Potential antitumour pro-drugs: 1-aryl-3-arylthiomethyl-3-methyltriazenes and 1-aryl-3-aryloxymethyl-3-methyltriazenes.
Date
1991
Authors
Merrin, Marcus Paul.
Journal Title
Journal ISSN
Volume Title
Publisher
Dalhousie University
Abstract
Description
The literature relating to antitumour triazenes has been reviewed with particular regard to the 3,3-dimethyltriazenes and their $\alpha$-substituted derivatives. Their metabolism and mechanism of action in biological systems has been examined and used as a rationale for the experimental efforts of the work.
A series of novel 1-aryl-3-arylthiomethyl-3-methyltriazenes have been synthesized and extensively characterized by a variety of techniques. These compounds have been tested in vivo for antitumour response and do show a degree of activity.
A further series of 1-ary1-3-aryloxymethyl-3-methyltriazenes were prepared and characterized. In addition, a novel series of 1-aryl-3-arylmethyl-3-methyltriazenes were characterized as a side product of the synthesis. The aryloxymethyl compounds were subjected to extensive experiments to determine their behaviour with respect to hydrolysis in aqueous media, an important consideration for a potential pro-drug that depends upon decomposition for its efficacy. As part of this work we were able, for the first time to measure the rate of initial decay of a hydroxymethyltriazene derivative by following the rate of formation of the nitrophenolate ion liberated in this first step.
The N(2)-N(3) rotation of hydroxymethyltriazenes and derivatives have been examined by high field NMR and for the first time rotational barriers have been measured for these compounds and some conclusions drawn about the preferred conformations of these species.
Thesis (Ph.D.)--Dalhousie University (Canada), 1991.
A series of novel 1-aryl-3-arylthiomethyl-3-methyltriazenes have been synthesized and extensively characterized by a variety of techniques. These compounds have been tested in vivo for antitumour response and do show a degree of activity.
A further series of 1-ary1-3-aryloxymethyl-3-methyltriazenes were prepared and characterized. In addition, a novel series of 1-aryl-3-arylmethyl-3-methyltriazenes were characterized as a side product of the synthesis. The aryloxymethyl compounds were subjected to extensive experiments to determine their behaviour with respect to hydrolysis in aqueous media, an important consideration for a potential pro-drug that depends upon decomposition for its efficacy. As part of this work we were able, for the first time to measure the rate of initial decay of a hydroxymethyltriazene derivative by following the rate of formation of the nitrophenolate ion liberated in this first step.
The N(2)-N(3) rotation of hydroxymethyltriazenes and derivatives have been examined by high field NMR and for the first time rotational barriers have been measured for these compounds and some conclusions drawn about the preferred conformations of these species.
Thesis (Ph.D.)--Dalhousie University (Canada), 1991.
Keywords
Health Sciences, Pharmacology.