- Email: [email protected]
Chap. 30 Antiradiation Agents
3 24 -
Sect. VI a a P * 30
-
Topics in Chemistry
S m i s s m a n , Ed.
ANTIRADIATION AGENTS William 0. Foye
Department of Chemistry Massachusetts College of Pharmacy Boston, Massachusetts The medicinal chemistry of antiradiation agents is concerned here primarily with the development of new radioprotective agents and their activity. Such a discussion necessarily omits much of the work in radiation biochemistry and contiguous areas, although interesting new developments where chemical interactions have been shown to take place are included. The subJect of ohemical radioprotection and radiosensitization of tumor-bearing systems has been touched only briefly, covering events subsequent to the reviews cited, and is really worthy of a separate review. Methods of biological radioprotection and clinical aspects have not been covered in this report. Preparations of potentially active antiradiation agents without report of protective activities regretfully have been left for future reviewers when radioprotective results may have become known.
-
Reviews. New books concerning chemical radioprotectionl and t m n c i p l e s of radiation protection2 have appeared. Current concepts of chemical protection against IonizrLng radiation have been re~iewed,~" and the role of copper and peroxides in radiobiology has been discussedOs The 92 papers presented at the First International Symposium on Radiosensitizers and Radioprotective Dmgs in 1964 have appeared in a well-organized volume.6 The use and pharmacology of radioprotective aminothiols, disulfides, nitriles, and other compounds has been r e v i e ~ e d . ~ Radioprotective Compounds 2 Mammals.- Chemical modification of the MEA and MBQ structures has continued actively, although no real improvement over these two basic structures has-been re: ported in the past two years. A new direction f o r syntheses of potential radiation protectors appears to be among heterocyclic systems, where protective activity is being found apart from any sulfur content of the molecules. Several non-basic thiols have also been reported active, and sulfur-containing analogs of the amino acids have shown some radioprotective effects. Protection by metal chelating agents, metal chelates, and metal ions themselves has pointed to the importance of the role of metal Ions in cellular radiation effects. Heterocycles. Among a group of 22 thiazolines tested in mice vs. 850r (V-radiation), "aminoethylthiazoline" provided up to 30rprotection, presumably because of its ability to hydrolyze to protective fragments in v i v ~ . Of ~ 15 imldazoles and related N-heterocycles, benzimidazole gave rats 90% protection 2. a lethal dose of x-raysOg In a subsequent series of imldazoles and benzimidazoles, ~~naphthylmethyl-2-imidazoleprovided 100% protection to mice.
Chap. 30
Antiradiation
Foye
325 -
3,5-Dlmethyl-l-( dlmethylcarbamoy1)-pyrazole was found to give 50s protection to mice E. x-rays (LDloo).lf Several C-alwlated thiazolines protected mice against a lethal dose of x-rays, and the activity was comparable to that from the mercaptoamlnes obtained on hydrolysis of the thiazolinea.12 A copolymer consisting of S-vinyl(2,2-dimethylthiazolidyl)-N-monothiolcarbamate and N-vivlpyrrolidone was also found effective E. x-rays in mice.13
Two 5,7-dihydroxyisoflavones, representing a class of compounds for which radioprotective ability has been controversial, were shown to afford 100% protection to mice 7OOr when administered percutaneously but were not protective by the intraperitoneal route l4
E.
.
Thiols. -Acetamldinlum thiosulfates, RNHC( =NH2+) CH2SS03-, were radioprotect1ve1%o mice 2. a lethal dose of x-rays, and a substituted 2-amlnothiosulfiric acid, prepared froma-amlnobutyric acid, also gave good protection.16 The thiosulfonate of NH~CH~CH~SOZSCHPCH~NH~, afforded good protection to mice, and it also protected 2. marcescens at pH 7, where it is decomposed to cystamlne and hypotaurine, but not at pH 4, where it is stable.18 The aminothio acids derived fromdC-and/J-alanine and gigcine showed Good prono protective activity in rodents but did in bacteria. tection in mice was provided by the@-aminoethylamlde,of thioglycollic acid, HSCHaCONHCH2CHzNHa, as well afsby N,N -bis(mercaptoN-Acetylthioacetyl)hydrazine, however, s.800r (x-rays) glycollic hydrazide, HSCH2CONHNHCOCH3, and its disulfide increased the LDSO of x-radiation in mice.20
T#,
.
