Nitrogen mustards types

Another type of dehalogenation occurs in xenobiotic metabolism, namely halide elimination with cyclization. These intramolecular nucleophilic substitutions are discussed in Sect. 11.4.2 (nitrogen mustards) and 11.8. 

Another interesting reaction is cyclization with halide elimination. The case of formation of aziridinium rings from A-(2-chloroethyl) derivatives (nitrogen mustards) has been reviewed in Sect. 11.4.2, as was sulfur mustard. The remainder of this subsection is devoted to comparable reactions in which the product is not a strongly electrophilic aziridinium ion, but another ring type. 

Alkylating agents were the first drugs to be used to treat highly proliferating cancers. They are mainly of two types the relatively non-specific nitrogen mustards and the even less selective nitrosoureas. 

Since the formation of the ethyleniminium ion is crucial for the cytotoxic activity of the nitrogen mustards, it is not surprising that stable ethylenimine derivatives have antitumor activity. Thiophospho-ramide or thiotepa is the best known compound of this type that has been used clinically. Both thiotepa and its primary metabolite, triethylenephos-phoramide (TEPA), to which it is rapidly converted by hepatic mixed-function oxygenases form crosslinks with DNA. It is mainly used as an intravesicu-lar agent in bladder cancer. Thiotepa produces little toxicity other than myelosuppression. 

Modem cancer chemotherapy originated in the 1940s with the demonstration that nitrogen mustard possessed antitumor activity against human lymphomas and leukemias. Approximately 10 types of human cancer have 40 to 80% cure rates using chemotherapy alone or chemotherapy plus surgery or radiation (Table 55.1). For this purpose cure is defined as the disappearance of any evidence of tumor for several years and a high actuarial probability of a normal life span. 

The production of human (Cu,Zn)-SOD by genetic engineering could make sufficient amounts available for a further testing of the promising applications in auto-inunune and inflammatory diseases, and as an adjuvant in the radio- and chemotherapy of certain types of tumors. In this respect the hemolysis observed as a secondary effect in patients treated with nitrogen mustards could be ascribed to a striking reduction of the (Cu,Zn)-SOD levels in their erythrocytes... 

All major mass spectral data collections consist of El mass spectra, mostly recorded under accepted standardized conditions such as an ionization voltage of 70 eV, an emission current of 100-200 xA, and an ion source temperature of 150-200°C. Several types of GC/MS systems may be applied, for instance, magnetic sector, quadrupole, or ion trap analyzers. Ion trap systems are considered less applicable, when data comparison is required with spectra from a reference library. In particular, basic compounds related to VX or the three nitrogen mustards tend to produce protonated molecular ions by self-protonation. Magnetic sector and quadrupole mass spectrometers suffer less from interference of self-protonation, and spectra produced with these types of instruments are generally reproducible. 

Chlornaltrexamine (/f-CNA, 15) another naltrexone derivative modified at C-6, is a nonequilibrium antagonist which blocks irreversibly the three major opioid receptor types (ji, k and 8). Portoghese and his collaborators have developed this compound as the first affinity labelling agent of its class [58-61]. Compound (15) has an alkylating function at C-6 (classic nitrogen mustards) able to bind covalently to opioid receptors. In the tail flick assay in mice, /f-CNA inhibited morphine-induced antinociception for 3-6... 

CWAs have been widely eondemned since they were first used on a massive scale during World War I. However, they are still stockpiled and used in many countries as they are cheap and relatively easy to produee, and can cause mass casualties. Although the blood agent CK is extremely volatile and undergoes rapid hydrolysis, the degradation of three types of vesicant CWAs, the sulfur mustards, nitrogen mustards, and Lewisite, results in persistent products. For... 

Carcinogens can be divided into two general types those that act directly and those that act indirectly. Direct-acting carcinogens are those that interact with cellular constituents such as protein, lipids, and nucleic acids. There are relatively few direct-acting carcinogens (e.g., bis(chloromethyl)ether, ethylene oxide, and nitrogen mustard). 

Once it was appreciated that the nitrogen mustards were acting as electrophilic reactants, alkylating essential cellular macromolecules, other types of chemical with similar properties were tested for their tumour inhibitory action. 

It is interesting to compare the relative toxicities of the two extreme types of nitrogen mustard. Over 90% of mechlorethamine is destroyed within... 

By chemically reacting with nitrogen and oxygen atoms in DNA, these compounds can modify bases in DNA so as to distort the normal pattern of base pairing. If these modified nucleotides are not repaired, they allow an Incorrect nucleotide to be incorporated during replication. This type of carcinogen includes ethylmethane sulfonate (EMS), dimethyl sulfate (DMS), and nitrogen mustards. 

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