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Correlations Between the Chemical Structure and Biological Activity of Arsenosobenzenes
Pages 7-44

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From page 7...
... D Syphilis Research Laboratory, USPHS, and University of North Carolina, School of Public Health, Chapel Hill, North Carolina, and the Microbiological Institute, National Institutes of Health, Bethesda, Maryland.
From page 8...
... Ehrlich, in his original studies, showed that although the arsonic acids were inactive iri vitro, they were therapeutically highly active, and concluded that the arsenic was reduced to an active trivalent form by the body tissues. 28 He therefore prepared both arseno and arsenoso compounds, and found both types active in vitro The arsenoso compounds, while extremely active, were discarded because of their high toxicity; but the arseno compounds, notably arsphenamine and neoarsphenamine, found wide therapeutic application.
From page 9...
... Fig. 1 Types of Aromatic Arsenicals Generally Used in Therapy AsO (OH)
From page 10...
... 10 TRYPANOC1DAL ACT1ON OF As7 AND Asffl 1N (SEMl-DlAGRAMMATlC, AFTER VOEGTL1N AND SMlTH) VIVO I ARSACET1N II NEOARSPHENAMlNE ffl ARSENOPHENYL6LYClNE ARSPHENAMlNE I OXOPHENARSlNE Fig 3 3 4 T1ME 1N HOURS The Trypanocidal Action of Pentavalent and Trivalent Arsenicals in Vivo (after Voegtlin and Smith58)
From page 11...
... THE TOXICITIES OF ARSONIC ACID AND THE CORRESPONDING ARSENOSO COMPOUNDS (B) THE TRYPANOCIDAL ACTIVITIES IN VIVO OF ARSONIC ACIDS AND THE CORRESPONDING ARSENOSO COMPOUNDS (Summarized from 18a, b, 20 and 211l)
From page 12...
... 3COOH 140 12 12 >190 1.26 >150 p-NH2 165 1. 5 110 TABLE III REPRESENTATIVE MONOSUBSTITUTED ARSENOSOBENZENES TESTED FOR BIOLOGICAL ACTIVITY (Summarized from 18a, b, 20, 21.i, b)
From page 13...
... Their parasiticidal activity was studied with Treponema pallidum and Trypanosoma equiperdum, both iri vitro and in vivo: and a few representative compounds were further tested ill vitro with Trypanosoma cruzi and Leishmania donovani. For the assay of treponemicidal activity uj vitro, an acute testicular syphiloma was emulsified, and graded concentrations of arsenicals added to the particle-free extract.
From page 14...
... 6) v X JC -- X OH X X X X Cl X CH3 X NO2 X X NHCOCH3 X X 'Number of isomeric compounds prepared THE CORRELATlON BETWEEN THE TOXlClTY OF ARSENOSOBENZENES IN MlCE AND RABBlTS 100 B 50 t 20 10 i 5 10 20 50 IOO RELATlVE TOXlClTY lN RABBlTS Fig.
From page 15...
... 20 0 K O -j £E uj§: gco O Ul 10 i 10 15 20 30 RELATIVE TREPONEMlCIDAL ACTIVlTY lN VITRO Fig. 5 Correlation Between Activity of Arsenosobenzenes on Treponema pallidum in Vivo and in Vitro 15' I8a' b- 21
From page 16...
... B Biological Activity of Substituted Arsenosobenzenes The effect of single substituents on the toxicity and treponemicidal activity of arsenosobenzene is shown in Fig.
From page 19...
... x z ri iM X U X O Z X Z U A Z ' O zo o u O X z z .i«.
From page 20...
... a fM V X X 0 v 0 0 -o ^H 0 L^ c X 8o§|? Comprt esubstituted pheeyl arseeo X X X K ^ o o o o S o o o o o u u u u o i^ m^Tj^i 'J O u u ~' I -COOH -CSH .CSH iMl iM U iM iT O U I I I 2 O Z Z Z CO D Ol ai < '-i cxi ai a| at cxi E| 01 m CX|fl (X|m .o 51 E g i £ '2 « *
From page 21...
... A third group of substituents concerning which it was possible to make some generalizations with respect to biological activity were the acid amides Compounds so substituted were remarkably uniform in their toxicity and parasiticidal activity. As shown in Table VII, their direct trypanocidal and treponemicidal activities were intermediate between those of the generally inactive acids and the highly active arsenosobenzene.
From page 22...
... 90 85 " 8.0 7.5 7.0 6.5 6.0 5.5 5.0 pH 4.S Fig. 8 The Effect of pH on the Trypanocidal Activity of Ac id-substituted Arsenosobenzenes 17 Figures given in parenthesis are the pK1 values of the various acids
From page 23...
... in ^O .M .S l o « U i O X O x 1 « > r0 r^] XX N eZ Z X N 0 Unsubstituted prteeyt arseeoxide r g rg Z iM 00 fMQ 5 u u o z p-CONHC2H4OH p-SO2NHC2H4OH p-CONHCH2CN 3-NH2-4-CONH2 3-OH-4-CONH2 a 1 U El ai al a| a; al ai H li al ai ai ai El ai ai
From page 24...