The mixed disulfide of MEA and o-mercaptobenzoic acid was protective in mice z. a lethal dose of x-rays; this compound showed remarkable structural specificity, neither the meta or para isomers nor a variety of other close relatives were protectivem21 Thiols lacking a basic function also appeared with radioprotective activity. 2,3-Dithiosuccinic acid (both meso and dl 1-Phenyl-1forms) protected 90% of mice 7OOr (x-rays).22 acetthio-2-nitroethane, and its next higher homolog, showed some activity in mice VS. an LDloo dose of x-rays, whereas the corresponding amlnothix, 2-mercapto-2-phenethylamlne, was
E.
Numerous other interesting amlnothiol derivatives were synthesized without report of activities. ~lOC-Diallcyl-~-amlnothiols, and addition of long chain however, were found inactive in mice, N-alkyl groups to AET and the trithiocarbonate of MJ3G, RMIC(=NH2+) CH2CH2SC(=S) S-, also resulted in loss of a~tivity.~” Other Compounds. Hexacoordinated chlorophyllin-metal chelatea= with Co,M&,Mn,V) have been claimed to be radioprotective in mice; and a series of 1,5-diphenylthiocarbohydrazides capable o f metal ion chelation provided 40-65s protection to rats 750rm27 An a w n analog, ~-2,4,5-trichlorophenoxyethanol,
E.
326
Sect. VI
-
Topics in Chemistry
S m i s s m a n , Ed.
E.
which reduces normal oxygen consumption, protected mice 800r (V-radiation).28 The proestrogen, chlorotrianisene (tri-p-anisylchloroethylene), has shown the surprising property of protecting 80% of mice(vs. 590-690r) when administered 5-30 days prior to x-irradiati o E 2*
E.
Pyromellitic and benzenepentacarboxylic acids, but not 102% when administered mellitic acid, were protective in mice in high doses.30 It was considered that the activity resided In the osmotic effect of these polyionic substances which could cause hypoxia, rather than in the chelation of calcium ions known to occur. 750r, were believed to Gallate esters, which protected rats inhibit chain oxidation
E.
E.
Radioprotection of Other Systems.- Glycine exerted a protective Soor, but showed little effect effect on the catalases in mice on ATPase, pyrophosphatase, or gl~taminase.~~ Selenomethionine and selenocystine showed a greater protective effect for amino acids, yeast alcohol dehydrogenase, and RNase than the analogous sulfur cornpo~nds.~~ The r@ioprotective effect of both glycerolg4 and dimethyl sulfoxide for catalase was attributed to complex formation with the of catalase. Protection of catalase by a++, pe*, and ~n ions, however, was explained by radical scavenging.36
irs
Iron and copper ions also inoreased radioresistance of ceruloplasmin and hemoglobin, and a similar effect was shown by Nipicolinic acid and Ni-glycine chelates.s7 Other chelates did not protect these proteins. A correlation between radioprotection of proteins b inorganic ions and hydration energy of the ions was discerned, Incorporation of iron in erythrocytes was not inhibited by radiation (75r in mice) in presence of MEA, histamine, or serotonin,g9 Ehrlich ascites cells in mice VS. 400r (V-rays) were protected by eitheroC- or 0-alanine followed by arginine.40 AET protected both cancerous and healthy cells in mice from x-rays, but did increase the survival rate of cancerous mice.41 The gastrointestinal tract of rats was protected by perfusion with MEG gOCr, but Dunning leukemia cells were not eradicatede4= The hematopoietic 5OOr system of mice was protected by cysteine thiosulfonate (x-rays), but Crocker sarcoma cells also received protection. 43 The subject of chemical radioprotection and tumors has been recently reviewed. 44
