Studies on the Carcinogenicity of Tricycloquinazoline. The effect of Substitution in the Peripheral Carbocyclic Rings on Carcinogenic Activity

Baldwin, Robert; Cunningham, Georgina; Partridge, M. W.; Vipond, H. J.

doi:10.1038/bjc.1962.32

Cited by 15 publications

(3 citation statements)

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“…None of these metabolites have yet been identified but it is feasible that hydroxylated quinazolines may be formed. Hence the virtual inactivity of quinazoline and 4-hydroxyquinazoline (Table II) supports the hypothesis originally developed from studies on the influence of peripheral ring substitution on the carcinogenic activity of TCQ (Baldwin, Cunningham, Partridge and Vipond, 1962) that the whole molecule rather than a metabolite is the proximate carcinogen.…”

Section: Discussionsupporting

confidence: 82%

“…Implicit in the changes in carcinogenicity induced by peripheral ring substitution in TCQ (Baldwin, Cunningham, Partridge and Vipond, 1962) is the requirement for high activity of a precise stereochemical fit of the carcinogen to a tissue receptor. The weak activity of iso-TCQ thus provides further evidence of the importance of stereochemical factors in TCQ carcinogenesis.…”

Section: Discussionmentioning

confidence: 99%

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mentioning

confidence: 99%

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Studies on the Carcinogenicity of Tricycloquinazoline: The Effect of Structural Modification

Baldwin¹,

Cunningham²,

Davey³

et al. 1963

Br J Cancer

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PREVIOUSLY it was shown (Baldwin, Cunningham, Partridge and Vipond, 1962) that substitution with methyl, hydroxy, or methoxy radicals in the 2-position of tricycloquinazoline (TCQ; I, Fig. 1) causes almost complete loss of carcinogenic activity. These findings imply the intervention of the 2-or equivalent 7-or 12-positions of the TCQ molecule in carcinogenesis.A direct three-point union of TCQ to a cellular receptor at these positions could occur however only by covalent bonding and thus the finding that TCQ is not strongly bound in skin (Baldwin, Palmer and Partridge, 1962) excludes this possibility.Methyl substitution in the other three possible ring positions in TCQ, namely 1-, 3-, or 4-, only partially reduces carcinogenicity, and these derivatives possess significant activities. Introduction of additional methyl substituents at the positions equivalent to the 3-position, namely 8-or 13-, brings about a very marked decrease in activity; thus both 3,8-dimethyl-TCQ and 3,8,13-trimethyl-TCQ have very low activity. These findings suggest that stereochemical factors are important and it is considered that the evidence relating structure to activity in TCQ can be most logically accommodated in terms of the precision of stereochemical fit of the planar carcinogen by multiple low-energy bonding to a planar cell receptor site. In order further to assess the importance of molecular shape for carcinogenicity, the effect of variations in the arrangement of the homocyclic and heterocyclic rings of TCQ have been examined. The analogues tested for carcinogenic activity following skin painting in mice included an isomer, iso-TCQ (IV, Fig. 1) in which the position of one benzene ring is altered so that the molecule possesses neither a symmetrical structure nor the same distribution of nitrogen atoms as in TCQ. This compound is basic and accordingly was examined as the free base and as its nitrate. The hexacyclic compound (II, Fig. 1) was also tested because of its similarity to iso-TCQ in being a base and because its molecular shape is close to that of both TCQ and iso-TCQ. Furthermore, an oxygen isostere of iso-TCQ (V, Fig. 1) was examined since this compound, although structurally related to iso-TCQ, resembles TCQ more closely in its feeble basic properties.A number of simpler azapolycyclic compouinds structurally related to TC(Q were examined also to assess the importance of overall molecular size for carcinogenicity. The compounds tested include a pentacyclic compound (VI, Fig. 1) which is equivalent to iso-TCQ less a benzene ring and quinazoline and 4-hydroxyquinazoline since these substanices may also be related to possible metabolites of TCQ.

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Section: Discussionsupporting

confidence: 82%

Section: Discussionmentioning

confidence: 99%