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Possibilities in the Realm of Synthetic Estrogens
Possibilities in the Realm of Synthetic Estrogens BY E. C. DODDS
CONTENTS
Page I. The Validity of Logia in Chemotherapeutic Research.. . . . . . . . . . . . . . . . . . . 229 11. From Estradiol t o Stilbestrol.. . . . . . . ;. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 231 111. The Problem of Activity in the Estrogens. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 233 References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 234
I. THEVALIDITYOF LOGICIN CHEMOTHERAPEUTIC RESEARCH Of all branches of research, chemotherapy has the reputation in the eyes of laymen of being one of the most scientific and logical of subjects. It is the object of this review to question the validity of this assumption. It is also proposed .to raise a number of questions, the correct answers to which would indicate whether various lines of research were worthy of prosecution. ’ The history of all chemotherapeutic researches can be divided into two parts. Firstly, the finding or stumbling upon a clue to the structure of a substance likely to be of value, and secondly, the development of variants with a view to finding the most potent substance. The most important part of the whole research is of course the discovery of the clue; this may be purely empirical or it may be the result of making compounds of a similar or allied structure to that of the naturally occurring substance. Many examples can be given but most of these are old history. For instance, the first classical example is the development of Salvaman by Ehrlich. Starting with the old knowledge that arsenic was of value in cases of syphilis, attempts were made to combine arsenic with a dye on the assumption that a substance capable of staining a microorganism would be fixed by it and if, so to speak, a poisonous charge could be attached to the dye, this would be dragged into the interior of the parasite which would subsequently be destroyed. Examples could be given in the case of the phenolic mtiseptic substances. As can be seen from such a study, simple logic works out very nicely up to a certain point, and an orderly series of compounds is obtained. However, as soon as a theory connecting structure with biological action is evolved, disastroiiw exceptions at once arise to upset the whole theory. Perhaps the most scientifically amusing example of this apparent orderliness can be seen in the researches leading up to the development of the sulfanilamide series of drugs. Working on the old Ehrlich doctrine-mn ugunt nisi $mtu-German investigators at I. G. Farbenindustrie evolved 229
230
E. C. DODDS
a red dyestuff, Prontosil, of the following formula (a), Here we have a very complicated molecule securely covered by patents which really gave a monopoly for the treatment of septicemic conditions. French workers, however, showed that when administered to rabbits, this substance was partly excreted in the urine as sulfanilamide, and they subsequently showed
a. Prontoail
that this was as effective as the original Prontosil. Here we see years of work on the part of the German chemists in building up this complicated molecule all being undone by the metabolic processes of the rabbit which extricates the relatively simple substance sulfanilamide from its elaborate trappings. The development of the sulfanilamide series of drugs became merely a question of working every type of substitute and finding by animal and clinical experimentation which was the better. Later the work of Fildes and his colleagues (see the review of Knight in this volume) provided a truly logical method of investigating the activity of drugs of this type. Another series of compounds illustrating the relationship between structure and function is found in the pressor substances related to adrenalin. I t is here for the first timc that the chemotherapeutic principle was applied to substances actually produced by the body and utilized for influencing the function:; of the body. Perhaps the most interesting questions, however, in this problem arise in relationship t o the sex hormones. This is not the place to give a complete summary of the development of our knotv!edge of this subject. By the early 1930s the constitution of the naturally occurring estrogens had been deduced and they are five in number; estriol, estrone, estradiol, equilene, and equilenin. The formulae are reproduced below (b, c, d, e, f ) , Ho#
& H
HO
b. Estriol
c.
e !?qu . m e
Estrode
no
f. Equilenin
d. Estradiol
SYNTHETIC ESTROGEKS
23 1
For the first time it appeared that the body produced a series of substances capable of producing the same biological reaction. In the case of the other hormones, only one substance had been isolated. Thus only adrenalin had been prepared from the suprarenal glands, only thyroxine had been obtained from the thyroid, and only one form of crystalline insulin from the pancreas. Admittedly, synthetic products had been obtained capable of reproducing most of the reactions of adrenalin, and di-iodothyronine was found to have qualitatively the same biological properties as thyroxine although quantitatively very much less. Also in the case of the body estrogens there were five substances all possessing the same qualitative reaction but again differing in their .quantitative activity, estradiol being the most active, weight for weight.
