First Symposium on Chemical-Biological Correlation, May 26-27, 1950 (1951) / Chapter Skim
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Influence of Isosteric Replacements Upon Biological Activity
Influence of Isosteric Replacements Upon Biological Activity
Pages 295-423
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From page 295... ...
INFLUENCE OF ISOSTERIC REPLACEMENTS UPON BIOLOGICAL ACTIVITY Harris L Friedman Lakeside Laboratories, Inc.
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From page 296... ...
It will be the object of this paper to survey the history of isosterism, to classify the varieties of isosteric replacements which are recorded in the literature, and to note the influence of these replacements on the biological activity of compounds. We shall then be able to see if any general relationships apply, and what conclusions may be drawn from such data.
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From page 297... ...
" 5 Br', Kr, Rb+, Sr+ + 8 N2, CO, CM' 9 CH4, NH4+ 10 CO2, N2O, N3* , CNO" I angmuir postulated that when isosteric comolecules are also isoelectric, that is when they have the same total charge, all their physical properties should be closely similar.
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From page 298... ...
It is obvious from this brief survey that the term "isosteric" has varied in meaning with different writers - from a narrow to a very broad concept. In this discussion we shall accept the term in its broadest meaning and study the influence of isosteric replacements on the biological activity of molecules.
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From page 299... ...
The following are illustrations of several types of isosteric replacement, where the resulting compounds give cross-reactions: CHART 3 SEROLOGICAL SPECIFICITY C6H5-0-C6H4-N=N-Protein C6H5-NH-C6H4-Protein -Protein -C6H4-PO3H2 -C6H4-As03H2 not -C6H4-SbO3H2 -C6H4-S03H -C6H4-SeO3H not -C6H4-SO2H -CO-NH-C6H4>-NH-C6H4not -CO-NH-C6H4H2N I and II ++ + I and III t II and III ++ III H2N CH, From Erlenmeyer4'
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From page 300... ...
However, this type of study should show when parts of a molecule are simple "space fillers", that is occupy specified geometrical bulk. Since the discovery that the antagonism of the suHonamides to £-amino benzoic acid is an antimetabolite effect, due to the close similarity of structure, isosteric replacements in other essential nutrients have yielded many compounds of interest.
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From page 301... ...
In either case, it is proof that isosteric replacement gives compounds acting by the same mechanism, that they are truly bio-isosteric. Ideally, to make comparisons between structure and biological activity, two criteria are necessary: (1)
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From page 302... ...
Above are the elements of the same periodic group, below are the isosteric hydrides. The following tables will show the effect of isosteric replacement on biological activity within each type.
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From page 303... ...
General Conclusions to Class 2. Isosteric replacement in this group has better promise of usefulness than in Class 1.
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From page 304... ...
That three dimensional spatial characteristics play a highly important role in biological activity is known to everyone. The vastly different activities often noted in optical or cis-trans isomers must be consi'dered in any attempt to explain the mechanism of biological activity.
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From page 305... ...
The similarity of biological activity in so many instances, and the successful results already achieved through isosteric replacements, show that this is a type of variation which the synthetic chemist must keep in mind. If chemical reactivity and polarities are considered, the predictability of bio-isosteric replacement is quite high.
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From page 307... ...
307 EXPLANATION OF TABLES In the first column the structural formulas of the compounds under consideration are written with the variable isosteric group represented as X In the second column the biological list is stated (e.g.
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From page 309... ...
309 X 0 X O C 0 U U J n H V) in J U BiologiUal A CoeffiUieet Artyphosus A A I o a o U a U)
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From page 311... ...
311 X u 1M 2 X o c 0 U W 03 H J U V Biolo o (M I u o u CM u Compo .2 1 a a .8 " 0 J EH D Q S H ° •?
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So nt SK a .0 "o Z X Z < > •o iM .
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314 n § U w J CO H en en J U I « 0.
