, 2000. 

Benigni, R. and Passerini, L., Carcinogenicity of the aromatic amines from structure-activity relationships to mechanisms of action and risk assessment, Mutation Res. Rev., 511, 191-206, 2002. 

Aryldiazonium salts are weak electrophiles. Consequently, they undergo Ar-SE reactions via sigma complexes (azo couplings) only with the most strongly activated aromatic compounds. Only phenolates and secondary and tertiary aromatic amines react with them. Primary aromatic amines react with diazonium salts, too, but via their N atom. Thus, triazenes, that is, compounds with the structure Ar—N=N—NH—Ar are produced. Phenol ethers or nonde-protonated phenols can react with aryldiazonium salts only when the latter are especially good... 

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