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VINCENT DU VIGNEAUD May ~ 8, ~ 901-December ~ I, ~ 978 BY KLAUS HOFMANN VINCENT DU VIGNEAUD was born in Chicago in 1901. He was of French ancestry, the son of Alfred du Vig- neaud, an inventor and machine designer, and Mary Theresa du Vigneaud. He attended Car! Schurz High School in Chi- cago, from which he graduated in 1918. When he was a freshman in high school, two friends, who had a chemical laboratory at home, invited him to join them in chemical ex- perimentation. They obtained chemicals from a pharmacist and conducted experiments that involved the fabrication of explosives containing sulfur. This was his first contact with science. World War I was under way, and young people were needed on the farms. Seniors in high school were offered the opportunity of working on the farms in spring and receiving their diplomas in tune. Young Vincent worked through spring and summer on a farm near Caledonia, Illinois. He was very proud of the fact that he could milk twenty cows by hand, and he decided to become a farmer. His older sister, Beatrice, changer] his mind and suggested that he go to the University of Illinois at Urbana-Champaign to study chem- istry. He followed her advice and registered in chemical en- gineering. He later recalled: 543

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544 BIOGRAPHICAL MEMOIRS I found during the first year that it was chemistry rather than engi- neering that appealed to me most. I switched to a major in chemistry since I was deeply impressed by the senior student's work, especially in organic chemistry. I also found that I was most interested in those aspects of or- ganic chemistry that had to do with m~rlir~1 cilhst~nc~s anal heron to rl~ velop an interest in biochemistry. Young flu Vigneaud had no money and had to put himself through college and graduate school. Tearing clown boilers, picking apples, working in the library, and jerking sodas were some of his occupations. But the job that helped most finan- cially was that of headwaiter. The next most remunerative job turned out to be the teaching of cavalry tactics and equi- tation as a reserve second lieutenant in the cavalry. One clay, while working as a waiter, Vincent saw a pretty rec~head and said to one of his colleagues, "That's the woman ~ am going to marry" and he clict. The young woman was ZelIa Zon Forct. She was an English major, but as she and Vincent became better acquainted he saw to it that she took classes in mathematics and chemistry. Although she gradu- atect as an English major, she knew sufficient chemistry so that after their marriage on June 12, 1924, she was able to teach chemistry in high school. One of the professors at Illinois who exerted a significant influence on young (lu Vigneaud was Car! Shipp Marvel, known as "Speect." Du Vigneauc] was much impressed with Marvel's lectures and research program, and he decided to do his senior thesis with him. Later he selectee! Speed to be- come his master's degree adviser. As he progressed with his studies, he became more and more interested! in the relations between biochemistry and organic chemistry. He took acI- vancect courses in biochemistry from H. B. Lewis and the nutritionist W. C. Rose, whose studies on nutrition of the white rat later became role models for some of clu Vigneaucl's metabolic investigations. He was particularly taken with a lec

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VINCENT DU VIGNEAUD 545 ture by Professor Rose in which the work of Banting and Best on insulin was cliscussed. Du Vigneauc! earnest his master's degree in February of 1924 anc! accepted a position with the Du Pont Company; he later worked for some time with Dr. Walter Karr at the Phil- adelphia General Hospital. Nevertheless, his minct was set on graduate study and the earning of a Ph.D. degree. Professor Marvel recalls the following episode: When du Vigneaud received his master's degree he was offered a job with Walter Karr in Philadelphia, but he was too poor and had no money to pay his way to Philadelphia. To help him out I gave him an assignment to make 10 pounds of cupferron for our organic preparations laboratory and told him I would pay him, as a wage, whatever amount he could pro- duce in material for under the price which we would sell it. He did not ask for any hourly work or time, but we generally agreed that way. In pro ducing the 10 pounds, he'd accumulated enough money to get to his Phil- adelphia job. In the spring of 1925 do Vigneauct received an invitation from Professor John R. Murlin to join the Department of Vital Economics at the University of Rochester, New York, to undertake graduate work on the chemistry of insulin. Pro- fessor Murlin was a physiologist and not a chemist, and du VigneaucI was eager to discuss his chemical problems with other chemists. In this connection, he became acquainted with Hans Clarke, who at the time was working for Eastman Kodak. Later, Clarke became professor and chairman of the Biochemistry Department at the College of Physicians and Surgeons in New York, and the two men struck up a lifelong friendship. In 1927 clu Vigneauc! graduated with a Ph.D. clegree; the thesis title was "The Sulfur in Insulin." During his last year in Rochester he was awardecl a National Research Council Fellowship, which enabled him to pursue postdoctoral stucl- ies with John Jacob Abel, professor of pharmacology at the