E. E.
Radiosensitizers.- A review has appeared on studies of radiosensitizers in radlothera y of tumors.45 Radiosensitization of Ehrlich carcinoma cells by -methyluracil and 5-hydroxymethyl-4methyluracil has been O b S e r ~ e d ,as ~ ~well as by propyl gallate and other antioxidant^.^^ Mice proved to be radiosensitive to bdeoxypyridoxine, INH, Dbtryptophan, and Dbkynurenine E. 590r; taurine afforded some protecti~n.~~ Dogs were found radiosensitive to quinoxalinedi-N-oxide, whereas mice had been protected by this compound.4s Colcemide and urethane increased radiosensitivity in
t
Chap. 30
Anti r a dia tion
Foy e
327 -
mice when administered twelve hours prigr, but protected when given 48 hours prior to x-irradiation. Erythrocytes were sensitized by iodoacetic acid and related alelating agents ncluding ethyl methanesulfonate, iodine, and N-ethylmaleimide.5f E, coli cells have shown radiosensitivity to $,8 -dichlorodietGl =one, whereas the monosulfoxide of cystamine was only slightly sensitizing, and ions gave some protection.s2 Folic acid analogs53 and spar~omycin~~ sensitized -E. -coli to ionizing radiation, and Cu* ions sensitized 2. flexneri under anaerobic but not aerobic condition~.~~
-
Modes of Radioprotection.- The various mechanisms proposed for chemicarradioprotection have been recently evaluated by Bacq: A convincing argument in favor of anoxia was made for the radioprotective action of histamine, acetylcholine, and the catecholmines, but it was believed that the thiols and disulfides protect by interactions with free radicals and oxygen. Arguments in favor of radical interaction, and transfer of energy to sulfur, in combination with mixed disulfide formation, have been advanced recently in regard to protection by thiols.56 None of the complexities of this problem of explaining radioprotection have been removed by recent results, but it appears pertinent nevertheless to cite evidence supporting some of the current concepts.
No correlation between hypothermia and radioprotection by
MEA, cysteine, cyanide, 5-hydroxytryptamlne, or diethyldithio-
carbamate has been reported from two l a b o r a t o r i e ~ ;both ~~~~~ groups conclude that the interaction of MEA, at least, with free radicals constitutes its major protective role. A direct relation between radical inhibitory action and radiation protection was observed for antioxidant phenols, pyridines, and gallic acid esters.5s A correlation between vasoconstrictive effect and radioprotection was reported for the indole aminesO6*
It has been postulated that the introduction of thiols or disulfides into cells upsets the thiol-disulfide equilibria present, resulting in the increased formation of free thiol groups which can react with radicalti Instantaneous repair of damage by H transfer then takes place. Some evidence for this idea has since been reported. Increased amounts of an endogenous compound with reactive thiol groups has been observed after MEA treatment,62 as well as an increase in the thiol level of spleen,63 and the The latter compound could release of intracellular gl~tathione.~~ eliminate H a 0 2 via the glutathione peroxidase pathwayO6' The complexation of enzymes by protective agents has been proposed, and evidence for the existence of a protective glyceroliron-catalase complex has been advanced.6s Spectrophotometric evidence for the existence of complexation between catalase and MEA, MEG, and diethyldithiocarbamate has been observed, and the subject of metalloenzyme complexation discussed.66 Radioprotection of lactatedehydrogenase by complex formation with D-lactate has been and decreased catalase inactivation in the presence of owgen has been attributed to formation of catalase-peroxide complexes. 88
3 28 -
Sect. VI
-
Topics in Chemistry
S m i s s m a n , Ed.
The problem of energy t r a n s f e r , from radiation-induced r a d i c a l s t o e i t h e r v i t a l o r p r o t e c t i v e molecules, l i e s a t t h e h e a r t of t h e molecular events t a k i n g p l a c e i n t h e course of r a d i a t i o n p r o t e c t i o n . Any of t h e c u r r e n t hypotheses of r a d i o p r o t e c t i o n must u l t i m a t e l y consider t h i s e f f e c t . However, some understanding of t h e process is emerging5s*e5*eB-71 mainly by use of e.s.r. spectroscopy. References
.