11. FROM ESTRADIOL TO STILRESTROL The problem as to how far one could depart from the structure of estradiol arose to the present writer and his colleagues. First an attempt was made t o imitate the action of the estrogenic agents with synthetic organic compounds, derivatives of phenanthrene. The first compound to have qualitatively the same activity as the naturally occurring estrogens was found to be the substance 1-keto-1:2:3 :4tetrahydrophenanthrene (formula 1 in the scheme below). Again it is not proposed to reviev in detail the laborious series of investigations that follbn-ed the discovery of the activity of this compound (see (1) to (6)). For the purpose of this review we can indicate the salient points. A very large number of derivatives of phenanthrene IF ere studied from the biological standpoint and found t o possess degrees of activity varying from one-millionth to one-fiftiet h of that of estriol. The next step was to decide whether the phenanthrene ring system was necessary. It was shown that certain derivatives of acenaphthene possessed estrogenic activity (7, 8). Proceeding to further simplification triphenyl carbinol was shown to be inactive whereas diphenyla-naphthyl carbinol (formula 4) IVW found to possess activity. ,Again proceeding with this simplification, the two-ring compound 4 :4’-dihydroxydiphenyl (formula 5) was found to possess activity. In view of the activity of the carbinol mentioned above, the activity of substituted methane and ethane compounds was studied. It was shown that diphenyl-ethane (formula 6) possessed activity which n-as increased if 2 hydroxyl groups were introduced into the 4:4’-position. If the compound 11 ere desaturated and a double linking put between the two central carbon atoms the hydrocarbon diphenyl-ethylene or stilbene results, which was also found to possess activity (formula 7)) and in a greater degree than the corresponding ethane derivative. The 4 :4‘-dihydroxystilbene (formula 8) was found to have still greater activity than the parcnt hydrocarbon (11). The problem now arose as to whether one could leave out one of the
232
E. C. DODDS
benzene rings and substitute it by a methyl group. The substance parahydroxypropenylbenzene or anol (formula 9) would obviously be the substance d o s e activity would be of interest. This was prepared very easily by the demethylation of anethole and was accomplished by heating this methoxy compound in a sealed tube with alcohol and potassium hydroxide. The resulting phenol wm separated by the standard method and its activity was investigated. The first specimen prepared was found to have a very high degree of activity-in fact approaching that of estrone itself. This fact was published (9, 10). Shortly after publication, however, it S C H E M E SHOWING SERIES OF COMPOUNDS IN ORDER
To STILBESTROL
l.l-Ketc-l:2:3:Ctetrahydrophenanthrene
LEADING FINALLY
2. Dibeneanthraesne diols
3. Di-k-naphthyl-dioxyAcenaphthene
OH
4. Diphenyl-a-naphthylearbinol
7. Stilbene
9. Anol
5. 4, 4'-Dihydroxgili~~henyl
5. Diphenylethane
8. 4, 4'-Dihydroxyatilbene
10. Disnol
wa8 found that the activity of all samples of anol was not identical, some being extremely active and others practically. without activity, and it became obvious that something was seriously wrong in the whole conception. An investigation of the activity of the mother liquor from which the an01 had been crystallized showed it to contain a glassy substance of roughly constant activity of about that of estrone. This material was found to be very difficult-in fact impossible-to crystallize. A study of the properties of anol indicated that it polymerized very rapidly and a possible assumption was that the activity in the highly active specimen
233
SYNTHETIC ESTROGENS
of anol must be due t o a contaminant-almost certainly a polymeride of anol. It was natural t o think of the dimerides of an01 and attempts were immediately put in hand to synthesize all the possible dimerides. Dianol (formula 10) had already been described; this was prepared and tested, but found to have an activity of an order that could not explain the nature of the contaminant. A symmetrical dimeride was obviously the most likely choice. Sir Robert Robinson and his co-workers a t Oxford had been interested in the synthesis of chrysene and bodies more blosely resembling the polycyclic estrogens, and it was decided that the workers in the writer’s department and those a t Oxford should combine. As a result of this collaboration a symmetrical dimeride was synthesized in 1938 and was proved to be very highly active. This substance, whose’ formula is shown below (g), is known as diethylstilbestrol, the term stilbestrol being used for the parent substance 4 :4’-dihydroxystilbene. In Great Britain the substance is commonly known as stilbestrol, although it should, of course, be referred to w diethylstilbestrol. As a result of careful study of the mother liquors from the anol crystallization after demethylating anethole it was possible to isolate an active contaminant, namely hexestrol, which proved to be hydrogenated stilbestrol. This possessed the formula (h) which is shown below. Another similar compound was obtained by synthesis, namely dienestrol, whose formula is shown at (i). We have, therefore, the three synthetic estrogens-stilbestrol, hexestrol, and dienestrol (11, 12, 13).
