The polypeptide and protein inhibitors considered here belong to the general classification of macromolecular antagonists, in contrast to the usual small molecule metabolic inhibitors. That such structures exhibit
biological antagonism is in itself not too remarkable, since such macro-molecular antagonisms are well known in immunology and immuno-chemistry. As pointed out by Martin {211), for example, even the inter
ference phenomenon between viruses represents a competitive biological antagonism involving structures of high molecular weights. It is curious, however, that there are as yet so few examples of macromolecules which appear to be antimetabolites in the "classic" sense* in view of the infinite possibilities for metabolic antagonism in biological systems concerned with structures as complex as polypeptides and proteins. Alteration or replacement of the nonprotein moiety of conjugated proteins, for example, might be expected to result in an antagonist of the parent structure; tor example, among the polypeptide hormones relatively minor alterations in amino acid sequence or content exert profound effects on biological activity.
The mechanisms of action of polypeptide and protein inhibitors at the present time appear to range from the simple displacement of growth factors or enzyme substrates to surface phenomena resembling detergent activity, with consequent disorganization and disruption of the surface of the cell. There are exceptions in either case, but in general, the bio
logical activity of cationic or anionic linear polypeptides appears to be related to their electrostatic effects (277), whereas the biological activity of the cyclic polypeptide antibiotics appears to be related to their surface activity. It is of interest too that, with few exceptions, these active linear and cyclic polypeptides are basic, being positively charged at neutral pH.
The literature reviewed here provides some evidence as to the structural characteristics essential for the biological activity of linear polypeptides.
There is, however, little information concerning the relationship between structure and activity in the case of the cyclic polypeptide antibiotics or hormones.
The lack of more precise information concerning the mechanism of action of these complex structures may represent nothing more than de
ficiencies in current knowledge, or it may be that the inhibitory activity of such structures is more like the noncompetitive inhibition induced by certain other agents bearing little configurational similarity to known metabolites, as discussed by Woolley (364). There is abundant evidence to suggest that this may be the case, particularly among the polypeptide antibitiotics; but, nonetheless, it is stimulating to think, e.g., that some
thing of the structure of penicillinase might be adduced from its com
petitive inhibition by cephalosporin C .
There is little doubt that a better understanding of the biological ac
tivity exhibited by these complex structures is dependent in large part upon advances in knowledge of the structural detail and surface properties of polypeptides and proteins. The data presently available certainly do
not preclude metabolite (enzyme)-antimetabolite(antienzyme) mechanisms, and the continued application of the antimetabolite concept to studies concerned with the mechanism of action of macromolecular inhibitors may well provide the basis, not only for structural alterations designed to im
prove biological activity and/or reduce toxicity, but for the planned synthesis of new inhibitors as well. Research in this area is increasing, as evidenced by interest in the "directed biosynthesis" of actinomycins (355, 356) and the alteration of biologically active polypeptide antibiotics by chemical means (38, 39, Jfi, 857-359). These are difficult areas of re
search, involving complex chemistry and biochemistry, and progress may be slow. Nonetheless, efforts in this area should be encouraged and ex
panded, since, in theory at least, this kind of metabolic inhibitor should be as amenable to structural modification as are biological antagonists of lower molecular weight. Indeed, distinction between natural products (i.e. antibiotics) and synthetic chemotherapeutic agents is merely one of categorical source, since, in the last analysis, the inhibitory activity of agents of either natural or synthetic origin is biological antagonism (360) ; when sufficient mechanistic information is at hand, the antibiotics may very well prove to be antimetabolites in the true sense.
R E F E R E N C E S
1. Ε. B . Chain, Ann. Rev. Biochem. 27, 167 (1958).
2. R . O. Roblin, Jr., Chem. Revs. 38, 255 (1946).
3. F. W . Schueler, Science 103, 221 (1946).
4. E. Brand and J. T . Edsall, Ann. Rev. Biochem. 16, 224 (1947).
5. H . W . Florey, E. Chain, N . G. Heatley, M . A . Jennings, A . G. Sanders, E. P.
Abraham, and M . E. Florey, ''Antibiotics," Vols. 1 and I I . Oxford Univ. Press, London and N e w York, 1949.