... 5. The Importance of the Terminal Grouping in a Substituent Single substituents have thus been shown to have widely varying effects on the toxicity and parasiticidal activity of arsenosobenzene.
From page 25...
... 5 -CONHC2H5 26 59 2.3 -CON(C2H5) 2 64 53 0.83 -CONHC6H5 101 97 0.96 TABLE IX THE TREPONEMICIDAL ACTIVITY AND TOXICITY OF AMINOPHENOL-SUBSTITUTED ARSENOSOBENZENES l 8b Substituent Groups Molar Toxicity Molar Treponemicidal Activity Ratio of Activity: Toxicity 3-NH2-4-OH 6.9 42 6.
From page 26...
... RAs(SR") 2 + 2R'SH Thioarsenite Tissue Tissue Free thiol thioarsenite thiol In such case an excess of thiol would inhibit parasiticidal activity by competing with the tissue thiol for the thioarsenite.
From page 27...
... 27 TABLE X THE RELATIVE TOXICITY AND TREPONEMIC1DAL ACTIVITY OF THIOARSENITES1 AND THE CORRESPONDING ARSENOSO COMPOUNDS183 Substituent Group Relative Molar Treponemicidal Activity in vitro Relative Molar Toxicity in White Mice SRl/ OA/ ^SR SRl/ Q.,o Ratio OA,o OA<*
From page 28...
... of 10^ sedimented organisms = 0.48 cc. Substituted Arsenosobenzene R-AsO Relative Trypanocidal Activity (referred to arsenosobenzene as 100)
From page 29...
... A few were, however, highly active against Trypanosoma equiperdum, Schizotrypanum cruzi and Le:.shmania donovani, and others were active against Treponema pallidum (cf. Table XI)
From page 30...
... 9. The Inhibition of the Trypanocidal Action of Oxophenarsine in White Mice by 2.
From page 31...
... * He showed that papain was inhibited by both arsenoso compounds and arsonic acids, and that this inhibition was reversed by glutathione.
From page 32...
... arsenoso compounds combine with sulfhydryl compounds to form reasonably stable thioarsenites; (b) many enzyme groups contain sulfhydryl groups which are necessary in the intact state for the action of the enzyme, and such enzymes are inactivated by arsenoso compounds and other arsenicals; (c)
From page 33...
... Actually, no correlation whatever was found between the Hammettlvalue's, and either the toxicity or the parasiticidal activity of the arsenoso compounds as previously described in Section II B Again on the basis of the Hammett equation, if the parasiticidal action of arsenicals and their toxicity to the host were quantitatively dependent upon their reactivity with thiol groups in the parasite and in the host, then the therapeutic index of a series of arsenoso compounds in a given infection should be reasonably uniform.
From page 35...
... It was first shown by Thuret that a suspension of red blcod cells in vitro_ bound the highly active arsenoso compounds, but not the relatively inactive arsonic acids. ° This finding was extended by Hogan and Eagle, who demonstrated that in a large series of arsenoso compounds the amount of arsenic bound by red blood cells ill vitro under standard conditions was roughly proportional to the systemic toxicity of the arsenical, 3^ strongly suggesting a causal relationship (Fig.
From page 36...
... The importance of cell permeability is further indicated by the effect of pH on the parasiticidal activity of acid substituted arsenoso compounds (Eagle'7)
From page 37...
... "°1 SUMMARY 1. Of the three types of arsenicals used in the treatment of spirochetal and protozoal diseases, only the arsenoso compounds have a direct parasiticidal activity, the arsonic acids and arseno compounds being active by virtue of their conversion to arsenoso compounds in the animal body.
From page 38...
... (g) Both the toxicity and direct tryponemicidal activity of thioarsenites were somewhat less than those of the corresponding arsenosobenzene; and in the treatment of rabbit syphilis, the therapeutic index was also no better than that of the parent compound.
From page 39...
... , Blood Levels, Renal Clearance and Chemotherapeutic Activity, with Particular Reference to Arsenicals and Penicillin. Chapter in "Evaluation of Chemotherapeutic Agents", New York Academy of Medicine, Section on Microbiology, Symposium No.
From page 40...
... 40 22. Eagle, H
From page 42...
... In attempting to plot either the log of the activity or the log of the toxicity, which must be a function of this sulfhydryl reaction, we made several attempts to isolate the actual reaction and study either the rate or the hydrolysis constants, and those studies are still going on. We have not been able, so far, actually to isolate the reaction and study either the rate or the hydrolysis.
From page 43...
... Burchenal's question this was a spontaneously occurring resistant variant, which developed in the absence of exposure to an arsenical. I wish we had some explanation of the fact that certain arsenicals are bound by these resistant strains just as actively as they are by normal trypanosomes, and are correspondingly active, while others are not bound at all, and are correspondingly inactive.


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