111. THEPROBLEM OF ACTIVITY IN THE ESTROGENS Whilst it is possible to write the formulae of stilbestrol and other synthetic estrogens in such a way that they bear a rough resemblance to the naturally occurring estrogens as shown by the diagram (j) from the strictly chemical point of view, literally the resemblance is nonexistent. Instead we are faced with the interesting problem of an extremely complictated biological reaction such as the action of naturally occurring estrogens, CH,
CH, CHI
I
I I CH, CH,
H
o g.
-
#
-
L
C
CH, ~
o
H
I
..fy-!!+oH
I
CH CH
h. Hcxestrol
floH
HO
i Dienestrul
CH,
Ho+!H-!H
Stilbeutrol (Diethylstilbeutrol).
CH3 CH,
CH3
1
H&
CHI
j. Stilbestrol formula illiietrating similarity to mtrone
234
E.
C. DODDS
embracing aa it does important biological reactions on the whole of the female genital tract, the secondary sexual characteristics such as development of the breasts, external genitalia, etc., the conferment of female sexual instincts, the action on the pituitary and many other biological reactions, being carried out by two groups of substances-first by those produced in the body of a complex steroid type, and second by the relatively simple derivatives of hexane. It would appear impossible to correlate the biological activity with the chemical structure. In this laboratory and in many others attempts have been made to modify the structure of the three synthetic estrogens-namely stilbestrol, hexestrol and dienestrol with a view to increasing their activity, but any alterations in their structure such m the introduction of other hydroxyl groups into the benzene rings, modification of the length of the side chains, etc., only result in a reduction in activity It is very difficult indesd to interpret the significance of these observations but it would appear to the writer that the most important question is to know whether the three synthetic estrogens mentioned above represent the most active substances that can be obtained. If we return to our first introductory remarks-namely the purely logical and scientific approach to these problems, we are at once confronted with the undeniable fact that these three substances, whilst apparently resulting from a planned and orderly research, really resulted from an error of judgment and that the path which led logically to anol-which incidentally proved to be of very low activity-was by chance led from anol to stilbestrol. Is it possible that there are otherasynthetic estrogens of an entirely different character and constitution still waiting to be discovered? If this applies to the estrogens, it almost certainly applies to mary other biologically active substances, and it may be that bold and empirical experimentation on these lines will lead to the synthesis of an even simpler type which will really give an answer to the question of structure in relation to function. REFERENCES 1. Dodds, E. C., Cook, J. W., and Hewett, C. L.: A Synthetic Oestrus-Exciting Compound. Nature 131, 56 (1933). 2. Dodds, E. C., and Cook, J. W.:, Sex Hormones and Cancer Producing Compounds. Nature 191, 205 (1933). 3. Dodds, E. C., Cook, J. W., and Hewebt, C . L.: Synthetische Brunst erregende
Verbindungen. Naturwissenschajten 21, 222 (1933). 4. Dodds, E. C.,Cook, J. W., Hewett, C. L., and Lawson, W . : The Oestrogenie Activity of some Condensed Carbon Ring Compounds in Relation to their (London) B, 114,272 (1934). other Biological Activity. Proc. Roy. SOC. 5. Dodds, E . C., Cook, J. W., apd Greenwood, A. W.: Sex Changes in the Plumage of Brown Leghorn Capons following the Injection of Certain Synthetic Oestrusproducing Compounds. Proc. Roy.SOC.(London) B. 114, 286 (1934).