6. W . S. Spector, ed., "Handbook of Toxicology," Vol. I I : Antibiotics. Saunders, Philadelphia, Pennsylvania, 1957.
7. H . Eagle and G. E. Foley, Am. J. Med. 21, 739 (1956).
8. H . Eagle and G. E. Foley, Cancer Research 18, 1017 (1958).
9. C. G. Smith, W . L . Lummis, and J. E. Grady, Cancer Research 19, 843, 847 (1959).
10. I . Toplin, Cancer Research 19, 959 (1959).
11. J. E. Grady, W . L . Lummis, and C. G. Smith, Proc. Soc. Exptl. Biol. Med. 103, 727 (1960).
12. P. Siminoff and V. S. Hursky, Cancer Research 20, 615, 618 (1960).
13. D . M . Schuurmans, D . T . Duncan, and Β . H . Olson, Antibiotics & Chemotherapy 10, 535 (1960).
14. P. P. Regna, in "Antibiotics, Their Chemistry and Non-Medical Uses" ( H . S.
Goldberg, ed.), p. 58. Van Nostrand, Princeton, N e w Jersey, 1959.
15. M . C. Rebstock, in "Medicinal Chemistry" ( A . Burger, ed.), 2nd ed., p. 877.
Interscience, N e w York, 1960.
16. E. P. Abraham, "Biochemistry of Some Peptide and Steroid Antibiotics." Wiley, N e w York, 1957.
17. R . E. Harman, Trans. Ν. Y. Acad. Sci. 21, 469 (1959).
18. L . C . Craig , Conf. et Rappts., 8
36. S. A . Waksman, Antibiotics & Chemotherapy 4, 502 (1954).
37. H . Brockmann and H . Grône, Chem. Ber. 87, 1036 (1954).
38. E. Bullock and A . W . Johnson, J. Chem. Soc. p. 1602 (1957).
39. H . Brockmann, Ann. Ν. Y. Acad. Sci. 89, 323 (1960).
40. A . W . Johnson, Ann. Ν. Y. Acad. Sci. 89, 336 (1960).
41. H . Brockmann and N . Pfennig, Naturwissenschaften 39, 429 (1952).
42. H . Brockmann, P. Boldt, and H . S. Petras, Naturwissenschaften 47, 62 (I960).
43. H . Brockmann and P . Boldt, Naturwissenschaften 46, 262 (1959).
44. H . Brockmann, G. Bohnsack, B . Franck, H . Grône, H . Muxfeldt, and C. H . Suling, Angew. Chem. 68, 70 (1956).
45. S. A . Waksman and E. Bugie, Proc. Soc. Exptl. Biol. Med. 54, 79 (1943).
46. W . J. Robbins, and R . M a , Bull. Torrey Botan. Club 69, 184 (1942).
47. H . M . Rauen and G. Hess, Z. physiol. Chem. 315, 70 (1959).
48. E. Mascitelli-Coriandoli, Biochem. Pharmacol. 2, 79 (1959).
49. C. Hackmann, Ann. N. Y. Acad. Sci. 89, 361 (1960).
50. G. E. Foley, in "Antibiotics Annual" ( H . Welch, éd.), p. 432. Medical Encyclo
pedia, N e w York, 1955-1956.
51. S. Farber, in "Amino Acids and Peptides with Antimetabolic Activity" (G. E. W . Wolstenholme and C. M . O'Connor, eds.), Ciba Foundation Symposium, p. 138. Little, Brown, Boston, Massachusetts, 1958.
52. C. L . Maddock, G. J. D'Angio, S. Farber, and A . H . Handler, Ann. Ν. Y. Acad.
Sci. 89, 386 (1960).
