Open-chain nitrogen compounds. Part XIV. Synthesis of 1-aryl-3-aryloxymethyl-3-methyltriazenes and 1-aryl-3-(hydroxyaryl)methyl-3-methyltriazenes

Abstract

The synthesis of a new series of I-aryl-3-aryloxymethyl-3-methyltriazenes (2) has been achieved by the reaction of the acetoxymethyltriazene (Ar-N=N-NMe-CH,OAc) with the appropriate phenol in dry chloroform solution. Tnazenes of type 2 are also formed by reaction of the acetoxymethyltriazene with the sodium phenolate, generated by reaction of the phenol with sodium hydride in dry chloroform, but under these conditions a second product is formed, which has been identified as an isomer of 2. The structure of the second product has been elucidated by spectroscopic analysis to be the I-aryl-3-(hydroxyaql)methyl-3-methyltriazene (3). The formation of these two isomeric products is accounted for by the ambident nature of the nucleophilic phenolate ion in the displacement of the acetoxy leaving group. The mass spectra of all the triazenes of type 2 exhibit a fairly intense peak at M -102, which is suggested to arise from a novel intramolecular rearrangement. Two examples of the triazenes of type 2 have been tested for antitumour activity on the NCI tumour panel and have shown statistically significant differential sensitivity in several cell lines. Preliminary investigation of the stability of these triazenes in physiological-pH buffer suggests that they may have the appropriate chemical stability for pro-drug application in therapy.Key words: triazene, synthesis, antitumour, phenol, spectroscopy, aryloxymethyltriazene, prodrugs. On a effectuC la synthkse d'une nouvelle sCrie de 1-aryl-3-aryloxymCthy1-3-mCthyltriaz6nes (2) par la reaction, en solution dans du chloroforme sec, de l'acCtoxymCthyltriazi3ne (Ar-N=N-NMe-CH,OAc) avec le phenol approprie. Le rkaction de I'acCtoxymCthyltriazkne avec le phenolate de sodium, genere par une reaction du phenol avec l'hydrure de sodium dans du chloroforme sec, conduit aussi a la formation des triazttnes du type 2; toutefois, dans ces conditions, il y a formation concomitante d'un autre produit que l'on a identifie comme un isomere du produit 2. Sur la base d'analyse spectroscopiques, on a Ctabli que le second produit est le I-aryl-3-(hydroxyaryl)mCthyl-3-mCthyltriazene (3). On explique la formation de ces deux produits isom2riques par la nature ambidente de l'ion phCnolate nucleophile dans la reaction de substitution du groupement acktoxyle nuclCofuge. Les spectres de masse des triazenes de type 2 prksentent tous un pic assez intense M -102 qui proviendrait d'un nouvel exemple de rearrangement intramolCculaire. On a Cvalu6 deux des triazenes de type 2 pour leur activitk antitumorale sur un ensemble de tumeurs NCI; ces produits prksentent des sensibilites diffkrentielles statistiquement significatives dans plusieurs lignCes de cellules. Une Ctude prCliminaire de la stabilite de ces triazknes dans des tampons a pH physiologique suggere qu'ils ont peut-Ctre la stabilitk chimique approprike pour &tre utilisCs cornrne prC-mCdicaments.

Triazenes: A Versatile Tool in Organic Synthesis

“…The groups of Vaughan40, 41 and Rosa42, 43 have synthesized hydroxymethyl derivatives of triazenes for studies relating to the development of prodrugs. Rosa and co‐workers have developed a general synthetic method for these systems, which involves loss of water in acidic solution followed by nucleophilic attack of the iminium ion by an alcohol 44.…”

Sustained antiproliferative mechanisms by RB24, a targeted precursor of multiple inhibitors of epidermal growth factor receptor and a DNA alkylating agent in the A431 epidermal carcinoma of the vulva cell line

“…Despite the significant body of results that confirm its formation during the process of hydrolysis of acetoxymethyltriazenes (Hemens et al, 1984;Hemens and Vaughan, 1986;Iley, 1987;Vaughan and Manning, 1988;Merrin and Hooper, 1992), its implication in the DNA-damaging properties of the latter class of compounds is yet to be demonstrated. In contrast, it is now common knowledge that the methyldiazonium is capable of inducing significantly high levels of DNA alkylation particularly at N7 and O6 positions of guanine, thereby inducing DNA damage and lethal mutations in tumour cells (Bodell et al, 1985;Tisdale, 1987;Baer et al, 1993).…”

Towards an efficient prodrug of the alkylating metabolite monomethyltriazene: Synthesis and stability of N-acylamino acid derivatives of triazenes

“…However, dimethyltriazenes are poorly metabolised by humans [12]. Consequently, with the aim of finding suitable prodrugs that by-pass the need for this oxidative metabolism, alongside hydroxymethyltriazenes 3 themselves [13], a range of derivatives of 3 and 4, including alkyl ether, aryl ether, alkanethioether, and acyl ester derivatives of 3 and acyl, acyloxymethylcarbamate and ureido derivatives of 4, have been synthesised by several groups, including ourselves [14][15][16][17][18][19][20][21][22][23][24][25]. Indeed, one such compound, the imidazo[3,4-e]tetrazin-5-one temozolomide 5, [18] has received FDA approval for the treatment of a specific type of brain cancer, anaplastic astrocytoma (http://www.fda.gov/cder/da/da0899.htm).…”