(1) Bacq, Z.M., "Chemical P r o t e c t i o n Against I o n i z i n g Radiation," Charles C Zhomas, S p r i n g f i e l d , Ill., 1965. (2) Eaves, G . , P r i n c i p l e s of Radiation P r o t e c t i o n , " I l i f f e Books, London, 1964. (3) Baraboy, V.A., "Current Concepts of Mechanisms $f t h e P r o t e c t i v e Effect of Chemical Compounds Against Radiation, Office Tech. 1964. Serv., J.P.R.S. Report 26,842, Washington, D.C. 4 Langendorff, HiI, Arzniemittel Forsch., 463 (1965). Copper and Peroxides i n Radiobiology and 151 Schubert , Medicine, Charles C. Thomas, S p r i n g f i e l d , Ill., 1964. (6) P a o l e t t i , R. and Vertua, R . , "Progress in Biochemical Pharmacology," Vol. 1, S. U r g e r A.G., B a s e l , and Butterworths, Washington, D.C., 1965. Shapiro, B . , Med. Clln. N. Am., 48, 547 Shashkov, V.S., & Radiobiologiya , R i n a l d i , R. and Bernard, Y., R i n a l d i , R., Bernard, Y., and
u,
u.,
(1965)
(11) b o x , J . M . , Freeman R.G., and T r o l l , D., A c t a Radiol., Therapy, Phys. B i o l . , 2, 66 11965) (12) Handrick, G.R., Atkinson, E.R., Granchelli, F.E., and Bruni, R.J., J . Med. Chem., 8, 762 (1965). (13) Overberger, C.G., Ringsdorf, H., and Avchen, B., U ., 8, 862
.
(1965) (14) Gazave, J . M . ,
Modigliani, D.C., and Ligny, G., Progr. Biochem. Pharmacol. Vol. 1, S. Karger A.G., Basel, 1965, P. 554. , 766 (1964). Bauer, L. and Sandberg, K . R . , J. Med. Chem., Gershon, H., and Rodin, R., U d . , 8, 864 (19 5 ) . F i e l d , L. F e r r e t t i , A., Crenshaw, R.R., and Owen, T.C., ibid.,
5
1,39 (1964). (18) Owen, T.C., Parker, M.S., and S t e r n , G.M., J . Pharm. Pharmacol., 108 (1965). (19) Atkinson, E.R., Handrick, G.R., Bruni, R.J., and G r a n c h e l l i , F.E., J. Med. Chem. 8, 29 (1965). (20) Rose, F.L. and Walpole, A.L., Pro r. Biochem. Pharmacol., Val. 1, S. Karger A.G., Basel, 19 5, P. 432. Crenshaw, R.R., and F i e l d , L., J . Org. Chem., 30, 175 (1965). Cugurra, F., and B a l e s t r i , E., Progr. Biochem. Pharmacol., v o i . 1, S. Karger A.G., Basel, 1965, P. 507.
z,
%
Chap. 30
Antiradiation
329 -
Foye
B h a t , K.V., and Mecarthy, W.C., J . Pharm. S c i . , 51, 1545 (1964). Stacy, G.W. Barnett, B.B., and Strong, P.L., J. Org. Chem., 311, 592 (1965) (25) Foye, W.O., Laiala, E.F. Georgiadis, M., and Meyer, W.L., J. Pharm. S c i . , 557 11965) 26 Kasugai, N., J. Pharm. SOC. J a b n , 84, 1152 (1964). (271 G o r d e t s k i i , A.A., e t a l . , Pato enez, Eksperim. P r o f i l a k t i k e i Porazhenii ~MOSCOW) , 1964, 179; Chem. Abstrs.,
s,
I
S t e e r s , C.W.,
and Norman, D.,
K. and Langendorff, M.,
Nature,
Strahlentherapie,
206,
207
128,109
Nature, 205, 816 (1965). A.A., Baraboi, V.A,, and C h e r n e t s k i i , V.P. , Vopr. Biofiz. i Mekhanizma D e i s t v i y a I o n i z i r . R a d i a t s i i , 1964, 159; Chem. Abstrs., 18617 (1965). (32) Capalna, S., Ghizari, E., S t e f a n , M., and Petec, G. , S t u d i i Cercetari F i z i o l . , 2, 369 (1964) ; Chem. Abstrs. , 62, 13488 (1965) Shimazu, F. and Tappel, A.L., Radiation Reg. , 310 (1964) Lohmann, W., MOSS., A.J., Perkins, W.H., and Fowler, C*F., Biophysik, 2, 16 (1964). (35) Lohmann W,, Moss, A.J., a n d ' p e r k i n s , W.H., J . Nucl. Med., 6 519 (1965) (36) Lo-m, W. Moss, A . J . , and Perkins, W.H., Radiation R e s . , 24, 9 (19655. (37) Krsmanovic-Simic, D. and Duchesne, J. , Compt Rend. , 260
a,
u,
6455 (1965). Ueno, Y., C o l l e c t i o n Czech. Chem. Commun. , 30, 2839 (1965) Koch, R. and S e i t e r , I., S t r a h l e n t h e r a p i e , 124, 99 (1964) Bregadze, I .F. , Radiobiologi-, 5, 97 (1965). Maisin, J.R.