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315 X U z X o U ffl H 3 u £ • a o o 0.1 Comprt I m U
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317 X U X 2 I O r- "H n c 0 U U J n CO J U jtf U c < Q U .= 8 3 i B u § JS s "S 3 O , o U 0= an X U X |
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321 = u rg I Z o § U w a H in o u .S o .g-s E>.
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322 X U CO u ffl J U o "5 s 3 O a o U I U S ...
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From page 323... ...
J O X X U U a gr £ o u I 1 X Z Z O rg U O rS rg .w U u fM gl ^s.
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J 8 iM X U u u 1 fM rsJ X X § x u u-z X 6 rg u „, 0 U fM S u Q *
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H X u U -U-ia Z -- U Z X O X y S o c £ 0.
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327 X u X z W J ft M J U i< OS • o >. .2 o S 0 c5 Comprti o*
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330 N U I 2 J U X-U as v P
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331 X u X z u J 03 lO en U « X 6 u a 9*
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From page 332... ...
NH-CH2-CH2-NEt2 Antimalarial inactive active Cl/'A-NH-^'^CH3 '-' CH3 (102)
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From page 333... ...
) CLASS 3 Aromatic Rings Compound Biological Test (Reference)
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From page 334... ...
) CLASS 3 Aromatic Rings Compound Biological Test (Reference)
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From page 335... ...
335 TABLE 9 CLASS 3 Compound Biological Test (Reference) = CH=N \ Antipyretic *
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From page 339... ...
.o O i4 S c 5 Z rg I 'J ^J X u c u .a i X Z-U-is.
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From page 340... ...
340 X CO « in en U J U W 0 , m X u X u E O h < .2 O .o o g a 8-i j: it .O C 3 SN Lf U O
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From page 341... ...
341 X z X u o u Id 3 en en U U , a, tn 1 o 0, o u a.
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From page 342... ...
clothes moth inactive active active (88) H2N\ /^XV\ /NH2 Antibacterial inactive weak active _ (120)
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From page 343... ...
343 TABLE 13 SPECIAL CLASS -COO-, CH2-CH2 Compound Biological Test (Reference) -CO-O -CH2-CH2HO OH Estrogenic (112)
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From page 344... ...
acetylcholine, Ba, histamine (84,17) active less active Antihistamine active inactive (126)
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From page 345... ...
) SPECIAL CLASS Spatial Fixation by Ring or Double Bond Compound Biological Test (Reference)
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From page 346... ...
) SPECIAL CLASSES Spatial Fixation by Ring or Double Bond Compound Biological Test (Reference Open Form Ring Form HN CO 1 Antithy roid 1 1 SC CH Thiouracil = 100 100 100 1 I /CH2 HN C-CHQ-f-H2 (137)
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From page 347... ...
) SPECIAL CLASS Spatial Fixation by Ring or Double Bond Compound Biological Test (Reference)
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From page 348... ...
#VNO-CO-NMe2 OG-CO-NMe2 R3N+ I (154,73,3) Active Active vs.
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From page 349... ...
) SPECIAL CLASS Polarity Shift TEST Exocyclic Endocyclic Antibacte rial vs.
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From page 350... ...
O I 9-Fluorenyl-O-C-CH2-CH2-NEi2 Activity ? Local anesthetic (61)
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From page 351... ...
) SPECIAL CLASS Reversed Polarity TEST Local anesthetic COOMe COOMe OH NH2 NH2" (56)
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From page 352... ...
352 REFERENCES TO TABLES 1. Acheson, R.M.
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From page 353... ...
353 26. Bywater, W
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354 53. Feldkamp, R
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From page 355... ...
355 81. Jenkins, G
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From page 356... ...
356 109. McGinty, D
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From page 357... ...
357 139. Stewart, H
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From page 358... ...
This is not true of many of the hormones. If in a vitamin various isosteric replacements are introduced, an antagonist, frequently a very powerful one, which has exactly the opposite effect to that of the vitamin, may result.
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From page 359... ...
