Open-chain nitrogen compounds. Part V. Hydroxymethyltriazenes: synthesis of some new alkyl homologues of the anti-tumour 3-methyl-3-hydroxymethyltriazenes and preparation of the derived acetoxymethyl-, benzoyloxymethyl-, and methoxymethyltriazenes

Abstract

TANG. Can. J . Chcm. 62, 741 (1984).The synthesis of somc ncw I-aryl-3-alkyl-3-hydroxymcthyltriazcncs is dcscribcd. Thc mcthod of coupling a diazonium salt with an alkylamine/formaldchyde mixture has been cxtcndcd to (a) somc diazonium ions withl~trrtr substituents other than -M groups, (b) those with substituents in thc nrthn position. and (c) to homologous alkylamincs (c.g. cthylamine, propylaminc, ctc.). Hydroxymethyltriazencs can also bc prcparcd by the rcaction of a I-aryl-3-mcthyltriazene with formaldchydc. Scvcral new derivatives of thc hydroxymcthyl function havc bccn prcparcd. Rcaction with acctic anhydridc or bcnzoyl chloride in pyridine affords respcctivcly the acctoxymcthyl-ant1 benzoyloxymcthyl-trinzcncs; thc acctatcs and bcnzoatcs rcact rcadily with methanol to give the novel mcthoxymethyltriazcncs. This is the first rcport of a scrics of dialkyltriazcncs with an ether linkagc in the a position. An ether of this type has also bccn obtaincd directly from thc diazonium tluoroboratc salt by coupling with a mixturc of benzylamine and formaldchydc in cthanolic solution.

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

“…The design of our combi-molecule, RB24, was based on the premise that acetoxymethyltriazenes are known to be hydrolysed to a hydroxymethyltriazene intermediate that rapidly degrades into the corresponding monoalkyltriazene (Hemens et al, 1984;Cameron et al, 1985;Hemens and Vaughan, 1986). The latter further heterolyses to an aromatic amine þ a DNA-damaging species.…”

“…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).…”

Open-chain nitrogen compounds. Part XV. A kinetic study of the hydrolysis of 1-aryl-3-aryloxymethyl-3-methyltriazenes and related triazenes

“…Thus we synthesized the methyl ether derivatives (lc) and the acetoxymethyltriazenes (Id) (6); the difference in chemical behavior of these two apparently similar derivatives is quite striking but can be rationalized by the difference in the facility of the leaving group X. The ether derivatives (lc) with a poor leaving group, OMe, are comparable in stability at pH 7.5 to the dimethyltriazene (la), whereas the acetoxymethyltriazene (Id) decomposes in solution as rapidly as the hydroxymethyltriazene (lb).…”

“…9 (iii), in which the anion A-causes a slow displacement of the aryloxy leaving group followed by fast displacement of A-by water. When A-is formate, the intermediate 5 is similar i n structure to an acetoxymethyltriazene (Id), which is known to hydyrolyse rapidly in buffer solution (6).…”

Open chain nitrogen compounds. Part XIII. 1-Aryl-3-arylthiomethyl-3-methyltriazenes and 3-(arylazo)-1,3-thiazolidines

“…To this end several derivatives of l b have been reported and do indeed have antitumour activity in animal models. Examples of such derivatives are the chemically reactive 3-acetoxymethyltriazenes ( l c ; "acetates") and the relatively inert 3-methoxymethyltriazenes ( I d ) (4).…”