53. J. A . DiPaolo, G. E. Moore, and T . F. Niedbala, Cancer Research 17, 1127 (1957).
54. I . J. Slotnick, Antibiotics & Chemotherapy 7, 387 (1957).
55. I . J. Slotnick, Antibiotics & Chemotherapy 8, 476 (1958).
56. I . J. Slotnick, Ann. Ν. Y. Acad. Sci. 89, 342 (1960).
57. I . J. Slotnick, Bacteriol. Proc. (Soc. Am. Bacteriologists) 59, 130 (1959).
58. A . B . Pardee and L . S. Prestidge, Biochim. et Biophys. Acta 23, 412 (1958).
70. J. H . Burchenal, H . F. Oettgen, J% A . Reppert, and V . Coley, Ann. N. Y. Acad.
80. E. J. Liebner, Am. J. Roentgenol. Radium Therapy Nuclear Med. 87, 94 (1962).
81. D . Pinkel, Pediatrics 23, 342 (1959).
82. C. T . C. Tan, H . W . Dargeon, and J. H . Burchenal, Pediatrics 24, 544 (1959).
83. R . I. Shaw, E. W . Moore, P. S. Mueller, E. Frei, I I I , and D . M . Watkin, A.M.A J. Diseases Children 99, 628 (1960).
84. A . L . Watne, J. Badillo, A . Koike, T . Kondo, and G. E. Moore, Ann. N. Y. Acad.
Sci. 89, 445 (1960).
85. G. Schmidt-Kastner, Naturwissenschaften 43, 131 (1956).
86. K . Sugiura and M . S. Schmid, Proc. Am. Assoc. Cancer Research 2, 151 (1956).
87. J. Porath, Nature 172, 871 (1953).
88. I. M . Lockhart, G . G . Newton, and E. P . Abraham, Nature 173, 536 (1954).
89. I. M . Lockhart and E. P. Abraham, Biochem. J. 58, 633 (1954).
90. L . C. Craig, W . Konigsberg, and R . J. Hill, in "Amino Acids and Peptides with Antimetabolic Activity'' ( G . E. W . Wolstenholme and C. M . O'Connor, eds.), Ciba Foundation Symposium, p. 226. Little, Brown, Boston, Massachusetts, 1958.
105. F. Sanger, Biochem. J. 40, 261 (1946).
106. R . L . M . Synge, Biochem. J. 39, 363 (1945).
107. R . Schwyzer and P. Sieber, Angew. Chem. 68, 518 (1956).
108. R . Schwyzer and P . Sieber, Helv. Chim. Acta 40, 624 (1957).
109. R . J. Dubos and R . D . Hotchkiss, J. Exptl. Med. 73, 629 (1941).
110. W . E. Herrell and D . Heilman, Am. J. Med. Sci. 206, 221 (1943).
111. E. McDonald, J. Franklin Inst. 229, 805 (1940).
112. R . D . Hotchkiss, Advances in Enzymol. 4, 153 (1944).
113. P. H . Long, Ann. Ν. Y. Acad. Sci. 51, 853 (1949).
114. S. Wilkinson, Nature 164, 622 (1949).
115. L . Crombie and S. H . Harper, J. Chem. Soc, Part I I I p. 2685 (1950).
Congr. intern, biochim., Brussels, I960 p. 423 (1956).
125. Α . V . Few, Biochim. et Biophys. Acta 16, 137 (1955).
126. C. Latterade and M . Macheboeuf, Ann. inst. Pasteur 78, 753 (1950).
127. Α . V . Few and J. H . Shulman, J. Gen. Microbiol. 9, 454 (1953).