PANEL DISCUSSION ON ANTIMETABOLITES, CARCINOGENESIS AND CANCER CHEMOTHERAPY M.J. Shear, Moderator National Cancer Institute National Institutes of Health Bethesda, Maryland
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From page 360... ...
From the work of Woods and from that of Miller, it is clear that p_-aminobenzoic acid is used as a substrate from which, by a'series of reactions, the living cell synthesizes folic acid. Practically all of the pathogenic bacteria carry out this reaction very well; that is, they produce their own j>-aminobenzoic acid, and they metabolize that further and produce folic a.cid.
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From page 361... ...
Because of the experience accumulated over the past decade, a rather good guess can be made as to how the structure of a'metabolite should be changed in order to form an anti-metabolite. The compound shown in the first slide was the first one tried; it is the dichloro-sulfanilide corresponding to pimelic acid, and it has the selective activity envisioned for it.
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From page 362... ...
> P* r fc 0 0 0 70 20 0 0 60 50 0 0 82 100 0 0 98 100 0.0005 0 66 100 0 3 70 Slide 2 The antagonism with pimelic acid was competitive whereas that with biotin was noncompetitive.
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From page 363... ...
In less than a decade, prior to the outbreak of World War II, several hundred new compounds were synthesized and tested for carcinogenic activity, including interesting series of homologues, and related derivatives, of certain key compounds, carefully chosen with an eye to the elucidation of the biochemical mechanism of carcinogenesis. In the short time available to me here, I shall only be able to pick out one or two illustrative examples from this important branch of carcinogenesis, and to deal equally briefly with other important groups of carcinogens of different chemical structures and biological properties, in order that I may devote a little time to a consideration of postulated mechanisms of action and chemical-biological correlations, and to conclusions that may be drawn about the validity of such associations.
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From page 364... ...
At the same time, it is now known that there are sterols in the body that possess weak, though definite carcinogenic activity. ^ The concept of a correlation between chemical structure and carcinogenic activity was faced with a more serious difficulty when Yoshida3S demonstrated that liver tumors could be induced in rats and mice by feeding or injections of an azo dye - 2-amino-5-azotoluene.
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From page 365... ...
) -NH2 CH3 2-amino-5-azotoluene p -dime thy laminoazobenzene Within the group of azo compounds, as in the case of polycyclic hydrocarbons, it is possible to discern a certain correlation between structure and biological activity.
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From page 366... ...
It will be noted that, so far, it is possible, by fanciful speculation, to correlate chemical structure and carcinogenic activity. But this breaks down completely when one passes on to other types of carcinogens, such as urethane (ethylcarbamate)
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From page 367... ...
Perhaps the most important outcome of the work on chemical carcinogenesis, and of the failure to find a close over-all correlation between chemical structure and carcinogenic activity, is the indication it affords that carcinogenesis is a more complex phenomenon than has hitherto been imagined.
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From page 368... ...
L , Survey of Compounds Which Have Been Tested for Carcinogenic Activity.
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From page 369... ...
J , Cancer Research, ±, 595(1941)
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From page 370... ...
When the symposium was being arranged, we expressed doubt that experimental cancer chemotherapy would at this time be a suitable part of a program on chemical-biological correlation; however, it may be worthwhile to review the present status of the field even though from published data only a few generalizations may be made with respect to correlations of chemical structure with antitumor activity. The introductory remarks have been collected under the title "A Consideration of Chemical-Biological Correlation in Experimental Cancer Chemotherapy", rather than a more imposing one such as "The Correlation of Anti-Tumor activity with Chemical Structure".
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From page 371... ...
371 h V as .*
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From page 372... ...
This is being done in the case of anti-amino acids, with analogs of carbohydrate metabolism and with purines, pyrimidines, and pteridines for possible interference with nucleic acid metabolism. 38 jn the latter category, weak tumor inhibitions have been observed which suggest some correlations.
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From page 373... ...