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BIOGRAPHICAL MEMOIRS . 546 Johns Hopkins University Medical School. Here, in colIabo- ration with Oscar Wintersteiner and Hans Jensen, the insulin studies were continued. A second fellowship enabled the young du Vigneaud to do some traveling abroad. He became acquainted with the synthesis of pepticles in the laboratory of Max Bergmann at the Kaiser Wilhelm Institut in Dresden and spent some time with Professor George Barger in Edin- burgh, ScotIanct. Bergmann, a former stud ent of Emil Fischer, was a pioneer in the peptide field who later became a member of the Rockefeller Institute for Medical Research (now Rockefeller University) in New York. Broadly equipped to engage in independent scientific pursuits, du Vigneaud accepted a position in the Department of Physiological Chemistry at his alma mater in Illinois. Bio- chemistry had become his chosen field, and the opportunity presented itself to have graduate students. He spent three happy years in Illinois; at age thirty-one he became professor and chairman of biochemistry at George Washington Uni- versity Meclical School in Washington, D.C. He was sacIdenect to leave the outstanding department at Urbana with such great professors as Adams, Marvel, Shriner, and Fuson in organic chemistry and Professor Rose in biochemistry, but the opportunity for greater inclepenclence was decisive. He stayed at George Washington from 1932 to 193S, when he was invited to head the Department of Biochemistry at Cornell Medical College in New York City, a chair that had been occupied by Stanley R. Ber~edict. In connection with this move he stated: When I came to Cornell Medical College, I brought along five mem- bers of my research group, Mildred Cohn, George W. Irving, Theodore Loring, Gail Miller, and John Wood. As in the transfer from Illinois to George Washington I thus had continuity, people with whom I had already been working. This I regard as very important when moving from one place to another. Just as in transplanting a tree with some soil around it, if possible it is well to move a man with some of his environment.

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VINCENT DU VIGNEAUD 547 The awarding of the 1955 Nobel Prize in Chemistry con- stituted an unquestionable triumph for clu VigneaucI, but he expressed definite opinions pertaining to the awarding of prizes for scientific achievement. He saicI to a reporter, "l am expecting to stay in the research field, in the academic world, but ~ want to tell you ~ will never work for any prize. I refuse to let my rewards rest in the hands of any committee." In answer to a congratulatory note I sent him on the oc- casion of his award, he answered: "The real thrill of such an aware! is sharing the pleasure with one's friends, and partic- ularly with those who have been associated with me on the trail." The highly productive career at Cornell Medical College came to an enct with his assumption of emeritus status in 1967. But a generous invitation from Professor HaroIc! A. Scheraga, then head of the Chemistry Department at Cornell University in Ithaca, made it possible for du Vigneauct to continue his investigations as professor of chemistry. He was very happy and productive in Ithaca and enjoyocl his new surroundings. He wrote to his former collaborators and stu- dents: "Those of you who know the Ithaca area will appre- ciate that ~ have a fantastic view from my office on the sixth floor of the Chemistry Research Building overlooking Ca- yuga Lake to the northwest anct Beebe Lake, waterfalls and the Fall Creek gorge down below." In addition to his outstanding contributions to science, do Vigneaud was a great teacher and lecturer. His lectures to students were interesting and well prepared. He emphasized the importance of teaching and his advice to the faculty was: "Remember your first obligation is teaching; when you are teaching it takes precedence over research." His presenta tions at home and abroad were masterpieces of staging. He wouIct go over his slicles with the projectionist in the greatest detail so that the presentation wouIc! proceec! flawlessly. He was a showman, an artist in communicating research find

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548 BIOGRAPHICAL MEMOIRS ings. It was a genuine pleasure to listen to his presentations, which were as meticulously prepared and rehearsed as were . . . ~ . 11S sclentluc papers. Professor flu Vigneaucl's scientific career was abruptly ter- minatect when he sufferer! a stroke in 1974. He cried on De- cember ~ I, 1978. His wife, ZelIa, had passed away one year earlier. Professor du Vigneaud is survived by a son, Vincent, Jr., and a daughter, Marilyn Renee Brown. Both are physi- cians. If one views the totality of clu Vigneaucl's contributions to science, one recognizes a thread of continuity connecting sulfur-containing, biologically important compounds. This threact extends from insulin to cysteine, homocysteine, me- thionine, cystathionine, biotin, penicillin, oxytocin, and va- sopressin. In the Messenger lectures, delivered at Cornell University in Ithaca in 1950, he likened his scientific work to a trail in research; he wrote: An attempt was made to retrace the research trails originating from a study of insulin that I have had the pleasure of working out in association with various collaborators over a period of twenty-five years. I attempted to present not only the findings encountered, but also in many instances the stepwise evolution of these findings, including the accidents of fate that played a part. Some of flu Vigneaucl's earliest researches clealt with the chemical nature of insulin. Abe! crystallized insulin in 1926, ant] Jensen, Wintersteiner, and clu Vigneauc! investigated the composition of acid hydrolysates of the crystalline hormone. With the rather primitive methods available at the time, the presence in such hyctrolysates of cystine and various other amino acids was establishect. Based on this evidence, it was . concluder! that insulin was a protein. Du VigneaucI com- mented later: "It may seem strange to speak of work estab- lishing insulin as a protein because it is now a generally ac