133. L . E. Sacks, Antibiotics & Chemotherapy 2, 79 (1952).
134. C. Levaditi and J. Henry, Press, méd. 56, 493 (1948).
135. T . P. King and L . C. Craig, J. Am. Chem. Soc. 77, 6624 (1955).
136. A . Paladini and L . C. Craig, Am. Chem. Soc. 76, 688 (1954).
137. T . P . King and L . C. Craig, J. Am. Chem. Soc. 77, 6627 (1955).
138. L . C. Craig, T . P. King, and A . Stracher, J. Am. Chem. Soc. 79, 3729 (1957).
139. F. Gros, M . Macheboeuf, and C. Latterade, Ann. inst. Pasteur 75, 411 (1948).
140. E. Bricas and C. Fromageot, Advances in Protein Chem. 8, 1, 1953.
141. B . A . Newton, in "The Strategy of Chemotherapy" (S. T . Cowan and E. Rowatt,
147a. G. B. Chapman, J. Bacteriol. 84, 169 (1962).
147b. G. B. Chapman, J. Bacteriol. 84, 180 (1962).
147c. Y . Koyama, A . Kurosasa, A . Tsuchiya, and K . Takakuta, J. Antibiotics Japan 3, 457 (1950).
148. R . D . Hotchkiss, Ann. Ν. Y. Acad. Sci. 46, 479 (1946).
149. A Rothstein and R . Meier, Cellular Comp. Physiol. 32, 77 (1948).
150. D . J. Demis, A . Rothstein, and R . Meier, Arch. Biochem. Biophys. 48, 55 (1954).
151. P . Mitchell and J. Moyle, Biochem. J. 64, 19P (1956).
152. J. Monod, in "Enzymes: Units of Biological Structure and Function" (Ο. H . Gaebler, ed.), Vol. 4, p. 7. Academic Press, N e w York, 1956. Non-Medical Uses" ( H . S. Goldberg, éd.), p. 1. Van Nostrand, Princeton, New Jersey, 1959.
167. P. A . Bunn, ed., " A Symposium on the N e w Dimethoxyphenyl Penicillin," State University of N e w York, Upstate Medical Center, Syracuse, N e w York, 1961.
167a. A . Gourevitch, G. A . Hunt, J. R. Luttinger, C. C. Carmack, and J. Lein, Proc. Soc.
Exptl. Biol. Med. 107, 455 U961).
167b. A . Gourevitch, G. A . Hunt, T . A . Pursiano, C. C. Carmack, A . J. Moses, and J.
Lein, Antibiotics & Chemotherapy 11, 780 U961).
167c. A . K . Saz, D . L . Lowery, and L. J. Jackson, Bacteriol. 82, 298 (1961).
168. Β. H . Olson and J. C. Jennings, Antibiotics & Chemotherapy 4, 11 (1954).
169. V . L . Benavides, Β. H . Olson, G. Varela, and S. H . Holt, J. Am. Med. Assoc. 157, J. H . Mowat, and N . Bohonos, in "Antibiotics Annual," p. 730. Medical Ency
clopedia, New York, 1957.
174. J. Ehrlich, G. L . Coffey, M . W . Fisher, A . B . Hillegas, D . L . Kohberger, H . E.
Machamer, W . A . Rightsel, and F. R . Roegner, Antibiotics & Chemotherapy 6, 487 (1956).
175. H . W . Dion, S. A . Fusari, Z. L . Jakubowski, J. G. Zora, and Q. R . Bartz, J. Am.
Chem. Soc. 78, 3075 (1956).
176. H . Umezawa, K . Oikawa, Y . Okami, and K . Maeda, J. Bacteriol. 66,118 (1953).
177. W . M . McLamore, W . D . Celmer, V . V . Bogert, F. C. Pennington, and I . A . Solomons, J. Am. Chem. Soc. 74, 2946 (1952).
178. B. A . Sobin, J. Am. Chem. Soc. 74, 2947 (1952).
179. J. R . Schenck and A . F. DeRose, Arch. Biochem. & Biophys. 40, 263 (1952).
180. R . K . Clark and J. R . Schenck, Arch. Biochem. & Biophys. 40, 270 (1952).
181. F. C. Pennington, W . D . Celmer, W . M . McLamore, V . V . Bogert, and I . A . Solomons, J. Am. Chem. Soc. 75, 109 (1953).