373 Recently we have had an opportunity to see relationships in the structure of certain steroids and their ability to inhibit the development of transplanted mouse lymphosarcomas. 50 Figure 1 shows the structure of cortisone acetate with the system of numbering indicated for »CH2OCCH3 1 1l = 0 0 COMPOUND E Figure 1 1 1-Dehydro-1 7-hydroxycorticosterone acetate reference ir» the use of Tables 3 and 4.
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From page 374... ...
It is to be hoped also that some of the panel members will be able to present from their unpublished data correlations in areas of interest which we have not discussed. Although the data at hand may permit only a few limited correlations of structure with anti-tumor activity, it can be anticipated that the increasing efforts devoted to experimental cancer chemotherapy studies will provide within the next few years chemical-biological correlations as important as those discussed in other meetings of this symposium.
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From page 375... ...
375 TABLE 3 STRUCTURAL RELATIONSHIPS OF A FEW STEROIDS WITH RESPECT TO INHIBITION OF MOUSE LYMPHOSARCOMA 1 1 -Keto 11 -OH 20 Keto 3-OH 17-OH 21 OH Activity Keto Cortisone + Compound F + + *
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From page 376... ...
37h TABLE 4 ASPECTS OF STRUCTURE OF STEROIDS INACTIVE AGAINST MOUSE LYMPHOSARCOMA 1 1-Oxy 20-Keto 3-OH 17-OH 20-OH 21 -OH 3-Keto + + Testoste rone i + Progesterone A -Pregnenolone _ + + . + Desoxycorticosterone 21 -OH-Pregnenolone •f .f 17a OH-Progesterone (A4)
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From page 377... ...
, Cancer Research, 10, 170 (1950)
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From page 378... ...
W , Cancer Research, 10, 186(1950)
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From page 379... ...
Chester, Cancer Research, 10, 178 (1950)
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From page 380... ...
The colon bacillus grows on a minimal medium containing only glucose and salts. It, therefore, synthesizes all its amino acids and other components from these materials.
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From page 381... ...
We fortunately have not only E coli mutants of the type described above, with a double requirement for isoleucine and valine; there is also one blocked later in isoleucine synthesis, which requires only this amino acid, and another blocked very early, which responds to either the 4-carbon compound a-aminobutyric acid (AAB)
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From page 382... ...
The compounds involved possess simple chemical structures ; the metabolic path involved is better understood than most others ; the affected reaction can be studied with non-growing cells; mutants with a high degree of resistance to D-serine can be obtained easily. Preliminary experiments have ruled out several mechanisms that have been widely assumed for drug resistance: it does not involve an increase in the production of either pantothenate or p-alanine, nor does it involve formation of pantothenate via
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From page 383... ...
383 an alternate metabolic pathway bypassing p-alanine. Among the remaining possibilities, D-serine may be prevented from reaching its site of action, or the previously sensitive enzyme may have been changed, qualitatively or quantitatively, in such a manner that it can now function adequately in the presence of the inhibitor.
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From page 384... ...
It may be that the molecule is a little too small to give the right distribution characteristics. I am impressed with the idea that, if we are ever going to understand the relationship between chemical structure and any kind of biological activity, we are going to have to take into account another factor, and that probably is the distribution characterisistic of the molecule, distribution particularly between lipophilic and hydrophilic phases.
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From page 385... ...
385 is a process of adsorption, or of some form of complex formation, and the requirement for specific chemical reactivity is merely to give the molecule sufficient pep so that it can form suitable complexes. It seems to me possible that the phenomenon of carcinogenesis may have some relationship to the ability of the carcinogenic hydrocarbons to form complexes with polynitro compounds.
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From page 386... ...
is the only one of a rather large series of this type compound which is very effective in prolonging life span in mouse leukemia. However, when one compares the anti-leukemic activity and the carcinogenic activity of carbamates (work by Dr.
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From page 387... ...
P Rusch University of Wisconsin Madison, Wisconsin I have a few slides which illustrate some of the relationships between the chemical structures of certain compounds and their carcinogenic activities.
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From page 388... ...