SYNTHETIC ESTROGENS
236
6. Dodds, E. C.: Chemistry of Oestrogenic Substances. Nature 136, 793, 959; 158, 912 (1935). 7. Dodda, E. C., and Lawson, W.: Synthetic Oestrogenic Agents Without the Phenanthrene Nucleus. Nature 137, 996 (1936). 8. Dodds, E. C., Cook, J. W., and Lawson, W.:'Further Observations on the Oestrogenic Activity of Synthetic Polycyclic Compounds. Proe. Roy. SOC.(London) B, 121, 133 (1936). 9. Dodds, E. C., Cook, J. W., and Lawson, W.: A Simple Aromatic Oestrogenic Agent with an Activity of the Same Order aa that of Oestrone. Nature 139,627 (1937). 10. Dodds, E. C., and Lawson, W.: Oestrogenic Activity of p-Hydroxy Propenyl Benzene (Anol). Nature 139, 1068 (1937). 11. Dodds, E. C., Fitzgerald, L., and Lawson, W.: Oestrogenic Activity of Some Hydrocarbon Derivatives of Ethylene. Nature 140.772 (1937). 12. Dodds, E. C., and Robinson, R.: Isomers of Stilboestrol and its Esters. Nature 161, 305 (1943). 13. Dodds, E. C.,Goldberg, L., Grunfeld, L., and Lawson, W.: Synthetic Oestrogenic Compounds Related to Stilbene and Diphenylethane. 11. Proc. Roy. Soc. (London) B, 132, 83 (1944).
CONTENTS
Page I. The Validity of Logia in Chemotherapeutic Research.. . . . . . . . . . . . . . . . . . . 229 11. From Estradiol t o Stilbestrol.. . . . . . . ;. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 231 111. The Problem of Activity in the Estrogens. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 233 References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 234
I. THEVALIDITYOF LOGICIN CHEMOTHERAPEUTIC RESEARCH Of all branches of research, chemotherapy has the reputation in the eyes of laymen of being one of the most scientific and logical of subjects. It is the object of this review to question the validity of this assumption. It is also proposed .to raise a number of questions, the correct answers to which would indicate whether various lines of research were worthy of prosecution. ’ The history of all chemotherapeutic researches can be divided into two parts. Firstly, the finding or stumbling upon a clue to the structure of a substance likely to be of value, and secondly, the development of variants with a view to finding the most potent substance. The most important part of the whole research is of course the discovery of the clue; this may be purely empirical or it may be the result of making compounds of a similar or allied structure to that of the naturally occurring substance. Many examples can be given but most of these are old history. For instance, the first classical example is the development of Salvaman by Ehrlich. Starting with the old knowledge that arsenic was of value in cases of syphilis, attempts were made to combine arsenic with a dye on the assumption that a substance capable of staining a microorganism would be fixed by it and if, so to speak, a poisonous charge could be attached to the dye, this would be dragged into the interior of the parasite which would subsequently be destroyed. Examples could be given in the case of the phenolic mtiseptic substances. As can be seen from such a study, simple logic works out very nicely up to a certain point, and an orderly series of compounds is obtained. However, as soon as a theory connecting structure with biological action is evolved, disastroiiw exceptions at once arise to upset the whole theory. Perhaps the most scientifically amusing example of this apparent orderliness can be seen in the researches leading up to the development of the sulfanilamide series of drugs. Working on the old Ehrlich doctrine-mn ugunt nisi $mtu-German investigators at I. G. Farbenindustrie evolved 229
230
E. C. DODDS
a red dyestuff, Prontosil, of the following formula (a), Here we have a very complicated molecule securely covered by patents which really gave a monopoly for the treatment of septicemic conditions. French workers, however, showed that when administered to rabbits, this substance was partly excreted in the urine as sulfanilamide, and they subsequently showed
a. Prontoail
