Nitrogen Mustards

2.1. Introduction

Sulfur mustard (mustard gas, yperite) was used in World War I for chemical warfare because it is an extremely irritant vesicant agent. After the war, it was realized that it also caused systemic effects such as leukopenia, aplasia of the bone marrow, dissolution of lymphoid tissue, and ulceration of the gastrointestinal tract. This suggested a possible role for this compound in cancer treatment, but after an exploratory study it was considered too toxic for systemic use.4 A nitrogen analog of sulfur mustard known as mechlorethamine (mustine), the first nitrogen mustard, was also initially conceived as a chemical weapon, but it was applied to a lymphosarcoma patient in 1943 following the observation in autopsies that exposure to mechlorethamine led to profound lymphoid and myeloid suppression after an air attack on a ship carrying a stock of this substance. This study was classified at the time and was not published until 1946, starting the modern era of cancer chemotherapy.5 Even at this early stage, it was soon apparent that the therapeutic effect was limited by marrow toxicity and the development of resistance, which are still a source of problems in cancer chemotherapy nowadays. These problems notwithstanding, mechlorethamine is still used for the chemotherapy of Hodgkin's lymphoma as part of some antitumor regimes.

Sulfur mustard Mechlorethamine

Sulfur mustard Mechlorethamine

2.2. DNA alkylation by nitrogen mustards and cytotoxicity mechanisms

Because of the relative unreactivity of alkyl chlorides as electrophiles, direct attack of DNA nucleophilic centers to nitrogen mustards under physiological conditions is too slow to be of therapeutic relevance. The reason why nitrogen mustards have a high reactivity as alkylating agents under mild conditions is the anchimeric assistance from the nitrogen atom, that is, the formation through an intramolecular nucleophilic substitution of the aziridinium cation 5.1, which is highly reactive because of the positive charge at the leaving group and the high strain of the three-membered ring, which is relieved in the alkylation process. Since the most nucleophilic atom in DNA is the N-7 nitrogen of guanine, the most common species arising from alkylation is 5.2 (Fig. 5.2).

As mentioned in Section 1 , one consequence of alkylation is the alteration of the normal pairing of DNA bases between adenine-thymine and guanine-cytosine (Watson-Crick base pairs). For instance, the three hydrogen bonds normally linking guanine and cytosine require the existence of a carbonyl group at the purine C-6 position. Because alkylation at N-7 creates a positive charge on this center, which is adjacent to the partial positive charge at C-6 due to the electron deficiency of the carbonyl group, the tautomeric equilibrium in guanine is displaced to the more stable 6-hydroxy form.6 This change in the normal tautomeric form converts hydrogen bond acceptor groups into donors, and vice versa.

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Responses

  • demsas alem
    How sulfur mustered as anticancer drug?
    1 year ago

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