182. P. A . Plattner and M . Clauson-Kaas, Helv. Chim. Acta 28, 188 (1945).
194. H . M . Felton, ed., "Host-Parasite Relationships in Living Cells." C. C Thomas, Springfield, Illinois, 1957.
195. G. Schramm, Ann. Rev. Biochem. 27, 101 (1958).
196. A . Isaacs and B. W . Lacey, eds., "Virus Growth and Variation." Cambridge Univ.
Press, London and N e w York, 1959.
203a. A . Isaacs and J. Lindenmann, Proc. Roy. Soc. B147, 258 (1957).
203b. M . H o , New Engl. J. Med. 266, 1258, 1313, 1367 (1962).
204. M . G. Sevag, "Immuno-Catalysis." C. C Thomas, Springfield, Illinois, 1945.
205. P. D . McMaster, in "The Cell" (J. Brachet and A . E. Mirsky, eds.), Vol. V , p.
325. Academic Press, N e w York, 1961.
206. L . Pauling, J. Am. Chem. Soc. 62, 2643 (1940)..
207. K . Landsteiner and J. van der Scheer, / . Exptl. Med. 48, 315 (1928).
208. K . Landsteiner and J. van der Scheer,J. Exptl. Med. 50, 407 (1929).
209. K . Landsteiner and J. van der Scheer, / . Exptl. Med. 55, 781 (1932).
210. K . Landsteiner and J. van der Scheer, J. Exptl. Med. 59, 769 (1934).
211. G. J. Martin, "Biological Antagonism." McGraw-Hill (Blakiston), N e w York, 1951.
212. K . Landsteiner, "The Specificity of Serological Reactions." Harvard Univ. Press, Cambridge, Massachusetts, 1947.
213. F. M . Burnet, "The Clonal Selection Theory of Acquired Immunity." Vanderbilt Univ. Press, Nashville, Tennessee, 1959.
214. A . M . Pappenheimer, Jr., Advances in Protein Chem. 4, 123 (1948).
217. F. Noc, Ann. inst. Pasteur 18, 387 (1904).
218. H . Eagle, J. Exptl. Med. 65, 613 (1937).
219. M . G. Macfarlane and B . C. J. G. Knight, Biochem. J. 35, 884 (1941).
220. B . D . Davis and R . J. Dubos, Arch. Biochem. 11, 201 (1946).
221. M . G. Macfarlane, Biochem. J. 42, 590 (1948).
222. P . C. Zamecnik and F. Lipmann, J. Exptl. Med. 85, 395 (1947).
223. J. H . Sang, Parasitology 30,141 (1938).
224. H . Tauber and I . S. Kleiner, J. Gen. Physiol. 15, 155 (1931).
225. P. Jolies, in "The Enzymes" (P. D . Boyer, H . Lardy, and K . Myrbàck, eds.), 2nd ed., Vol. 4, p. 431. Academic Press, N e w York, 1960.
226. R . C. Skarnes and D . W . Watson, Bacteriol. Revs. 21, 273 (1957).
226a. F. Bergel, "Chemistry of Enzymes in Cancer," pp. 60-70. C. C. Thomas, Spring
field, Illinois, 1961.
226b. B . Sallman and M . N . Streifeld, in "Antibiotics Annual," p. 647. Medical Ency
clopedia, N e w York, 1958-1959.
227. F. Bergel, Acta Unio Intern, contra Cancrum 16, 979 (1960).
228. A . Haddow, G. de Lamirande, F. Bergel, R . C. Bray, and D . A . Gilbert, Nature 182,1144 (1958).
229. L . Ledoux, Nature 175, 258 (1955).
229a. G. de Lamirande, Proc. Am. Assoc. Cancer Research 3, 105 (1960).
230. P . Desnuelle, in "The Enzymes" ( P . D . Boyer, H . Lardy, and K . Myrbàck, eds.), 2nd ed., Vol. 4, p. 128. Academic Press, N e w York, 1960.
