Bifunctional alkylating agents

Other interesting synthetic applications of the ketone-derived enamine alkylation are found in the monomethylation of steroid enamines (249), extension of the benzylation reaction (250) to a ferrocene derivative (251), the use of a-bromoesters (252) and ketones (252) or their vinylogues (25J), in the syntheses of alantolactone (254-256), isoalantolactone (257), and with a bridged bis-enamine (258). The use of bifunctional alkylating agents is also seen in the introduction of an acetylenic substituent in the synthesis of the characteristic fragrant constituent of jasmine (259), the synthesis of macrocyclic ketolactones (260), the use of butyrolactone (261), and the intermolecular or intramolecular double alkylations of enamines with dihalides (262). 

Cross-linkage. Bifunctional alkylating agents, such as the nitrogen mustards, may form covalent bonds with each of two adjacent guanine residues. Such interstrand cross-linkages will inhibit DNA replication and transcription. Intrastrand cross-links also may be produced between DNA and a nearby protein. 

The mechanism of mutagenesis by sulfur mustard (and other mustards) involves the alkylation of DNA. As a bifunctional alkylating agent, sulfur mustard causes cross-linkage of DNA strands, as well as monofunctional alkylation products.19 Sulfur mustard and nitrogen mustard have been used In mutation studies In a variety of organisms, but data on the relative frequencies of induction of different alky-... 

Diepoxybutane is a potent bifunctional alkylating agent which reacts with DNA in vitro and in vivo. As a result, it is mutagenic in virtually all test systems including effects in somatic and germ cells of mammals exposed in vivo. In vivo, it induced DNA adducts, dominant lethal mutations and gene mutations in mice chromosomal aberrations... 

Thier, R., Muller, M., Taylor, J.B., Pemble, S.E., Ketterer, B. Guengerich, F.P. (1995) Enhancement of bacterial mutagenicity of bifunctional alkylating agents by expression of mammalian glutathione S-transferase. Chem. Res. Toxicol., 8, 465-472... 

Quinto, I. Radman, M. (1987) Carcinogenic potency in rodents versus genotoxic potency in E. coli. a correlation analysis for bifunctional alkylating agents. Mutat. Res., 181, 235-242... 

Sulfur mustard (mustard gas) remains one of the CW agents of greatest concern because of its ease of production, favorable physicochemical properties, and potent vesicant action. It is a bifunctional alkylating agent, which reacts rapidly under physiological conditions with nucleophilic sites in proteins and DNA to form covalent adducts, via an intermediate episulfonium ion (see Figure 1). In the sections below, the various adducts (as unambiguously elucidated in recent years by mass spectrometry) are addressed, and methods for their analysis are discussed. 

The final type of chemical toxicity that will be presented are the vesicants, chemicals that cause blisters on the skin. There are two classes of blisters that implicate different mechanisms of vesication. Intraepidermal blisters are usually formed due to the loss of intercellular attachment caused by cytotoxicity or cell death. The second class occurs within the epidermal-dermal junction (EDJ) due to chemical-induced defects in the basement membrane components. The classic chemical associated with EDJ blisters is the chemical warfare agent sulfur mustard (bis-2-chloroethyl sulfide HD). HD is a bifunctional alkylating agent that is highly reactive with many biological macromolecules, especially those containing nucleophilic groups such as DNA and proteins. 

Minsavage, G.D., Dillman lii, J.F. (2007). Bifunctional alkylating agent-induced p53 and nonclassical nuclear factor-kappa B (NF-ICB) responses and cell death are altered by caffeic acid phenethyl ester (CAPE) a potential role for antioxidant/elec-trophilic response element (ARE/EpRE) signaling. J. Pharmacol. Exp. Ther. 321 202-12. 

As pointed out earlier, cycloalkylation reactions can also result from the reaction of arenes with bifunctional alkylating agents or in cases where bifunctional intermediates are involved. An example of the former is shown in equation (114), where a chiral, lactone-substituted alkene cyclizes with the arene to produce a chiral tetrahydronaphthalene derivative. 

Busulfan is a bifunctional alkylating agent. It consists of two methanesulfonate groups attached at opposite ends of a four-carbon alkyl chain. Alkylating agents form covalent DNA interstrand cross-links that inhibit DNA synthesis. Toxicity of busulfan s alkylation of intercellular nucleophiles is associated with its... 

Chlorambucil is a cytotoxic agent. As a bifunctional alkylating agent, it causes breaks in DNA thus interfering with DNA replication and transcription. 

More recently a group of halogenated sugars have been found to have similar properties to the bifunctional alkylating agents 1. 1,6-Dibromo- 1,6-dideoxy-D-mannitol, for example (DBD, Mitobronitol 10) is now in clinical use, but it is believed to act at least in part by transformation in vivo to the bis epoxide... 

Despite obvious similarities to the bifunctional alkylating agents, the nitrosoureas have a completely different spectrum of anti-tumour action. Although little is known about their mechanism of action, they can break down in vivo... 

Bifunctional alkylating agent (two reactive groups) forms inter-and intrastrand DNA cross-links inhibits DNA, RNA, and protein synthesis... 

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