that this was as effective as the original Prontosil. Here we see years of work on the part of the German chemists in building up this complicated molecule all being undone by the metabolic processes of the rabbit which extricates the relatively simple substance sulfanilamide from its elaborate trappings. The development of the sulfanilamide series of drugs became merely a question of working every type of substitute and finding by animal and clinical experimentation which was the better. Later the work of Fildes and his colleagues (see the review of Knight in this volume) provided a truly logical method of investigating the activity of drugs of this type. Another series of compounds illustrating the relationship between structure and function is found in the pressor substances related to adrenalin. I t is here for the first timc that the chemotherapeutic principle was applied to substances actually produced by the body and utilized for influencing the function:; of the body. Perhaps the most interesting questions, however, in this problem arise in relationship t o the sex hormones. This is not the place to give a complete summary of the development of our knotv!edge of this subject. By the early 1930s the constitution of the naturally occurring estrogens had been deduced and they are five in number; estriol, estrone, estradiol, equilene, and equilenin. The formulae are reproduced below (b, c, d, e, f ) , Ho#
& H
HO
b. Estriol
c.
e !?qu . m e
Estrode
no
f. Equilenin
d. Estradiol
SYNTHETIC ESTROGEKS
23 1
For the first time it appeared that the body produced a series of substances capable of producing the same biological reaction. In the case of the other hormones, only one substance had been isolated. Thus only adrenalin had been prepared from the suprarenal glands, only thyroxine had been obtained from the thyroid, and only one form of crystalline insulin from the pancreas. Admittedly, synthetic products had been obtained capable of reproducing most of the reactions of adrenalin, and di-iodothyronine was found to have qualitatively the same biological properties as thyroxine although quantitatively very much less. Also in the case of the body estrogens there were five substances all possessing the same qualitative reaction but again differing in their .quantitative activity, estradiol being the most active, weight for weight.
11. FROM ESTRADIOL TO STILRESTROL The problem as to how far one could depart from the structure of estradiol arose to the present writer and his colleagues. First an attempt was made t o imitate the action of the estrogenic agents with synthetic organic compounds, derivatives of phenanthrene. The first compound to have qualitatively the same activity as the naturally occurring estrogens was found to be the substance 1-keto-1:2:3 :4tetrahydrophenanthrene (formula 1 in the scheme below). Again it is not proposed to reviev in detail the laborious series of investigations that follbn-ed the discovery of the activity of this compound (see (1) to (6)). For the purpose of this review we can indicate the salient points. A very large number of derivatives of phenanthrene IF ere studied from the biological standpoint and found t o possess degrees of activity varying from one-millionth to one-fiftiet h of that of estriol. The next step was to decide whether the phenanthrene ring system was necessary. It was shown that certain derivatives of acenaphthene possessed estrogenic activity (7, 8). Proceeding to further simplification triphenyl carbinol was shown to be inactive whereas diphenyla-naphthyl carbinol (formula 4) IVW found to possess activity. ,Again proceeding with this simplification, the two-ring compound 4 :4’-dihydroxydiphenyl (formula 5) was found to possess activity. In view of the activity of the carbinol mentioned above, the activity of substituted methane and ethane compounds was studied. It was shown that diphenyl-ethane (formula 6) possessed activity which n-as increased if 2 hydroxyl groups were introduced into the 4:4’-position. If the compound 11 ere desaturated and a double linking put between the two central carbon atoms the hydrocarbon diphenyl-ethylene or stilbene results, which was also found to possess activity (formula 7)) and in a greater degree than the corresponding ethane derivative. The 4 :4‘-dihydroxystilbene (formula 8) was found to have still greater activity than the parcnt hydrocarbon (11). The problem now arose as to whether one could leave out one of the