231. M . Laskowski and M . Laskowski, Jr., Advances in Protein Chem. 9 203 (1954).
232. Ν . M . Green and H . Neurath, in "The Proteins" ( H . Neurath and K . Bailey,
236. M . Sela and E. Katchalski, Advances in Protein Chem. 14, 391 (1959).
237. B . Hagihara, in "The Enzymes" ( P . D . Boyer, H . Lardy, and K . Myrbàck, eds.), 2nd ed., Vol. 4, p. 193. Academic Press, N e w York, 1960.
238. K . Matsushima, Agr. Chem. Soc. Japan 31, 38 (1957).
239. K . Matsushima, Science 127, 1178 (1958).
240. J. L. Tullis and D . M . Surgenor, Ann. Ν. Y. Acad. Sci. 66, 386 (1956).
241. T . J. Mackie and M . H . Finkelstein, J. Hyg. 31, 35 (1931).
242. T . J. Mackie and M . H . Finkelstein, / . Hyg. 32, 1 (1932).
243. K . Landsteiner, "The Specificity of Serological Reactions," p. 31. Harvard Univ.
Press, Cambridge, Massachusetts, 1945.
244. L . Pillemer, L . Blum, I . H . Lepow, O. A . Ross, E. W . Todd, and A . C. Wardlaw, Science 120, 279 (1955).
245. O. v . St. Whitelock, ed., "Natural Resistance to Infections." Ann. Ν. Y. Acad.
Sci. 66, 233 (1956).
246. C M . Southam, Cancer Research 20, 271 (1960).
247. B. F. Miller, R . Abrams, A . Dorfman, and M . Klein, Science 96, 428 (1942).
248. P. Negroni and I . Fischer, Rev. soc. arg. biol. 20, 307 (1944).
249. A . Kossel, "The Protamines and Histones." Longmans Green, London, 1928.
250. Ν . Weissman and L . H . Graf, J. Infectious Diseases 80, 145 (1947).
251. J. Kleczkowski and A . Kleczkowski, J. Gen. Microbiol. 14, 449 (1956).
252. D . McClean, Pathol. Bacteriol. 34, 459 (1931).
253. J. Warren, M . L . Weil, S. B. Russ, and H . Jeffries, Proc. Soc. Exptl. Biol. Med.
267. P. Mascherpa, Antibiotic Med. & Clin. Therapy 8, 45 (1961).
268. W . W . Yotis and R. D . Ekstedt, Bacteriol. 78, 567 (1959).
269. W . W . Yotis and R. D . Ekstedt, Bacteriol. 80, 719 (1960).
269a. G. Ivanovics, Bacteriol. Revs. 26, 108 (1962).
269b. R . F. Nigrelli, Trans. Ν. Y. Acad. Sci. 24, 496 (1962).
269c. C. P. Li, B. Prescott, W . G. Jahnes, and E. C. Martino, Trans. Ν. Y. Acad. Sci.
24, 504 (1962).
270. L . B . Jacques, in "The Coagulation of Blood" ( L . M . Tocantins, ed.), p. 208.
Grune & Stratton, N e w York, 1955.
271. E. G. Krebs, Biochim. et Biophys. Acta 15, 508 (1954).
272. Ν . B. Madsen and C. F. Cori, Biochim. et Biophys. Acta 15, 516 (1954).
273. E. D . Korn, Biol. Chem. 215, 1 (1955).
274. C. H . Bamford, A . Elliott, and W . E. Hanby, "Synthetic Polypeptides." Academic Press, N e w York, 1956.
275. E. Katchalski and M . Sela, Advances in Protein Chem. 13, 243 (1958).
276. E. R . Blout, R . H . Karlson, P. Doty, and B . Hargitay, J. Am. Chem. Soc. 76, 4492 (1954) and succeeding publications.
277. M . A . Stahmann, "Polyamino Acids, Polypeptides, and Proteins." University of Wisconsin Press, Madison, Wisconsin, 1962.