Leonare, A . , and Hugon, J., J. Belge Radiol.,
a, 511 (1964).
(42) &&ms, J .L., Ambrus, C.M. , Pickren, J e w . t Felt23 E-, and Back, N., Cancer R e s . , E , 609 (1965) (43) Zebro, T., Stachura, J., Prochnicka, B. , and Syczepkowski, T. , Acta Med. Polona, 6, 155, 171 (1965). (44) Greco, S . , Gasso, G., and B i l l i t t e r i , A., Progr. Biochem. pharmacol., Voi. 1, S. Karger, A.G., Basel, 1965, P. 277. M i t c h e l l , J .So i b i d . , 335. Polsklna, R.I., Bychenkova, M., and Zalesskaya, L. , Acts unio 1219 (1964); Chem. Abstrs. 62, I n t e r n . Contra Cancrum, 9429 (1965) (47) Afanas'ev, G.G., Lipchina, L.P., and Pelevina, I.I., ibid., 1213 (1964) ; Chem. A b s t r s . , 62, 9428 (1965) (48) Melching, H.J. Abe, M., and S t r e f f e r , C., S t r a h l e n t h e r a p i e , 125,352 (19643 (49) m l e y , T.J., Trwnbull, W.E., and Cannon, J.A. , Progr. Biochem. pharmacoi., Voi. 1, S. Karger A.G., Basel, 1965, P o 359.
.
a,
a,
0
Sect. VI
3 30 -
-
Topics in Chemistry
Rothe, W.E., Grenan, M.M., and Wilson, S.M., i b i d . , 372. Bianchi, M.R., Boccacci, M., Misiti-Donello, P., and Q u i n t i l i a n i , M., I n t e r n . J . Radiation Biol., 8, 329 (1964) 8, 519 (1964). S t u y v a e r t , J . and Bacq, Z.M., iu., P i t i l l o , R.F., Lucas, M., Blackwell, R.T., and Wooley, C., J. Bacteriol., 1548 (1965) 773 (1965) P i t i i i o , R.F., e,t a l . , Nature Cramp, W.A., i b i d . 7 2 0 6 , 636 P i h l , A . and E e r , T , , Progr. Biochem. Pharmacol., Vol. 1, S. Karger A.G., Basel, 1965, P. 85. Bacq, Z.M.,Beaumariage, M.L., and Liebecq-Hutter, s o , I n t e r n . J. Radiation B i o l . , 2, 175 (1965). Magdon, E., Nature, 204, 484 (1965) Burlakova, E.B., et Dokl. Akad. Nauk S.S.S.R. ,
.
a,
(57)
S m i s s m a n , Ed.
.
z,
934 (1965).
(60) Zherebchenko, P.G.,
.
164,
e t a l . , Patogenez, Eksperim. P r o f i l a k t i k e i Porazhenii (Moscow), 1964, 193; Chem. Abstrs.,
Nature, 203, 162 (1964) M.M., Sokolova, O.M. , and Tarasenko, A.G., Dokl. Akad. Nauk S .S.S.R., 441 (1965) Jamieson, D., Nature, 207, 541 (1965). Revesz, L. and Modig, H., U d . , 207, 430 (1965). Lohmanrl,W., Progr. Biochem. Pharmacol., Vol. 1, S Karger A.G. Basel, 1965, p . 118. Foye, W.O., and Mickles, J . , i b i d . , 152. Dose, K., i b i d . , 161. Magdon, E., S t r a h l e n t h e r a p i e , 258 (1965). Alexander, P., L e t t , J.T., and Dean, C . J . , Progr. Biochem. Pharmacol., Voi. 1, S. Karger A.G., Basel, 1965, p . 22. Nicolau, C., Qrigorescu, S., and Nedelcu, C., i b i d . , 472. C a s t e l e i j n , G., Depireux, J., and Muller, A . , Intern. J . Radiation B i o l , 8, 157 (1964)
P.,
164,
126,
.
.
,
Sect. VI a a P * 30
-
Topics in Chemistry
S m i s s m a n , Ed.
