Nitrogen mustards development

The discovery of penicillin and its successful application in World War II inspired the antibiotic era, and a broad search for other cures for infectious diseases. Cancer has a totally different cause, as it arises through the malignant mutation of normal cells instead of from the actions of bacterial or other outside organisms. Penicillin destroys the bacteria cell walls, but not the mammalian cell membranes. Unless a dmg could be found that could tell the difference between a normal cell and a cancer cell, then it was not clear that there would be an effective cancer drug, that is until the first report by Goodman in 1946 that nitrogen mustard, developed as a war gas, was an effective chemotherapeutic for human leukemia. 

According to a hypothesis launched by Larionov et al in the 1960s, some new nitrogen mustard derivatives were developed. They contain metabolites and heterocyclic structures as carriers of the cytotoxic chloroethylamine groups. By this way the synthesis of aliylating metabolites started melphalan (sarcolysine) as L- or DL-phenylalanine derivative prospidine with a tricyclic piperazine moiety and chlorambucil as butyric acid derivative. It was proven that each alkylating metabolite has its own spectrum of selective antitumor activity. 

Chemotherapy of cancer started in the early 1940s when nitrogen mustard was administered to patients with lymphoma. Since then, numerous agents have been developed for the treatment of different cancers. 

Nitrogen mustard agents were introduced before the development of nerve agents. Nitrogen mustard agent HN-1 was developed by accident by the German and Czech pharmaceutical industries. It was originally developed to remove warts and kill... 

Much the most developed example of prodrug activation comes from our own laboratory. The cytotoxicity of nitrogen mustards is dependent on substitution on the nitrogen atom electron-withdrawing substituents... 

Anslow, W.P., and Houck, C.R. Systemic pharmacology and pathology of sulfur and nitrogen mustards. IN Chemical Warfare Agents, and Related Chemical Problems, 2 vol. (Summary Technical Report of Division 9, National Defense Research Committee) Washington, D.C. Office of Scientific Research and Development. 1946. p. 440-478. 

In some instances, researchers are able to develop separate Hansch equations for both activity and toxicity of a drug. Differing parameters between the activity and toxicity QSAR equations allow researchers to optimize properties that boost desired activity and minimize toxicity. The following two QSAR equations give the activity (12.d) and toxicity (12.e) for a series of nitrogen mustard antitumor compounds (see Chapter 6). Based on these equations, is it likely that a nontoxic nitrogen mustard will be developed Explain. 

Mechlorethamine [me klor ETH a meen] was developed as a vesicant (nitrogen mustard) during World War I. Its ability to cause lymphocytopenia led to its use in lymphatic cancers. Because it can bind and react at two separate sites, it is called a bifunctional agent. ... 

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... 

Haskin, D. (1948). Some effects of nitrogen mustards on the development of the external body form in the fetal rat. Anat. Rec. 102 493-511. 

The action of thalidomide on the production of limb abnormalities in the chick are similar to those produced by nitrogen mustard (165). Only mesodermal tissues are affected differentiation is arrested and the mesodermal cells regroup beneath the ectodermal cap. The latter no longer induces development of the proximal portion of the limb, but only of its terminal part, which explains the occurrence of phocomelia. 

There may be no skin lesions following mild vapor exposures. However, severe vapor or liquid exposure to nitrogen mustard will produce effects similar to those of sulfur mustard (but the onset is sooner than with sulfur mustard). These effects include erythema, irritation, and itching, with blisters developing in the erythematous areas. 

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