2- and 3methyl-4-dimethylaminoazobenzene are both inactive under our conditions. Similarly, introduction of a chloro or nitro group in the 3' position results in a more active compound than if the same group is inserted into the 2' or 4' position.
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From page 389... ...
389 2 3 Relolive Activities (unsubst1tuted dye = 61 4' 3' 2' 2 3 H00 0 0 0 0-12 2 3 0 0 NOg0 9 3 Cli-e 5-6 2 F10 10 7 Slide 3 Recent studies on the effects of various alterations in the structure of 2-acetylaminofluorene on its carcinogenic activity are presented in the fourth slide. Replacing the -CH2-bridge in 2-acetylaminofluorene by -S- as in 3-acetylaminodibenzothiophene did not alter the carcinoTABLE I TX UnONOGEMC AC1MTES OF ANALOGS OF J.ACETYLAMNOFLUOnENE wiTH THE GC'CRAL FORMULA Of-f^lt^ .HP*
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From page 390... ...
Unlike 2-acetylaminofluorene, however, none of these three compounds had any carcinogenic activity towards the rat liver. Further studies will be necessary to determine what features these various carcinogenic processes have in common and how these relatively small variations in structure interfere with or promote the reactions which lead to tumor formation.
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From page 391... ...
The basic structure we have up here, which includes the pteridine nucleus, the methylene linkage to the benzoic acid portion of the molecule and the PABA residue. We see there are four different substituents on here.
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From page 392... ...
Angier just showed you. Our studies were made, first, with two folic acid antagonists, without the amino in the 4-position.
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From page 393... ...
When one begins to work with patients with cancer incurable by surgery or radiation, the patient is included in the research team, as is the mouse. Since the purpose of cancer chemotherapy is the cure of cancer in man, it is essential that the splendid work going on with other agents, must be accompanied by actual observation on the living human being with cancer which is incurable by present methods of the rapy.
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From page 394... ...
Our approach to new chemotherapeutic agents has been via the biochemistry of nucleic acids. It was felt that quite generally there must be a differential requirement between host and parasitic tissues for the precursors of nucleic acids, since the rapid growth of the parasitic tissue must involve a rapid synthesis of nucleic acids.
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From page 395... ...
I think it is not too far-fetched to suggest that we have found in the field of antagonists of nucleic acid derivatives as related to cancer, substances of potential chemotherapeutic value substances which stand to the chemotherapy of cancer about as sulfanilic acid might stand to the chemotherapy of bacterial diseases. A substance like 2, 6-diaminopurine, for example, has only a small and rather questionable differential effect on sarcoma 180 in the whole mouse, but, as has been found by Dr.
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From page 396... ...
) Some of these azo compounds showed inhibition of tumor growth (sarcoma 37 and Walker carcinoma 256, to be published in Cancer)
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From page 397... ...
The correlation between tumors in experimental animals and neoplastic disease in man is not known. Precise information on the biochemical similarities or dissimilarities between the animal and human disease would be of tremendous value for the evaluation of observations made in cancer chemotherapy studies in experimental animals.
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From page 398... ...
Morris Engelman at the Columbia University Cancer Research Institute and tested against a spectrum of neoplasms in experimental animals. The technique of evaluation consists in transplanting the tumor fragments into the axillae of the appropriate hosts and instituting therapy 24 to 48 hours later.
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From page 399... ...
399 TABLE 2 EXPERIMENTAL NEOPLASM Compound 755 RC EO771 Brown-Pearce Sa.
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From page 400... ...
400 TABLE 3 EXPERIMENTAL NEOPLASM Compound 755 RC EO771 Brown-Pearce Sa.
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From page 401... ...
azaguanine probably interferes with nucleic acid metabolism and further understanding in this area could not fail to be of interest, (2) azaguanine appears to have a more selective action on neoplastic tissue than on normal tissue and, therefore, more potent carcinostatic or carcinoclastic agents might have clinical application and (3)
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From page 402... ...