ANTIRADIATION AGENTS William 0. Foye
Department of Chemistry Massachusetts College of Pharmacy Boston, Massachusetts The medicinal chemistry of antiradiation agents is concerned here primarily with the development of new radioprotective agents and their activity. Such a discussion necessarily omits much of the work in radiation biochemistry and contiguous areas, although interesting new developments where chemical interactions have been shown to take place are included. The subJect of ohemical radioprotection and radiosensitization of tumor-bearing systems has been touched only briefly, covering events subsequent to the reviews cited, and is really worthy of a separate review. Methods of biological radioprotection and clinical aspects have not been covered in this report. Preparations of potentially active antiradiation agents without report of protective activities regretfully have been left for future reviewers when radioprotective results may have become known.
-
Reviews. New books concerning chemical radioprotectionl and t m n c i p l e s of radiation protection2 have appeared. Current concepts of chemical protection against IonizrLng radiation have been re~iewed,~" and the role of copper and peroxides in radiobiology has been discussedOs The 92 papers presented at the First International Symposium on Radiosensitizers and Radioprotective Dmgs in 1964 have appeared in a well-organized volume.6 The use and pharmacology of radioprotective aminothiols, disulfides, nitriles, and other compounds has been r e v i e ~ e d . ~ Radioprotective Compounds 2 Mammals.- Chemical modification of the MEA and MBQ structures has continued actively, although no real improvement over these two basic structures has-been re: ported in the past two years. A new direction f o r syntheses of potential radiation protectors appears to be among heterocyclic systems, where protective activity is being found apart from any sulfur content of the molecules. Several non-basic thiols have also been reported active, and sulfur-containing analogs of the amino acids have shown some radioprotective effects. Protection by metal chelating agents, metal chelates, and metal ions themselves has pointed to the importance of the role of metal Ions in cellular radiation effects. Heterocycles. Among a group of 22 thiazolines tested in mice vs. 850r (V-radiation), "aminoethylthiazoline" provided up to 30rprotection, presumably because of its ability to hydrolyze to protective fragments in v i v ~ . Of ~ 15 imldazoles and related N-heterocycles, benzimidazole gave rats 90% protection 2. a lethal dose of x-raysOg In a subsequent series of imldazoles and benzimidazoles, ~~naphthylmethyl-2-imidazoleprovided 100% protection to mice.
Chap. 30
Antiradiation
Foye
325 -
3,5-Dlmethyl-l-( dlmethylcarbamoy1)-pyrazole was found to give 50s protection to mice E. x-rays (LDloo).lf Several C-alwlated thiazolines protected mice against a lethal dose of x-rays, and the activity was comparable to that from the mercaptoamlnes obtained on hydrolysis of the thiazolinea.12 A copolymer consisting of S-vinyl(2,2-dimethylthiazolidyl)-N-monothiolcarbamate and N-vivlpyrrolidone was also found effective E. x-rays in mice.13
Two 5,7-dihydroxyisoflavones, representing a class of compounds for which radioprotective ability has been controversial, were shown to afford 100% protection to mice 7OOr when administered percutaneously but were not protective by the intraperitoneal route l4
E.
.
Thiols. -Acetamldinlum thiosulfates, RNHC( =NH2+) CH2SS03-, were radioprotect1ve1%o mice 2. a lethal dose of x-rays, and a substituted 2-amlnothiosulfiric acid, prepared froma-amlnobutyric acid, also gave good protection.16 The thiosulfonate of NH~CH~CH~SOZSCHPCH~NH~, afforded good protection to mice, and it also protected 2. marcescens at pH 7, where it is decomposed to cystamlne and hypotaurine, but not at pH 4, where it is stable.18 The aminothio acids derived fromdC-and/J-alanine and gigcine showed Good prono protective activity in rodents but did in bacteria. tection in mice was provided by the@-aminoethylamlde,of thioglycollic acid, HSCHaCONHCH2CHzNHa, as well afsby N,N -bis(mercaptoN-Acetylthioacetyl)hydrazine, however, s.800r (x-rays) glycollic hydrazide, HSCH2CONHNHCOCH3, and its disulfide increased the LDSO of x-radiation in mice.20
T#,
.
The mixed disulfide of MEA and o-mercaptobenzoic acid was protective in mice z. a lethal dose of x-rays; this compound showed remarkable structural specificity, neither the meta or para isomers nor a variety of other close relatives were protectivem21 Thiols lacking a basic function also appeared with radioprotective activity. 2,3-Dithiosuccinic acid (both meso and dl 1-Phenyl-1forms) protected 90% of mice 7OOr (x-rays).22 acetthio-2-nitroethane, and its next higher homolog, showed some activity in mice VS. an LDloo dose of x-rays, whereas the corresponding amlnothix, 2-mercapto-2-phenethylamlne, was
E.