232
E. C. DODDS
benzene rings and substitute it by a methyl group. The substance parahydroxypropenylbenzene or anol (formula 9) would obviously be the substance d o s e activity would be of interest. This was prepared very easily by the demethylation of anethole and was accomplished by heating this methoxy compound in a sealed tube with alcohol and potassium hydroxide. The resulting phenol wm separated by the standard method and its activity was investigated. The first specimen prepared was found to have a very high degree of activity-in fact approaching that of estrone itself. This fact was published (9, 10). Shortly after publication, however, it S C H E M E SHOWING SERIES OF COMPOUNDS IN ORDER
To STILBESTROL
l.l-Ketc-l:2:3:Ctetrahydrophenanthrene
LEADING FINALLY
2. Dibeneanthraesne diols
3. Di-k-naphthyl-dioxyAcenaphthene
OH
4. Diphenyl-a-naphthylearbinol
7. Stilbene
9. Anol
5. 4, 4'-Dihydroxgili~~henyl
5. Diphenylethane
8. 4, 4'-Dihydroxyatilbene
10. Disnol
wa8 found that the activity of all samples of anol was not identical, some being extremely active and others practically. without activity, and it became obvious that something was seriously wrong in the whole conception. An investigation of the activity of the mother liquor from which the an01 had been crystallized showed it to contain a glassy substance of roughly constant activity of about that of estrone. This material was found to be very difficult-in fact impossible-to crystallize. A study of the properties of anol indicated that it polymerized very rapidly and a possible assumption was that the activity in the highly active specimen
233
SYNTHETIC ESTROGENS
of anol must be due t o a contaminant-almost certainly a polymeride of anol. It was natural t o think of the dimerides of an01 and attempts were immediately put in hand to synthesize all the possible dimerides. Dianol (formula 10) had already been described; this was prepared and tested, but found to have an activity of an order that could not explain the nature of the contaminant. A symmetrical dimeride was obviously the most likely choice. Sir Robert Robinson and his co-workers a t Oxford had been interested in the synthesis of chrysene and bodies more blosely resembling the polycyclic estrogens, and it was decided that the workers in the writer’s department and those a t Oxford should combine. As a result of this collaboration a symmetrical dimeride was synthesized in 1938 and was proved to be very highly active. This substance, whose’ formula is shown below (g), is known as diethylstilbestrol, the term stilbestrol being used for the parent substance 4 :4’-dihydroxystilbene. In Great Britain the substance is commonly known as stilbestrol, although it should, of course, be referred to w diethylstilbestrol. As a result of careful study of the mother liquors from the anol crystallization after demethylating anethole it was possible to isolate an active contaminant, namely hexestrol, which proved to be hydrogenated stilbestrol. This possessed the formula (h) which is shown below. Another similar compound was obtained by synthesis, namely dienestrol, whose formula is shown at (i). We have, therefore, the three synthetic estrogens-stilbestrol, hexestrol, and dienestrol (11, 12, 13).
111. THEPROBLEM OF ACTIVITY IN THE ESTROGENS Whilst it is possible to write the formulae of stilbestrol and other synthetic estrogens in such a way that they bear a rough resemblance to the naturally occurring estrogens as shown by the diagram (j) from the strictly chemical point of view, literally the resemblance is nonexistent. Instead we are faced with the interesting problem of an extremely complictated biological reaction such as the action of naturally occurring estrogens, CH,
CH, CHI
I
I I CH, CH,
H
o g.
-
#
-
L
C
CH, ~
o
H
I
..fy-!!+oH
I
CH CH
h. Hcxestrol
floH
HO
i Dienestrul
CH,
Ho+!H-!H
Stilbeutrol (Diethylstilbeutrol).
CH3 CH,
CH3
1
H&
CHI
j. Stilbestrol formula illiietrating similarity to mtrone
234
E.
