Alkylating agents, triazenes

Other subgroups of alkylating agents are the nitrosoureas (examples carmustine, BCNU lomustine, CCNXJ) and the triazenes (example dacarbazine, DTIC). Platinum derivatives (cisplatin, carboplatin, oxaliplatin) have an action that is analogous to that of alkylating agents (formation of crosslinks) and therefore are appended to this class, as well. 

The main drawback to this reaction is the toxicity of diazomethane and some of its precursors. One possible alternative is the use of alkyltriazenes as reactive alkylating agents.52 Alkyltriazenes are readily prepared from primary amines and aryldiazonium salts.53 The triazenes, on being protonated by the carboxylic acid, generate a reactive alkylating agent that is equivalent, if not identical, to the alkyldiazonium ions generated from diazoalkanes. 

Safety Note. Because acyclic triazenes are potent biological alkylating agents, it is only prudent to assume that triazolines are also potentially toxic and carcinogenic. Efficient hoods and protective clothing should be used in working with these substances. Alkyl azides are treacherously explosive and should be treated with extreme caution. Wherever possible these compounds should only be handled as solutions. 

Table 3. The effect of different classes of anti-tumour agent on some transplanted tumours. The TLX5 (R) is a line with acquired resistance to a triazene and is cross resistant to BCNU. Triazenes and BCNU are active against tumours which do not respond to anti-metabolites and others that are insensitive to alkylating agents. The platinum complex was cis dichloro-bis(cyclopentylamine)platinum(II) and the triazene 5-(3,3-dimethyl-l-triazeno)-4-carbethoxy-2-me thy limidazole...

Like the triazenes, the nitrosoureas show many points of resemblance to the difunctional alkylating agents. They inhibit a range of animal tumours sensitive to alkylating agents, but not a hamster tumour with acquired resis-... 

Increased activity of DNA repair pathways, which may differ for the various alkylating agents. Thus, increased activity of the complex nucleotide excision repair (NER) pathway seems to correlate with resistance to most chloroethyl and platinum adducts. Alkyl guanine transferase (AGT) activity determines response to BCNU and to methylating drugs such as the triazenes, procarbazine, and busulfan ... 

A soln. of p-chlorobenzenediazonium hexafluorophosphate in dimethylform-amide added slowly with stirring at — 5° to a mixture of n-butylamine, powdered Na-carbonate, and dimethylformamide, warmed to 0°, and stirred a few min. until a negative test is obtained with 2-naphthol, ether added, filtered, the filtrate washed and dried, this soln. of the resulting crude l-(n-butyl)-3-(4-chlorophenyl)triazene (Y ca. 100% when isolated) treated with ethereal 3,5-dinitrobenzoic acid, and kept 1-2 hrs. at 25° until Ng-evolution ceases n-butyl 3,5-dinitrobenzoate. Y 63-73%.— Triazenes may be used as alkylating agents for carboxylic acids, phenols, mercaptans, and certain alcohols. F. e. s. E. H. White and H. Scherrer, Tetrah. Let. 1961, 758. 

R. Preussmann, H. Druckrey, S. Ivankovic, and A. von Hodenberg, Chemical structure and carcinogenicity of aliphatic hydrazo, azo, and azoxy compounds and of triazenes, potential in vivo alkylating agents, Ann. N. Y. Acad. Sci. 163, 697-714 (1969). 

Those carcinogens that are proximate mutagens in Salmonella are chemicals that S-9 can metabolize to reactive species like alkylating and arylat-ing agents. Proximate mutagens generally activated by S-9 include triazenes, azoxy compounds, A -nitrosamines, aromatic amines, polyaromatics, heteroaromatics, and some proximate mustards. The nitroaromatics, though active without activation per se, are metabolized by bacterial nitroreductases to their reactive forms. 

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