Nitrogen Mustard bis

Osborne MR, Wilman DE and Lawley PD (1995). Alkylation of DNA by the nitrogen mustard bis(2-chloroethyl)methylamine. Chem Res Toxicol, 8, 316-320. 

Nitrogen mustards bis(2-Chloroethyl) ethylamine HNl CHjCHzCI CHjCHz N GHjCHiCI Ethyldiethanolamine EDEA CH2CH2OH CHsCHz N CHzCHzOH... 

Write a mechanism for the hydrolysis of the nitrogen mustard bis(2-chloroethyl) methylamine. 

Some hydantoias are very useful carriers of the nitrogen mustard moiety bis (P-chloroethyl)amine, and are useful ia several tumors and multiagent therapy regimens (128,129). Besides that, some 3-(2-chloro-ethyl)hydantoiQS (32) (130) and oxyranyLmethyUiydantoias, eg,... 

The adventitious discovery of the antitumor action of the nitrogen mustard poison war gases led to intensive investigation of the mode of action of these compounds. In brief, it has been fairly well established that these agents owe their effect to the presence of the highly reactive bis(2-chloroethyl)amine group. The cytotoxic activity of... 

Therapeutic Function Cancer chemotherapy Chemical Name 4-[bis(2-chloroethyl)amino]-L-phenylalanine Common Name Alanine nitrogen mustard L-sarcolysine Structural Formula... 

O. M. Friedman and E. Boger, Colorimetric estimation of nitrogen mustards in aqueous media. Hydrolytic behavior of bis(2-chloroethyl)amine, nor-HN2. Analytical Chemistry, 1961,33,906-910. 

Figure 14.6 Resonance stabilization of reactive intermediates from (i) bis(chloromethyl) ether, (ii) aliphatic nitrogen mustard, (iii) allyl chloride, (iv) benzyl chloride, (v) bis(morpholino)methane, (vi) benzoyl chloride, and (vii) dimethylcarbamyl chloride.

The activity of nitrogen mustards depends on the presence of a bis-(-2-chloroethy 1) grouping ... 

Cyclophosphamide (6.31) is a nitrogen mustard used for cancer treatment (Scheme 6.9). In the body, cyclophosphamide is oxidized to aminal 6.32. Compound 6.32 opens and loses acrolein to form phosphoramide mustard (6.33). Structure 6.33 is a strong bis-electrophile and reacts readily with nucleophiles. In DNA, the nucleophile tends to be N7 of guanine, which is oriented outward into the major groove (Figure 6.6). By reacting twice, 6.33 crosslinks DNA either within the same strand (intrastrand) or across the double helix (interstrand).16... 

Chemically, it is a bis(2-chloroethyl)amine (a nitrogen mustard), and its biological activity is related to the ability to function as an alkylating -gent in physiological conditions. 

Melphalan and the racemic analog have been prepared by two general routes (Scheme I). In Approach (A) the amino acid function is protected, and the nitrogen mustard moiety is prepared by conventional methods from aromatic nitro-derivatives. Thus, the ethyl ester of N-phthaloyl-phenylalanine was nitrated and reduced catalytically to amine I. Compound I was reacted with ethylene oxide to form the corresponding bis(2-hydroxyethyl)amino derivative II, which was then treated with phosphorus oxychloride or thionyl chloride. The blocking groups were removed by acidic hydrolysis. Melphalan was precipitated by addition of sodium acetate and was recrystallized from methanol. No racemization was detected [10,28—30]. The hydrochloride was obtained in pure form from the final hydrolysis mixture by partial neutralization to pH 0.5 [31]. Variants of this approach, used for the preparation of the racemic compound, followed the same route via the a-acylamino-a-p-aminobenzyl malonic ester III [10,28—30,32,33] or the hydantoin IV [12]. 

Nitrogen mustards include HNl [bis(2-chloroethyl) ethylamine], HN2 (2,2 -dichloro-V-methyldiethylamine), and HN3 [tris(2-chloroethyl)amine hydrochloride]. As will be discussed later, some of these found application in therapeutic arenas rather than in warfare. 

Philips, F.8., Thiersch, J.B. (1950). The nitrogen mustard-like actions of 2,4,6-tris (ethylenimino)-s-triazine and other bis(ethylenimines). J. Pharmacol. Exp. Ther. 100 398 07. 

Goodman, L.S., Wintrobe, M.M., Dameshek, W., Goodman, M.J., Gilman, A., McLennan, M.T. (1984). Landmark article Sept. 21, 1946 nitrogen mustard therapy. Use of methyl-bis(beta-chloroethyl)amine hydrochloride and tris(beta-chloroethyl)-amine hydrochloride for Hodgkin s disease, lymphosarcoma, leukemia and certain allied and miscellaneous disorders. JAMA 251 2255-61. 

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