The growth-inhibitory and carcinogenic properties of 4-aminostilbene and derivatives

Abstract

Plates 2 t o 4] CONTENTS PAGE I. Introduction 148 II. Influence upon growth-inhibitory ACTION OF MODIFICATIONS IN CHEMICAL CONSTITUTION 151 1. Modifications involving the polar group 151 2. Modifications of the ethylene bridge 152 3. Substitution affecting ring A 160 4. Substitution affecting ring B 160 5. Stereoisomerism 162 6. Heterocyclic modifications 162 7. Conclusions 162 Marked inhibition of the growth of the Walker rat carcinoma 256 is produced by administration of 4-aminostilbene and of 4-dimethylaminostilbene. From similar experiments with the Crocker sarcoma 180, the carcinoma C63, and spontaneous mammary cancer, it appears that the growthinhibitory action of these compounds is much less pronounced in mice. In a dosage of 200 to 250 mg./kg. in the rat, both 4-amino-and 4-dimethylaminostilbene produce (a) gastro-intestinal submucous haemorrhage most evident in the pyloric portion of the stomach, (b) haematuria, and (c) haemolymph changes, while the former compound induces methaemoglobinaemia in addition.Using the Walker rat carcinoma 256 as the biological test object, a series of derivatives of 4-amino stilbene has been examined to determine the relationship between the growth-inhibitory effect and chemical constitution. / The great majority of the active compounds can be defined as stilbenes with a basic substituent, the position of which is of paramount importance; thus o-dimethylaminostilbene is very much less active than the />-isomeride, and the ra-compound is completely inactive. A further essential feature is the ethylene bridge, since activity disappears when either of its hydrogen atoms is substituted, when the bridge is reduced, when it is extended to contain three or four carbon atoms, or when either methine group is replaced by a nitrogen atom. Compounds in which the ethylene bridge is absent, or is replaced by oxygen or sulphur, are also inactive, and activity is further dependent upon the Irans configuration of the molecule about the ethylenic bond, and to a large extent upon a free p' -position. These and other facts have suggested the working hypothesis that one of the features required for activity is an unbroken conjugation of the amino group with both nuclei, enabling the compound to assume some dipolar quinonoid character, which depends, among other things, on the co-planar arrangement of the two benzene nuclei which characterizes the trans form of the stilbenes. PAGE I I I . T h e u l t r a -v io l e t a b s o r p t io n s p e c t r o s c o p y o f s e l e c t e d s t ilb e n e s 165 8. General theoretical considerations 165 9. Technique and results 166 10. Discussion 168 IV . T he carcinogenic action o f 4-amino stilbene AND DERIVATIVES 175 V . General discussion 177 VI. Experimental: preparation of stil benes 184 R eferences 192 D escription of Plates 195 V ol. 241. A. 830. (Price 155.) 19 [animals, the tumour weights at the 11th day totalled 262-4 g. (mean 23:8 g.) in the latter series, against a total of only 4-0 g. in the former. In a third experiment, twelve implanted rats rec...

N-Hydroxylation in Aminostilbene Carcinogenesis

“…Thus N-hydroxy-2-acetamidofluorene was shown (Miller, Miller and Hartmann, 1961) to be more active than AAF towards rat liver and additionally, induced tumours at other sites including the peritoneum and forestomach. Similarly, N-hydroxy-4-acetamidobiphenyl proved to have an enhanced carcinogenic activity with a greater spectrum of action (Miller, Wyatt, Miller and Hartmann, 1961) and 2-naphthylhydroxylamine was a more potent carcinogen than the parent amide (Boyland, Dukes and Grover, 1963).trans-4-Aminostilbene and its derivatives, initally studied on account of their tumour inhibitory properties (Haddow, Harris, Kon and Roe, 1948), are highly carcinogenic in the rat inducing ear duct carcinomata following oral administration. These compounds thus provide a further class of aromatic amines for investigation of the significance of N-hydroxylation in carcinogepesis.…”

“…trans-4-Aminostilbene and its derivatives, initally studied on account of their tumour inhibitory properties (Haddow, Harris, Kon and Roe, 1948), are highly carcinogenic in the rat inducing ear duct carcinomata following oral administration. These compounds thus provide a further class of aromatic amines for investigation of the significance of N-hydroxylation in carcinogepesis.…”

The Function of the Lymphatic System in Cancer

“…E . B o yland [26] [27] as w ell as Haddotv, H a rris, K o n and Roe [28] confirm th a t carcino genic su b sta n c e s serve as g ro w th in h ib ito rs. W e m u st, therefo re, n o t w onder t h a t we find such paradoxical fu n ctio n s o f the lym phatic system .…”

“…T hese nodes show ed clearly w idening of th e ly m p h atic-ch an n els a n d d im in u tio n o f th e ly m p h o id tissue. [28] w rite t h a t 4-am ino a n d 4-d im e th y la m in o stilb e n e p ro d u ced in th e r a t c h a ra c teristic changes. T h e m o st in te re s tin g w as th e fo rm atio n of h acm o ly m p h nodes, a p h en o m en o n id e n tic a l w ith t h a t described by L a sn itzk y and Woodhouse [40], in r a ts tre a te d w ith th e carcinogens 1, 2, 5, 6-dib en zan th ra c e n e 3 :4 b e n z p y re n e a n d 2 0 -m eth y lch o lan th ren e.…”

Synthesis and biological evaluation of (E)-cinnamic acid, (E)-2-styrylthiazole and (E)-2-[2-(naphthalen-1-yl)vinyl]thiazole derivatives

“…4 Cinnamic acid analogues act as precursors of many commercially important synthetic cinnamic esters 5 and as reactants in the preparation of chalcones and stilbenes. 6 Cinnamic acid derivatives have also been reported to possess antidiabetic, 7 hepato-protective, 8 antioxidant, 9 antimicrobial, 10 anti-tuberculosis 11 and anti-cancer properties. 12 On the other hand, compounds containing the thiazole nucleus have also been reported to exhibit various biological activities, the specificity of action often being dictated by the attached functionalities.…”