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VINCENT DU VIGNEAUD 549 ceptec! fact that a hormone can be a protein or that a protein can be a hormone, yet at that time (1928) there was great reluctance in accepting this viewpoint." The thinking at that time was strongly influences! by the concepts of WilIstatter regarding the chemical nature of enzymes that were assumed to be composed of a small functional coenzyme anti a protein carrier. Insulin was believed to be a small molecule that was attacher! or absorber! to a high molecular weight carrier. In 1930 clu Vigneaud became acquainted with L. F. Au- drieth, a faculty colleague at the University of Illinois, who was an expert in the liquid ammonia field. He was impressed with liquid ammonia as a solvent for insulin and the sparingly soluble cystine. Au~rieth's use of metallic sodium as a recluc- ing agent in liquid ammonia promptest du Vigneaucl to apply this method to the conversion of cystine to cysteine. He de- vised the technique of S-benzylation of cysteine by a(lding be n zy! chloride to sodium in l iqu icI ammo nia- reducer! cys- tine. The observation that the S-benzy! group was remover! from S-benzy~cysteine by reduction with sodium in liquid am- monia represented a significant contribution to peptide . . . -my, ~ me possible tne transient protection of the thio] group of cysteine during peptide syntheses. In 1932 Bergmann and Zervas introducec! the benzyloxy- carbony! group (carbobenzoxy group) into amino acids anti pepticles, and with the discovery that this protecting group could be cleavecI by catalytic hydrogenolysis they laicl the groundwork for the (development of modern pepti(le synthe- sis. Du Vigneaud became interested in this method ant! em- barkocI on synthesizing carbobenzoxy derivatives of amino acids. The story has it that in his laboratory the carboben- zoxyamino acids failed to crystallize. One clay, Max Berg- mann came to visit the laboratory anti, lo and behoIcI, from that time on the carbobenzoxyamino acids crystallized beau- tifully. Dic! Bergmann carry seer! crystals in his pockets? The ~1 ~ ~. ~ _ : ~1 _ 1 1 . 1 . -

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550 BIOGRAPHICAL MEMOIRS discovery that benzyloxycarbonyl groups can be removed from cysteine and cysteine-containing peptides by sodium in liquid ammonia broadened the scope of the carbobenzoxy method and opened its applicability to peptides containing sulfur. As we proceed with this discussion, it will become appar- ent that the techniques du Vigneaud developed early in his career provided answers to problems he encountered at a later time (oxytocin and vasopressin). Much of du Vigneaud's work in intermediary metabolism concerned the formation of cysteine in the animal organism and the metabolic rela- tionships among methionine, cysteine, homocysteine, cysta- thionine, and choline. He called the underlying reactions "transulfuration" and "transmethylation." It was known that methionine could support growth of laboratory rats on a cys- teine-free diet, and Rose had shown that methionine was an essential dietary constituent for the rat. In short, the rat is capable of synthesizing cysteine but not methionine. In 193 ~ du Vigneaud discovered a new sulfur-containing amino acid while exposing methionine to strong sulfuric acid. This com- pound was the next higher symmetrical homolog of cystine and he named it "homocystine." Later, he ctiscovered that the reduced form of this amino acid, homocysteine, was a meta- bolically important compound. Du Vigneaud observed that homocysteine, like methionine, could support the growth of . ,~ . . . rats on c lets c Accent In costing. These observations pointed to a metabolic relationship between methionine and homocysteine and suggested that demethylation of methionine could be involved in cysteine biosynthesis. Du Vigneaud synthesized r-cystathionine, a thioether in which the carbon chains of cysteine and homo- cysteine are connected by a single sulfur atom, and found that this compound sustained growth of rats on a cysteine- deficient diet. This observation indicated that the rat was ca- pable of cleaving the thioether linkage with formation of cys

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VINCENT DU VIGNEAUD 55 seine. It was observed further that cystathionine dicl not give rise to homocysteine, an observation that was supported by in vitro studies with liver slices. The acictition to liver slices of a mixture of homocysteine and serine resultect in a 60 per- cent conversion of homocysteine sulfur into cysteine, provict- ing strong evidence for the hypothesis that homocysteine was indeed! an intermediate in the formation of cystathionine. The importance of serine as a precursor of cysteine had been clemonstrated earlier by Dewitt Stetten. Before continuing the discussion of du Vigneaucl's work on the intermediary metabolism of sulfur compounds, it seems fitting to have a short synopsis of the status of bio- chemistry in the 1930s. At that time, the Biochemistry De- partment of the College of Physicians and Surgeons at Co- lumbia University, under the leaclership of Hans Clarke, had ctevelopect into one of the outstanding departments in the country and one that macle scientific history. It was in this department that Rudolf Schonheimer and his colleagues per- formed the classical tracer experiments pointing to "the cly- namic state of the body constituents." The application of iso- topes to the solution of biochemical problems provided the key for these clevelopments, which revolutionized biochemi- cal thinking. Harold C. Urey, also of Columbia University, had cleveloped the methoclology for the preparation of cleu- terium oxide and other elements enriched with respect to stable isotopes, anct the availability of these compounds opened far-reaching biochemical frontiers. Because growth experiments had severe limitations, du Vigneaud applied the new tracer techniques to the study of the conversion of me- thionine to cysteine. He synthesized D~-methionine labeler] in the ,B and By positions with ~3C and containing 34S and fed this compounc! to rats. The rats were shaved at the beginning of the experiment and received another haircut after thirty- eight days in the experiment. The cystine isolated from the hair contained 34S, but no i3C. From the results of this ex .