C. DODDS
embracing aa it does important biological reactions on the whole of the female genital tract, the secondary sexual characteristics such as development of the breasts, external genitalia, etc., the conferment of female sexual instincts, the action on the pituitary and many other biological reactions, being carried out by two groups of substances-first by those produced in the body of a complex steroid type, and second by the relatively simple derivatives of hexane. It would appear impossible to correlate the biological activity with the chemical structure. In this laboratory and in many others attempts have been made to modify the structure of the three synthetic estrogens-namely stilbestrol, hexestrol and dienestrol with a view to increasing their activity, but any alterations in their structure such m the introduction of other hydroxyl groups into the benzene rings, modification of the length of the side chains, etc., only result in a reduction in activity It is very difficult indesd to interpret the significance of these observations but it would appear to the writer that the most important question is to know whether the three synthetic estrogens mentioned above represent the most active substances that can be obtained. If we return to our first introductory remarks-namely the purely logical and scientific approach to these problems, we are at once confronted with the undeniable fact that these three substances, whilst apparently resulting from a planned and orderly research, really resulted from an error of judgment and that the path which led logically to anol-which incidentally proved to be of very low activity-was by chance led from anol to stilbestrol. Is it possible that there are otherasynthetic estrogens of an entirely different character and constitution still waiting to be discovered? If this applies to the estrogens, it almost certainly applies to mary other biologically active substances, and it may be that bold and empirical experimentation on these lines will lead to the synthesis of an even simpler type which will really give an answer to the question of structure in relation to function. REFERENCES 1. Dodds, E. C., Cook, J. W., and Hewett, C. L.: A Synthetic Oestrus-Exciting Compound. Nature 131, 56 (1933). 2. Dodds, E. C., and Cook, J. W.:, Sex Hormones and Cancer Producing Compounds. Nature 191, 205 (1933). 3. Dodds, E. C., Cook, J. W., and Hewebt, C . L.: Synthetische Brunst erregende
Verbindungen. Naturwissenschajten 21, 222 (1933). 4. Dodds, E. C.,Cook, J. W., Hewett, C. L., and Lawson, W . : The Oestrogenie Activity of some Condensed Carbon Ring Compounds in Relation to their (London) B, 114,272 (1934). other Biological Activity. Proc. Roy. SOC. 5. Dodds, E . C., Cook, J. W., apd Greenwood, A. W.: Sex Changes in the Plumage of Brown Leghorn Capons following the Injection of Certain Synthetic Oestrusproducing Compounds. Proc. Roy.SOC.(London) B. 114, 286 (1934).
SYNTHETIC ESTROGENS
236
6. Dodds, E. C.: Chemistry of Oestrogenic Substances. Nature 136, 793, 959; 158, 912 (1935). 7. Dodda, E. C., and Lawson, W.: Synthetic Oestrogenic Agents Without the Phenanthrene Nucleus. Nature 137, 996 (1936). 8. Dodds, E. C., Cook, J. W., and Lawson, W.:'Further Observations on the Oestrogenic Activity of Synthetic Polycyclic Compounds. Proe. Roy. SOC.(London) B, 121, 133 (1936). 9. Dodds, E. C., Cook, J. W., and Lawson, W.: A Simple Aromatic Oestrogenic Agent with an Activity of the Same Order aa that of Oestrone. Nature 139,627 (1937). 10. Dodds, E. C., and Lawson, W.: Oestrogenic Activity of p-Hydroxy Propenyl Benzene (Anol). Nature 139, 1068 (1937). 11. Dodds, E. C., Fitzgerald, L., and Lawson, W.: Oestrogenic Activity of Some Hydrocarbon Derivatives of Ethylene. Nature 140.772 (1937). 12. Dodds, E. C., and Robinson, R.: Isomers of Stilboestrol and its Esters. Nature 161, 305 (1943). 13. Dodds, E. C.,Goldberg, L., Grunfeld, L., and Lawson, W.: Synthetic Oestrogenic Compounds Related to Stilbene and Diphenylethane. 11. Proc. Roy. Soc. (London) B, 132, 83 (1944).