283. P . H . Maurer, D . Subrahmanyam, E. Katchalski, and E. R . Blout, / . Immunol.
287. G. W . Anderson, in "Medicinal Chemistry" (A. Burger, ed.), 2nd ed., Chapter 39 pp. 783-795. Interscience, N e w York, 1960.
288. C. Ressler and V . du Vigneaud, J. Am. Chem. Soc. 79, 4511 (1957). B. Berde, Nature 178, 260 (1956).
294. P . - A . Jaquenoud and R . A . Boissonnas, Helv. Chim. Acta 42, 788 (1959).
295. J. Rudinger, J. Honzl, and M . Zaoral, Collection Czechoslov. Chem. Communs. 21, 770 (1956).
296. P . G. Katsoyannis and V . du Vigneaud, Arch. Biochem. Biophys. 78, 555 (1958).
297. P . G. Katsoyannis, / . Am. Chem. Soc. 79, 109 (1957).
298. P . G. Katsoyannis and V . du Vigneaud, J. Biol. Chem. 233,1352 (1958).
299. R . Acher, Ann. Rev. Biochem. 29, 550 (1960).
300. St. Guttmann, P . - A . Jaquenoud, R . A . Boissonnas, H . Konzett, and B. Berde, Naturwissenschaften 44, 632 (1957).
300a. H . Konzett, Helv. Physiol. et Pharmacol. Acta 15, 419 (1957).
300b. D . Jarvis, M . Bodanszky, and V . du Vigneaud, J. Am. Chem. Soc. 83,4780 (1961).
301. F. M . Bumpus, P . A . Khairallah, K . Arakawa, I . H . Page, and R . R . Smeby, Biochim. et Biophys. Acta 46, 38 (1961).
301a. J. E. Wood and R . P. Ahlquist, eds., "Symposiun on Angiotensin." American Heart Association, Monograph N o . 3, 1962.
302. F. M . Bumpus, I . H . Page, and R . R . Smeby, Circulation Research 9, 762 (1961).
303. R . A . Boissonnas, St. Guttmann, P . - A . Jacquenoud, H . Konzett, and E. Sturmer, Experientia 16, 326 (1960).
303a. "Structure and Function of Biologically Active Peptides: Bradykinin, Kallidin, and Congeners" Ann. N. Y. Acad. Sci., in press (1963).
304. M . Sonenberg and W . L . Money, Endocrinology 61, 12 (1957).
305. Ε. H . Frieden and J. T . Velardo, Proc. Soc. Exptl. Biol. Med. 81, 98 (1952).
306. Ε. H . Frieden and J. T . Velardo, Acta Endocrinol. 34, 312 (1960).
307. Z. Berânkovâ, I . Rychlik, and F. Sorm, Experientia 15, 298 (1959).
308. A . I . Cohen and Ε. H . Frieden, J. Biol. Chem., 236, 765 (1961).
309. A . I . Cohen and J. Furth, Cancer Research 19, 72 (1959).
310. W . M . Bayliss, "The Nature of Enzyme Action," 2nd ed. Longmans, Green, N e w York, 1911.
311. A . R . Beam and W . Cramer, Biochem. J. 2, 174 (1907).
312. Y . Yagi, Symposia on Enzyme Chem. (Japan) 2, 7 (1949); from Chem. Abstr. 45, 4755 (1951).
313. J. B . Sumner and J. S. Kirk, Science 74, 102 (1931).
314. F. M . Burnet, "Enzyme, Antigen and Virus." Cambridge Univ. Press, London and N e w York, 1956.
315. G. J. Martin, "Biological Antagonism," p. 214. McGraw-Hill (Blakiston), N e w York, 1951.
316. Ε. H . Frieden, J. Am. Chem. Soc. 78, 961 (1956).