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552 . BIOGRAPHICAL MEMOIRS percent it was concluclect that only the sulfur, not the carbon chain of methionine, was utilizect for cysteine biosynthesis. This proviclec! final proof that, in the rat, cysteine synthesis from methionine involves demethylation with formation of homocysteine followed by condensation of the homocysteine with serine to form cystathionine. The latter is cleaved with formation of cysteine anct c~-ketobutyric acid. In essence, the conversion of methionine to cysteine involves a transfer of the methionine sulfur to serine. This, according to du Vig- neaud, became known as "transulfuration." An interesting coincidence led to the discovery of the con- cept of transmethylation or methyl transfer. Here again the crucial evidence was derived from rat feeding experiments. Rose observer! good growth of rats fed a methionine- cysteine-free diet that was supplemented with homocysteine. Similar experiments carried out in du Vigneauct's laboratory produced negative results; the rats failecT to grow. The ani- mals in both laboratories grew well when the diet was forti- fiec! with methionine. The difference in the results was traced to the vitamin supplements used. Du Vigneau(1 employe(1 crystalline B complex vitamins, but Rose used rice bran ex- tract (Tikitiki) as the vitamin source. Du Vigneaud notect that his rats developed fatty livers while on experiment. It was known from the work of Best that choline inhibited fatty infiltration of the liver, and Du Vigneaud reasoned that this pathology could be the result of a choline deficiency. He cle- cicled that the factor missing in his diet couIct be choline, and this proved to be correct. Accordingly, diets containing both homocysteine and choline were fecI, and such a regimen sup- portect growth as well as did methionine. On the basis of these findings du Vigneaud speculatecl that choline, a compound rich in methyl groups, couIcl act as a methyl donor for the conversion of homocysteine to me- thionine. These early findings led to the concept of trans- methylation and that of "labile" methyl groups. The obser

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VINCENT DU VIGNEAUD 585 With Miklos Bodanszky. An improved synthesis of oxytocin. I. Am. Chem. Soc., 81:2504-7. With Miklos Bodanszky. Synthesis of oxytocin by the nitrophenyl ester method. Nature, 183: 1324-25. With Albert Light and Rolf Studer. Isolation of oxytocin and ar- ginine vasopressin by way of a protein complex on a preparative scale. Arch. Biochem. Biophys., 83:84-87. With Miklos Bodanszky. A method of synthesis of long peptide chains using a synthesis of oxytocin as an example. J. Am. Chem. Soc., 81:5688-91. With Miklos Bodanszky. Synthesis of a biologically active analog of oxytocin, with phenylalanine replacing tyrosine. J. Am. Chem. Soc., 81:6072-75. With Panayotis G. Katsoyannis. Arginine vasotocin. Nature, 184: 1465. With Miklos Bodanszky. A new crystalline salt of oxytocin. Nature, 184:981-82. 1960 With Rolf Studer. Synthetic work related to arginine-vasopressin. i. Am. Chem. Soc., 82:1499-1501. With Johannes Meienhofer. Preparation of lysine-vasopressin through a crystalline protected nonapeptide intermediate and purification of the hormone by chromatography. }. Am. Chem. Soc., 82:2279-82. With Thomas F. Dillon, R. Gordon Douglas, and M. L. Barber. Transbuccal administration of pitocin for induction and stim- ulation of labor. Obstet. Gynecol., 15: 587-92. With Miklos Bodanszky and Johannes Meienhofer. Synthesis of Ivsine-vasonressin by the nitrophenyl ester method. i. Am. Chem. Soc., 82:3195-98. Experiences in the polypeptide field: Insulin to oxytocin. Ann. N.Y. Acad. Sci., 88:537-48. With Harry D. Law. Synthesis of 2-p-methoxyphenylalanine oxy- tocin (O-methyl-oxytocin) and some observations on its phar- macological behavior. I. Am. Chem. Soc., 82:4579-81. With Peter S. Fitt, Miklos Bodanszky, and Maureen O'Connell. Syn- thesis and some pharmacological properties of a peptide deriv

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586 BIOGRAPHICAL MEMOIRS alive of oxytocin: Glycyloxytocin. Proc. Soc. Exp. Biol. Med., 104:653-56. With Gershen Winestock, V. V. S. Murti, Derek B. Hope, and Ray- mond D. Kimbrough, in Synthesis of 1-~-mercaptopropionic acid oxytocin (desaminooxytocin), a highly potent analogue of oxytocin. }. Biol. Chem., 235:PC64-66. With Johannes Meienhofer. Synthesis of a biologically active analog of lysine-vasopressin, with phenylalanine replacing tyrosine: 2- Phenylalanine lysine-vasopressin. i. Am. Chem. Soc., 82:6336- 37. 1961 With Johannes Meienhofer. Synthesis of a lysine-vasopressin deriv- ative with a methyl substituent on the imino nitrogen of the peptide bond between lysine and glycinamide (9-sarcosine lys- ine-vasopressin). I. Am. Chem. Soc., 83:142-45. With Raymond D. Kimbrough, Jr. Lysine-vasotocin, a synthetic an- alogue of the posterior pituitary hormones containing the ring of oxytocin and the side chain of lysine-vasopressin. T Biol. Chem., 236:778-80. With Derek iarvis and Miklos Bodanszky. The synthesis of 1-(hemi- homocystine).oxytocin and a study of some of its pharma- cological properties. }. Am. Chem. Soc., 83:4780-84. . 1962 With Conrad H. Schneider, Tohn E. Stouffer, V. V. S. Murti, tan- ardan P. Aroskar, and Gershen Winestock. fritiation of oxyto- cin by the Wilzbach method and the synthesis of oxytocin from tritium-labelled leucine. ~. Am. Chem. Soc., 84:409-13. With William D. Cash, Logan McCulloch Mahaffey, Alfred S. Buck, Donald E. Nettleton, ir., and Christos Romas. Synthesis and biological properties of 9-sarcosine oxytocin. }. Med. Pharm. Chem., 5:413-23. With Derek B. Hope and V. V. S. Murti. A highly potent analogue of oxytocin, desamino-oxytocin. i. Biol. Chem., 237: 1563 -66. With Miklos Bodanszky. p-Nitrophenyl carbobenzoxyglycinate. - Biochem. Prep., 9: 110-12. With Conrad H. Schneider. Synthesis of D-leucine-oxytocin, a bio- logically active diastereoisomer of oxytocin, and demonstration