D National Cancer Institute National Institutes of Health Bethesda, Maryland It becomes increasingly apparent that the attempts at establishing consistent and generally applicable correlations between the structure and carcinogenicity of chemicals may suffer the same fate that has overtaken similar efforts aimed at correlating chemical structure and pharmacologic and toxic action of chemicals or the various types of microorganisms and their pathogenicity.
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From page 403... ...
The correlation of chemical structure and antihormonogenic activity is still very little understood. If one considers that a slight change in the structure of a steroid hormone, often affords a striking change of biological action in most instances, a wide field for therapeutic trial is open as long as the chemist is willing to produce variations in the steroid structure and make compounds available in large enough amounts for testing.
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From page 404... ...
There is a great deal of controversy as to whether they are really folic acid antagonists, but we have definitely shown that at least the anti-leukemic effect of A-methopterin can be prevented by folic acid. It also might be appropriate to mention that this anti-leukemic effect can be prevented much more readily by the citrovorum factor.
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From page 405... ...
I think one could summarize a good deal of what has been said today, and our .own attitude, in the words of Lewis Carroll that because we breathe when we sleep does not necessarily imply that we sleep when we breathe. When we first found that the antifolic acid compound, 4-aminopteroylglutamic acid, exerted a definite inhibitory effect on the growth of sarcoma 180 and changed the cytologic appearance of the cells, we felt we should investigate to see whether these alterations were induced by the antifolic properties of this compound or whether the structural alteration in the configuration of the molecule had resulted in some new chemical compound which induced inhibition of tumor growth.
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From page 406... ...
and to liver slices, and found that the latter are able to convert folic acid into the citrovorum factor or, at least, into materials which permit growth of the particular microorganism used in assaying for the new factor. Using a normal rat liver, a considerable formation of the citrovorum factor is observed during incubation of liver slices for two hours; the amount of activity can be doubled, approximately, by the addition, per gram of liver, of 100 micrograms of folic acid, for example, raising the amount from 1700 units to about 3400 units.
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From page 407... ...
There seems to be little doubt that this factor is produced from folic acid, and that the conversion is facilitated by ascorbic acid. It is suspected that the citrovorum factor is more closely related than is folic acid to a prosthetic group of which folic acid serves as a precursor.
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From page 408... ...
408 in those of Dr. Burchenal, and in others.
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From page 409... ...
The three-membered heterocycles mentioned above are characterized by high chemical reactivity and, when investigated, have been found to alkylate a large variety of important biochemical radicals. Alkylation takes place with groups in both simple organic molecules and in complex biochemical entities such as proteins or nucleic acids.
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From page 410... ...
/kgm. Moreover, in effective doses the mono-ethylenimines may cause lesions in tissues other than those containing proliferating cells.
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From page 411... ...
Similar isolations with added "free" 8-azoguanine showed that the isolation procedure did not concentrate 8-azoguanine. One cannot be too bold in interpretation of these results; however, we feel that the presence of this non-metabolite in nucleic acids might be expected to affect nucleic acid metabolism of the 8-azoguanine injected mice.
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From page 412... ...
We have used the rate of incorporation of Cl4-formate into nucleic acid purines as a means of estimating the rate of uj vivo synthesis of nucleic acid purines and in turn, nucleic acids. Once one has established a base line for incorporation of formate, it is then possible to study the effects of various means of therapy on nucleic acid metabolism.
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From page 413... ...
Skipper. From the tracer studies with this chemical compound which he mentioned, I understand that there is no specific localization in the nucleic acids of tumor when compared to normal tissues.
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From page 414... ...
SKIPPER: No. In this work we isolated combined nucleic acids and combined nucleic acid purines.
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From page 415... ...
415 want to take regression as the criterion, I think there might be certain tumors or certain test conditions in which you would not need to get regression before considering the compounds for clinical trials. If you want one which is really going to be a cure, then 1 would agree with you that remarkable anti-tumor effects must be observed in the experimental tumors.
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