317. E. J. Modest, G. E. Foley, and S. Farber, Acta Unto Intern, contra Cancrum 16, 702 (1960).
318. A . Burger, ed., "Medicinal Chemistry," 2nd ed. Interscience, N e w York, 1960.
319. S. Farber, E. C. Cutler, J. W . Hawkins, J. H . Harrison, E. C. Pierce I I , and G. C.
328. F. Bergel, J. Pharm. and Pharmacol. 7, 297 (1955).
329. F. Bergel, V . C. E. Burnop, and J. A . Stock, J. Chem. Soc. p. 1223 (1955).
330. F. Bergel and J. A . Stock, British Patent 750,155 (1956).
331. J. A . Stock, in "Amino Acids and Peptides With Antimetabolic Activity" (G. E. W . Wolstenholme and C. M . O'Connor, eds.), Ciba Foundation Symposium, p. 89.
Little, Brown, Boston, Massachusetts, 1958. Trusheikina, U.S.S.R. Patent 104, 781; from Chem. Abstr. 51, 14811c (1957).
336. F. Bergel and J. A . Stock, J. Chem. Soc. p. 4563 (1957).
337. F. Bergel and J. A . Stock, / . Chem. Soc. p. 3658 (1960).
338. L . F. Larionov, Acta Unio. Intern, contra Cancrum 13, 393 (1957).
339. L . F. Larionov, Acta Unio. Intern, contra Cancrum 15, 42 (1959).
340. L. F. Larionov, Cancer Research 21, 99 (1961).
340a. S.-C. J. Fu, J. Med. Pharm. Chem. 5, 33 (1962).
341. J. M . Ravel and W . Shive, / . Biol. Chem. 166, 407 (1946).
342. G. N . Cohen, G. Cohen-Bazire, and B. Minz, Compt. rend. acad. sci. 229, 260 (1949).
343. D . W . Woolley, " A Study of Antimetabolites," p. 45. Wiley, N e w York, 1952.
344. G. J. Martin, "Biological Antagonism," p. 225. McGraw-Hill (Blakiston), N e w York, 1951.
345. C. Kaiser, in "Medicinal Chemistry" (A. Burger, ed.), 2nd ed., p. 89. Interscience, New York, 1960.
346. W . E. Knox, in "The Enzymes" ( P . D . Boyer, H . Lardy, and K . Myrbàck, eds.), 2nd ed., Vol. 2, p. 276. Academic Press, N e w York, 1960.
347. Ο. K . Behrens, / . Biol Chem. 141, 503 (1941).
348. W . O. Kermack and N . A . Matheson, Biochem. J. 65, 48 (1957).
349. G. E. Woodward and F. E. Reinhardt, J. Biol. Chem. 145, 471 (1942).
350. Ε. M . Crook, ed., "Glutathione," Biochemical Society Symposium N o . 17. Cam
bridge Univ. Press, London and N e w York, 1959.
351. Ε. E. Cliffe and S. G. Waley, Biochem. J. 73, 25P (1959).
352. S. G. Waley, Biochem. J. 68, 189 (1958).
353. S. Shankman, S. Higa, and V . Gold, J. Am. Chem. Soc. 82, 990 (1960).
354. D . W . Woolley, " A Study of Antimetabolites." Wiley, N e w York, 1952.
355. G. Schmidt-Kastner, Ann. Ν. Y. Acad. Sci. 89, 299 (1960).
356. E. Katz, Ann. Ν. Y. Acad. Sci. 89, 304 (1960).
357. E. Bullock and A . W . Johnson, J. Chem. Soc. p. 3280 (1957).
358. A . J. Birch and H . Smith, in "Amino Acids and Peptides with Antimetabolic Activity" (G. E. W . Wolstenholme and C. M . O'Connor, eds.), Ciba Foundation Symposium, p. 247. Little, Brown, Boston, Massachusetts, 1958.
359. R . Schwyzer, in "Amino Acids and Peptides with Antimetabolic Activity" ( G . E.
W . Wolstenholme and C. M . O'Connor, eds.), Ciba Foundation Symposium, p. 171. Little, Brown, Boston, Massachusetts, 1958.
360. G. E. Foley, Antibiotics & Chemotherapy 11, 225 (1961).