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VINCENT DU VIGNEAUD 587 of its separability from oxytocin upon countercurrent distri- bution. I. Am. Chem. Soc., 84:3005-8. With Derek B. Hope. Synthesis of desamino-desoxy-oxytocin, a biologically active analogue of oxytocin. i. Biol. Chem., 237: 3146-50. With W. Y. Chan. Comparison of the pharmacologic properties of oxytocin and its highly potent analogue, desamino-oxytocin. Endocrinology, 71:977-82. With John E. Stouffer and Derek B. Hope. Neurophysin, oxytocin and desamino-oxytocin. In: Perspectives in Biology, ed. C. F. Cori, V. G. Foglia, L. F. Leloir, and S. Ochoa, pp.75-80. Amsterdam: Elsevier Publishing Company. With Thomas F. Dillon and R. Gordon Douglas. Further observa- tions on transbuccal administration of pitocin for induction and stimulation of labor. Obstet. Gynecol., 20:434-41. 1963 With Julius Golubow. Comparison of susceptibility of oxytocin and desamino-oxytocin to inactivation by leucine aminopeptidase and cx-chymotrypsin. Proc. Soc. Exp. Biol. Med., 112:218-19. With Raymond D. Kimbrough, Jr., William D. Cash, Luis A. Branda, and W. Y. Chan. Synthesis and biological properties of 1-desamino-8-lysine-vasopressin. I. Biol. Chem., 238:1411-14. With George S. Denning, Jr., Stefania Drabarek, and W. Y. Chan. The effect of replacement of the carboxamide group by hydro- gen in the glutamine or asparagine residue of oxytocin on its biological activity. }. Biol. Chem., 238:PC1560-61. With Julius Golubow and W. Y. Chan. Effect of human pregnancy serum on avian depressor activities of oxytocin and desamino- oxytocin. Proc. Soc. Exp. Biol. Med., 113:113-15. With Derek B. Hope and V. V. S. Murti. Synthesis of 1-hemi-D- cystine-oxytocin. }. Am. Chem. Soc., 85:3686-88. 1964 With t. P. Aroskar, W. Y. Chan, }. E. Stouffer, C. H. Schneider, and V. V. S. Murti. Renal excretion and tissue distribution of radio- activity after administration of tritium-labeled oxytocin to rats. Endocrinology, 74:226 -32. With Derek Tarvis. Crystalline deamino-oxytocin. Science, 143: 545-48.

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588 BIOGRAPHICAL MEMOIRS With George S. Denning, Jr., Stefania Drabarek, and W. Y. Chan. The synthesis and pharmacological study of 4-decarboxamido- oxytocin (4-`x-aminobutyric acid-oxytocin) and 5-decarbox- amido-oxytocin (5-alanine-oxytocin). J. Biol. Chem., 239:472- 77. With julian R. Rachele, John E. Wilson, Fred Plum, and Lester I. Reed. The administration of radioactive L-cystathionine to a human cystinuric. Adv. Chem., 44:82. Significance of the chemical functional groups of oxytocin to its pharmacological activity. Abstr. 6th Int. Congr. Biochem., New York City:97-98. An organic chemical approach to the study of the significance of the chemical functional groups of oxytocin to its biological ac- tivities. Proc. 8th Robert A. Welch Found. Conf. Chem. Res. Selected Topics in Modern Biochemistry. 1965 With Julian R. Rachele. The concept of transmethylation in mam- malian metabolism and its establishment by isotopic labeling through in viva experimentation. In: Transmethylation and Me- thionine Biosynthesis, ed. Shapiro and Schlenk, pp. 1-20. Chi- cago: University of Chicago Press. With Iphigenia Photaki.4-Deamido-oxytocin, an analog of the hor- mone containing glutamic acid in olace of ~lutamine. I. Am. Chem. Soc., 87:908-9. . ~ With Miklos Bodanszky and George S. Denning, Jr. p-Nitrophenyl carbobenzoxy-L-asparaginate. Biochem. Prep., 10:122-25. The hormones of the posterior pituitary gland with special refer- ence to their milk-ejecting ability. Bull. N.Y. Acad. Med., 41: 802-3. With Donald Yamashiro and H. L. Aaning. Inactivation of oxytocin by acetone. Proc. Natl. Acad. Sci. USA, 54:166-71. With Derek Jarvis and Barbara M. Ferrier. The effect of increasing the size of the ring present in deamino-oxytocin by one meth- ylene group on its biological properties: The synthesis of 1-^y- mercaptobutyric acid-oxytocin. I. Biol. Chem., 240:3553-57. With Stefania Drabarek. 2-D-tyrosine-oxytocin and 2-D-tyrosine- deamino-oxytocin, diastereoisomers of oxytocin and deamino- oxytocin. J. Am. Chem. Soc., 87:3974-78.

