N2,N4,N6-tri(hydroxymethyl)-N2,N4,N6-trimethylmelamine (trimelamol) is an efficient DNA cross-linking agent in vitro.
An investigation of the mechanism of action of the antitumour agent trimelamol has established that it is an efficient interstrand DNA cross-linker in vitro, comparable to nitrogen mustards such as melphalan. Studies have shown that the cross-linking reaction is acid-catalysed but, unlike the nitrogen mustards, only partially reversible after treatment with piperidine. The bisalkylation (cross-linking) reaction appears to be concerted, and no "second arm" reaction has been detected. The results of thermal denaturation studies are consistent with general DNA binding, and suggest a preference for GC-rich sites. The acid-catalysed reaction of trimelamol with a model nucleophile (thiophenol) has also been investigated and an adduct resulting from displacement of the three carbinolamine functions has been isolated and characterized.
Jackson
C
C
School of Pharmacy and Biomedical Sciences, Portsmouth Polytechnic, Hants.
Hartley
J A
JA
Jenkins
T C
TC
Godfrey
R
R
Saunders
R
R
Thurston
D E
DE
D000970:Antineoplastic Agents / Q000378:metabolism* / Q000494:pharmacology; D003432:Cross-Linking Reagents / Q000378:metabolism; D004247:DNA / Q000187:drug effects / Q000378:metabolism*; D004277:DNA, Single-Stranded / Q000187:drug effects / Q000378:metabolism; D004587:Electrophoresis, Agar Gel; D007700:Kinetics; D013696:Temperature; D014227:Triazines / Q000378:metabolism* / Q000494:pharmacology
D000970:Antineoplastic Agents; D003432:Cross-Linking Reagents; D004277:DNA, Single-Stranded; D014227:Triazines; C049507:trimelamol; D004247:DNA