Numerous other interesting amlnothiol derivatives were synthesized without report of activities. ~lOC-Diallcyl-~-amlnothiols, and addition of long chain however, were found inactive in mice, N-alkyl groups to AET and the trithiocarbonate of MJ3G, RMIC(=NH2+) CH2CH2SC(=S) S-, also resulted in loss of a~tivity.~” Other Compounds. Hexacoordinated chlorophyllin-metal chelatea= with Co,M&,Mn,V) have been claimed to be radioprotective in mice; and a series of 1,5-diphenylthiocarbohydrazides capable o f metal ion chelation provided 40-65s protection to rats 750rm27 An a w n analog, ~-2,4,5-trichlorophenoxyethanol,
E.
326
Sect. VI
-
Topics in Chemistry
S m i s s m a n , Ed.
E.
which reduces normal oxygen consumption, protected mice 800r (V-radiation).28 The proestrogen, chlorotrianisene (tri-p-anisylchloroethylene), has shown the surprising property of protecting 80% of mice(vs. 590-690r) when administered 5-30 days prior to x-irradiati o E 2*
E.
Pyromellitic and benzenepentacarboxylic acids, but not 102% when administered mellitic acid, were protective in mice in high doses.30 It was considered that the activity resided In the osmotic effect of these polyionic substances which could cause hypoxia, rather than in the chelation of calcium ions known to occur. 750r, were believed to Gallate esters, which protected rats inhibit chain oxidation
E.
E.
Radioprotection of Other Systems.- Glycine exerted a protective Soor, but showed little effect effect on the catalases in mice on ATPase, pyrophosphatase, or gl~taminase.~~ Selenomethionine and selenocystine showed a greater protective effect for amino acids, yeast alcohol dehydrogenase, and RNase than the analogous sulfur cornpo~nds.~~ The r@ioprotective effect of both glycerolg4 and dimethyl sulfoxide for catalase was attributed to complex formation with the of catalase. Protection of catalase by a++, pe*, and ~n ions, however, was explained by radical scavenging.36
irs
Iron and copper ions also inoreased radioresistance of ceruloplasmin and hemoglobin, and a similar effect was shown by Nipicolinic acid and Ni-glycine chelates.s7 Other chelates did not protect these proteins. A correlation between radioprotection of proteins b inorganic ions and hydration energy of the ions was discerned, Incorporation of iron in erythrocytes was not inhibited by radiation (75r in mice) in presence of MEA, histamine, or serotonin,g9 Ehrlich ascites cells in mice VS. 400r (V-rays) were protected by eitheroC- or 0-alanine followed by arginine.40 AET protected both cancerous and healthy cells in mice from x-rays, but did increase the survival rate of cancerous mice.41 The gastrointestinal tract of rats was protected by perfusion with MEG gOCr, but Dunning leukemia cells were not eradicatede4= The hematopoietic 5OOr system of mice was protected by cysteine thiosulfonate (x-rays), but Crocker sarcoma cells also received protection. 43 The subject of chemical radioprotection and tumors has been recently reviewed. 44
E. E.
Radiosensitizers.- A review has appeared on studies of radiosensitizers in radlothera y of tumors.45 Radiosensitization of Ehrlich carcinoma cells by -methyluracil and 5-hydroxymethyl-4methyluracil has been O b S e r ~ e d ,as ~ ~well as by propyl gallate and other antioxidant^.^^ Mice proved to be radiosensitive to bdeoxypyridoxine, INH, Dbtryptophan, and Dbkynurenine E. 590r; taurine afforded some protecti~n.~~ Dogs were found radiosensitive to quinoxalinedi-N-oxide, whereas mice had been protected by this compound.4s Colcemide and urethane increased radiosensitivity in
t
Chap. 30
Anti r a dia tion
Foy e
327 -
mice when administered twelve hours prigr, but protected when given 48 hours prior to x-irradiation. Erythrocytes were sensitized by iodoacetic acid and related alelating agents ncluding ethyl methanesulfonate, iodine, and N-ethylmaleimide.5f E, coli cells have shown radiosensitivity to $,8 -dichlorodietGl =one, whereas the monosulfoxide of cystamine was only slightly sensitizing, and ions gave some protection.s2 Folic acid analogs53 and spar~omycin~~ sensitized -E. -coli to ionizing radiation, and Cu* ions sensitized 2. flexneri under anaerobic but not aerobic condition~.~~
-
Modes of Radioprotection.- The various mechanisms proposed for chemicarradioprotection have been recently evaluated by Bacq: A convincing argument in favor of anoxia was made for the radioprotective action of histamine, acetylcholine, and the catecholmines, but it was believed that the thiols and disulfides protect by interactions with free radicals and oxygen. Arguments in favor of radical interaction, and transfer of energy to sulfur, in combination with mixed disulfide formation, have been advanced recently in regard to protection by thiols.56 None of the complexities of this problem of explaining radioprotection have been removed by recent results, but it appears pertinent nevertheless to cite evidence supporting some of the current concepts.