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VINCENT DU VIGNEAUD 589 With Maurice Manning.6-Hemi-D-cystine-oxytocin, a diastereoiso- mer of the posterior pituitary hormone oxytocin. J. Am. Chem. Soc., 87:3978-82. With Maurice Manning. 4-~-Alanine-oxytocin: An oxytocin analog containing a twenty-one-membered disulfide ring. Biochemis- try, 4:1884-87. With George Flouret. The synthesis of D-oxytocin, the enantiomer of the posterior pituitary hormone, oxytocin. }. Am. Chem. Soc., 87:3775-76. With Roderich Walter. 6-Hemi-L-selenocystine-oxytocin and 1- deamino-6-hemi-L-selenocystine-oxytocin, highly potent iso- logs of oxytocin and 1-deamino-oxytocin. }. Am. Chem. Soc., 87:4192-93. With Barbara M. Ferrier and Derek Carves. Deamino-oxytocin: Its isolation by partition chromatography on sephadex and crys- tallization from water, and its biological activities. }. Biol. Chem., 240:4264-66. 1966 With Barbara M. Ferrier. 9-Deamido-oxytocin, an analog of the hormone containing a glycine residue in place of the glycinam- ide residue. I. Med. Chem., 9:55-57. With Luis A. Branda. Synthesis and pharmacological properties of 9-decarboxamido-oxytocin. I Med. Chem., 9: 169 -72. With Donald Yamashiro and Dieter Gillessen. Simultaneous syn- thesis of 1-hemi-D-cystine-oxytocin and oxytocin and separa- tion of the diastereoisomers by partition chromatography on Sephadex by countercurrent distribution. I. Am. Chem. Soc., 88: 1310-13. With Roderich Walter. 1-Deamino-1,6-L-selenocystine-oxytocin, a highly potent isolog of 1-deamino-oxytocin. I. Am. Chem. Soc., 88: 1331-32. With George Flouret and Roderich Walter. Synthesis and some bio- logical properties of 4-valine-oxytocin and 1-deamino-4-valine- oxytocin. }. Biol. Chem., 241:2093-96. With Luis A. Branda and Stefania Drabarek. The synthesis and pharmacological properties of deamino-4-decarboxamido- oxytocin ~ 1-,3-mercaptopropionic acid-4-cx-aminobutyric acid- oxytocin). I. Biol. Chem., 241:2572-75.

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590 BIOGRAPHICAL MEMOIRS With John l. Ferraro.7-D-proline-oxytocin and its deamino analog. Diastereoisomers of oxytocin and deamino-oxytocin. I. Am. Chem. Soc., 88:3847-50. With Horst Schulz. Synthesis of 1-L-penicillamine-oxytocin, 1-D- penicillamine-oxytocin, and 1-deaminopenicillamine-oxytocin. potent inhibitors of the oxytocic response of oxytocin. I. Med. Chem., 9:647-50. With Luis A. Branda. Deoxy-4-decarboxamido-oxytocin and deamino-deoxy-4-decarboxamidooxytocin. I. Biol. Chem., 241:4051-54. With Horst Schulz. The effect of replacing one of the hydrogens of the ,B-carbon of the p-mercaptopropionic acid residue in deamino-oxytocin by a methyl group on its oxytocic and avian vasodepressor activity. I. Am. Chem. Soc., 88:5015-18. With Donald Yamashiro and Dieter Gillessen. Oxytoceine and deamino-oxytoceine. Biochemistry, 5:3711-19. With Roderich Walter. 8-Alanine-oxytocin, 8-alanine-oxypressin, and their deamino analogs. Their synthesis and some of their pharmacological properties. Biochemistry, 5:3720-27. 1967 With Donald Yamashiro, Robert T. Havran, and H. L. Aanning. Inactivation of lysine-vasopressin by acetone. Proc. Natl. Acad. Sci. USA, 57: 1058-59. With Derek Jarvis. The effect of decreasing the size of the ring present in deamino-oxytocin by one methylene group on its biological properties: The synthesis of 1-mercaptoacetic acid- oxytocin. I. Biol. Chem., 242:1768-71. With Luis A. Branda and Victor l. Hruby. 2-Isoleucine-oxytocin and deamino-2-isoleucine-oxytocin: Their synthesis and some of their pharmacological activities. Mol. Pharmacol., 3:248-53. With Derek Jarvis and Maurice Manning. 1-Mercaptoacetic acid-4- ,B-alanine-oxytocin. Biochemistry, 6: 1223-30. With W. Y. Chan and Robert Fear. Some pharmacologic studies on 1-L-penicillamine-oxytocin and 1-deaminopenicillamine- osytocin: Two potent osytocin inhibitors. Endocrinology, 81: 1267-77. With Dieter Gillessen. The synthesis and pharmacological prop- erties of 4-decarboxamido-8-lysine-vasopressin, 5-decarbox

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VINCENT DU VIGNEAUD 591 amido-8-lysine-vasopressin, and their 1-deamino analogues. }. Biol. Chem., 242:4806-12. With Horst Schulz. Synthesis and some pharmacological properties of 6-L-penicillamine-oxytocin. J. Med. Chem., 10: 1037-39. 1968 With Donald Yamashiro. Synthesis of"acetone-oxytocin" from an isopropylidene derivative of S-benzyl-L-cysteinyl-L-tyrosine. }. Am. Chem. Soc., 90:487-90. With Herbert Takashima and R. B. Merrifield. The synthesis of deamino-oxytocin by the solid phase method. I. Am. Chem. Soc., 90: 1323-25. With Donald Yamashiro and Derek B. Hope. Isomeric dimers of oxytocin. }. Am. Chem. Soc., 90:3857-60. With Donald Yamashiro, H. L. Aanning, Luis A. Branda, William D. Cash, and V. V. S. Murti. A synthesis of Fl-(N-methyl-hemi- L-cystine)~-oxytocin and a study of its reaction with acetone. I. Am. Chem. Soc., 90:4141-44. With W. Y. Chan, Victor J. Hruby, and George Flouret. 4-Leucine- oxytocin: A natriuretic, diuretic and anti-ADH polypeptide. Science, 161: 280-81. With Alfred T. Blomquist, Daniel H. Rich, Victor I. Hruby, Louis L. Nangeroni, and Paula Glose. Deuterated oxytocins. The syn- thesis and biological properties of three crystalline analogs of deamino-oxytocin deuterated in the 1-,3-mercaptopropionic acid position. Proc. Natl. Acad. Sci. USA, 61:688-92. With Victor I. Hruby and Donald Yamashiro. The structure of ace- tone-oxytocin with studies on the reaction of acetone with var- ious peptides. I. Am. Chem. Soc., 90:7106-10. Hormones of the mammalian posterior pituitary gland and their naturally occurring analogues. Johns Hopkins Med. J., 124:53- 65. With Robert T. Havran. The structure of acetone-lysine-vaso- pressin as established through its synthesis from the acetone derivative of S-benzyl-L-cysteinyl-L-tyrosine. I. Am. Chem. Soc., 91:2696-98. With Victor I. Hruby. The detection of a SchiE base intermediate in the formation of acetone-oxytocin. I. Am. Chem. Soc., 91 :3624-26.

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592 BIOGRAPHICAL MEMOIRS With Robert T. Havran. The synthesis and pharmacological prop- erties of L2-isoleucinel-8-lysine-vasopressin and its 1-deamino analog. i. Am. Chem. Soc., 91:3626-28. With Victor }. Hruby and George Flouret. The synthesis and some of the pharmacological properties of L4-L-isoleucine]-oxytocin and t4-L-leucine]-oxytocin i. Biol. Chem., 244:3890-94. With Victor l. Hruby. Synthesis and some pharmacological activi- ties of t2-L-valinel-oxytocin and F2-L-leucine]-oxytocin. }. Med. Chem., 12:731-33. With Alfred T. Blomquist, Daniel H. Rich, Bruce A. Carlson, G. Ashley Allen, Victor }. Hruby, Herbert Takashima, Louis L. Nangeroni, and Paula Glose. Deuterated oxytocins: The syn- thesis and biological properties of a crystalline analog of de- amino-oxytocin deuterated in the 5-asparagine position. Proc. Natl. Acad. Sci. USA, 64:263-66. With George Flouret. The synthesis and some pharmacological activities of L4-L-norvaline]-oxytocin and L4-L-norleucine]- oxytocin and their deamino analogs. i. Med. Chem., 12:1035- 38. With Herbert Takashima and Wolfgang Fraefel. The synthesis and certain pharmacological properties of deamino-oxytocinoic acid methylamide and deamino-oxytocinoic acid dimethyl- amide. l. Am. Chem. Soc., 91:6182-85. 1970 With Herbert Takashima and Victor i. Hruby. The synthesis of ~ 1-deamino,4-L-leucine1-oxytocin and ~ 1-deamino,4-L-isoleu- cine]-oxytocin and some of their pharmacological properties. J. Am. Chem. Soc., 92:677-80. With Wolfgang Fraefel. The synthesis and pharmacological prop- erties of F1-~-mercaptovaleric acid)~-oxytocin, a homolog of deamino-oxytocin containing a twenty-two-membered ring. J. Am. Chem. Soc., 92:1030-32. With Victor }. H ruby and W. Y. Chan. t2,4-Diisoleucine]-oxytocin. An analog of oxytocin with natriuretic and diuretic activities. }. Med. Chem., 13: 185-87. With Herbert Takashima. The synthesis of deamino-oxytocinoic acid and acetone-oxytocinoic acid and their use in the prepa- ration of deamino-oxytocinoxyloxytocin and oxytocinoyloxy- tocin. }. Am. Chem. Soc., 92:2501-4.

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VINCENT DU VIGNEAUD 593 With Dieter Gillessen. Synthesis and pharmacological properties of 4-decarboxamido-8-arginine-vasopressin and its 1-deamino analog. I. Med. Chem., 13:346-49. With Wolfgang Fraefel. L1-~-Mercaptoundecanoic acid)~-oxytocin, a 28-membered ring homolog of deamino-oxytocin. I. Am. Chem. Soc., 92:4426-27. With W. Y. Chan. Natriuretic, diuretic and anti-arginine-vasopres- sin (ADH) effects of two analogs of oxytocin: L4-Leucinel- oxytocin and L2,4-diisoleucine]-oxytocin. i. Pharmacol. Exp. Ther., 174:541 - 49. 1971 With George Flouret. Deamino-D-oxytocin. I. Med. Chem., 14: 556-57. With P. H. Von Dreele, A. I. Brewster, H. A. Scheraga, and M. F. Ferger. Nuclear magnetic resonance spectrum of lysine-vaso- pressin and its structural implications. Proc. Natl. Acad. Sci. USA, 68: 1028-31. With Victor i. Hruby and Martha F. Ferger. Synthesis and phar- macological properties of deaminotocinamide and a new syn- thesis of tocinamide. I. Am. Chem. Soc., 93:5539-42. With Jim D. Meador, Martha F. Ferger, G. Ashley Allen, and Alfred T. Blomquist. The synthesis and biological properties of L1- deaminopenicillaminel-oxytocin deuterated in the 1-position. Bioorg. Chem., 1: 123-28. 1972 With Myles A. Wille and W. Y. Chan. Solid phase synthesis of L3,4- dileucine]-oxytocin and a study of some of its pharmacological properties. i. Med. Chem., 15: 11 ~12. With Raymond I. Vavrek, Martha F. Ferger, G. Ashley Allen, Daniel H. Rich, and Alfred T. Blomquist. Synthesis of three oxytocin analogs related to L1-deaminopenicillamine1-oxytocin possess- ing antioxytocic activity. I. Med. Chem., 15: 123-26. With Martha F. Ferger, Warren C. ~ones, Jr., and Douglas F. Dyckes. Four cyclic disulfide pentapeptides possessing the ring of va- sopressin. }. Am. Chem. Soc., 94:982-84. With P. H. Von Dreele, A. I. Brewster, F. A. Bovey, H. A. Scheraga, and M. F. Ferger. Nuclear magnetic resonance studies of lysine- vasopressin: Structural constraints. Proc. Natl. Acad. Sci. USA, 68:3088-91.