No correlation between hypothermia and radioprotection by
MEA, cysteine, cyanide, 5-hydroxytryptamlne, or diethyldithio-
carbamate has been reported from two l a b o r a t o r i e ~ ;both ~~~~~ groups conclude that the interaction of MEA, at least, with free radicals constitutes its major protective role. A direct relation between radical inhibitory action and radiation protection was observed for antioxidant phenols, pyridines, and gallic acid esters.5s A correlation between vasoconstrictive effect and radioprotection was reported for the indole aminesO6*
It has been postulated that the introduction of thiols or disulfides into cells upsets the thiol-disulfide equilibria present, resulting in the increased formation of free thiol groups which can react with radicalti Instantaneous repair of damage by H transfer then takes place. Some evidence for this idea has since been reported. Increased amounts of an endogenous compound with reactive thiol groups has been observed after MEA treatment,62 as well as an increase in the thiol level of spleen,63 and the The latter compound could release of intracellular gl~tathione.~~ eliminate H a 0 2 via the glutathione peroxidase pathwayO6' The complexation of enzymes by protective agents has been proposed, and evidence for the existence of a protective glyceroliron-catalase complex has been advanced.6s Spectrophotometric evidence for the existence of complexation between catalase and MEA, MEG, and diethyldithiocarbamate has been observed, and the subject of metalloenzyme complexation discussed.66 Radioprotection of lactatedehydrogenase by complex formation with D-lactate has been and decreased catalase inactivation in the presence of owgen has been attributed to formation of catalase-peroxide complexes. 88
3 28 -
Sect. VI
-
Topics in Chemistry
S m i s s m a n , Ed.
The problem of energy t r a n s f e r , from radiation-induced r a d i c a l s t o e i t h e r v i t a l o r p r o t e c t i v e molecules, l i e s a t t h e h e a r t of t h e molecular events t a k i n g p l a c e i n t h e course of r a d i a t i o n p r o t e c t i o n . Any of t h e c u r r e n t hypotheses of r a d i o p r o t e c t i o n must u l t i m a t e l y consider t h i s e f f e c t . However, some understanding of t h e process is emerging5s*e5*eB-71 mainly by use of e.s.r. spectroscopy. References
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(1) Bacq, Z.M., "Chemical P r o t e c t i o n Against I o n i z i n g Radiation," Charles C Zhomas, S p r i n g f i e l d , Ill., 1965. (2) Eaves, G . , P r i n c i p l e s of Radiation P r o t e c t i o n , " I l i f f e Books, London, 1964. (3) Baraboy, V.A., "Current Concepts of Mechanisms $f t h e P r o t e c t i v e Effect of Chemical Compounds Against Radiation, Office Tech. 1964. Serv., J.P.R.S. Report 26,842, Washington, D.C. 4 Langendorff, HiI, Arzniemittel Forsch., 463 (1965). Copper and Peroxides i n Radiobiology and 151 Schubert , Medicine, Charles C. Thomas, S p r i n g f i e l d , Ill., 1964. (6) P a o l e t t i , R. and Vertua, R . , "Progress in Biochemical Pharmacology," Vol. 1, S. U r g e r A.G., B a s e l , and Butterworths, Washington, D.C., 1965. Shapiro, B . , Med. Clln. N. Am., 48, 547 Shashkov, V.S., & Radiobiologiya , R i n a l d i , R. and Bernard, Y., R i n a l d i , R., Bernard, Y., and
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Topics in Chemistry
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