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594 BIOGRAPHICAL MEMOIRS With John D. Glass. Synthesis and certain pharmacological prop- erties of lysine-vasopressinoic acid methylamide and lysine- vasopressinoic acid dimethylamide. I. Med. Chem., 15:486-88. With Victor l. Hruby, Clark W. Smith, David K. Linn, and Martha F. Ferger. Synthesis and some pharmacological properties of tocinoic acid and deaminotocinoic acid. I. Am. Chem. Soc., 94:5478-80. With P. ~ Von Dreele, A. I. Brewster, l. Dadok, H. S. Scheraga, F. A. Bovey, and M. F. Ferger. Nuclear magnetic resonance spectrum of lysine-vasopressin in aqueous solution and its structural implications. Proc. Natl. Acad. Sci. USA, 69:2169- 73. With P. H. Von Dreele, H. A. Scheraga, D. F. Dyckes, and M. F. Ferger. Nuclear magnetic resonance spectrum of deamino- lysine-vasopressin in aqueous solution and its structural impli- cations. Proc. Natl. Acad. Sci. USA, 69:3322-26. 1973 With John D. Glass. Solid-phase synthesis and presser potency of ~ l-deamino-9-ethylenediamine]-lysine-vasopressin. }. Med. Chem., 16:160-61. With Douglas F. Dyckes, Martha F. Ferger, and W. Y. Chan. Syn- thesis and some of the pharmacological properties of t4- leucinel-8-lysine-vasopressin and ~ 1-deamino,4-leucinel-8-ly- sine vasopressin. }. Med. Chem., 1 6:843 - 47 . With Warren C. Tones, Tr., and John I. Nestor, fir. Synthesis and some pharmacological properties of ~ 1-deamino,9-thiogly- cineloxytocin. I. Am. Chem. Soc., 95:5677-79. 1974 With Douglas F. Dyckes, John I. Nestor, Jr., and Martha F. Ferger. ~ 1-~-Mercapto-,B,,8-diethylpropionic acid]-8-lysine-vasopressin, a potent inhibitor of 8-lysine-vasopressin and of oxytocin. J. Med. Chem., 17:250-52. With W. Y. Chan and Victor J. Hruby. Effects of magnesium ion and oxytocin inhibitors on the utertonic activity of oxytocin and prostaglandins E2 and F2a. I. Pharmacol. Exp. Ther., 190:77- 87. With W. Y. Chan, John I. Nestor, fir., and Martha F. Ferger. Inhi- bition of oxytocic responses to oxytocin in pregnant rats by

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VINCENT DU VIGNEAUD 595 [ l-L-penicillamine]oxytocin and [ l-~-mercapto-,B,0-diethylpro- pionic acidjoxytocin. Proc. Soc. Exp. Biol. Med., 146:364-66. With Douglas F. Dyckes, John J. Nestor, Jr., Martha F. Ferger, and W. Y. Chan. [l-~-Mercapto-g,~-diethylpropionic acid, 4-leu- cinel-8-lysine-vasopressin and [1-~-mercapto-,13,,(3-diethylpro- pionic acid, 4-leucineloxytocin, compounds possessing antihor- monal properties. J. Med. Chem., 17 :969-71. With Douglas F. Dyckes, Clark W. Smith, and Martha F. Ferger. Synthesis and some pharmacological properties of [1-~- Maa]LVP and [l-l~y-MbalLVP. J. Am. Chem. Soc., 96:7549-51. 1975 With John J. Nestor, Jr., and Martha F. Ferger. [l-~-Mercapto-,(3,,8- pentamethylenepropionic acid]oxytocin, a potent inhibitor of oxytocin. J. Med. Chem., 18: 284-87. With J.J. Nestor, Jr., and M. F. Ferger. The retention of anti- oxytocic activity by the ring moieties of L 1-~-mercapto-p ,B-diethylpropionic acid]-oxytocin and [l-,B-mercapto-,l3,-pen- tamethylenepropionic acidioxytocin. Proc. 4th Am. Peptide Symp., pp.755 - 59. Ann Arbor, Mich.: Ann Arbor Science Pub- lishers. ~, . ~. ~ 1976 With R. A. Plane. Reminiscences of a biochemist. J. Chem. Ed., 53:8-12.