Yellapragada Subbarow

Yellapragada Subbarow (12 January 1895 – 9 Au- discovered the role of phosphocreatine and adenosine gust 1948) was an Indian biochemist who discovered the triphosphate (ATP) in muscular activity, which earned function of adenosine triphosphate as an energy source him an entry into biochemistry textbooks in the 1930s. in the cell, and developed methotrexate for the treat- He obtained his Ph.D. degree the same year. He joined ment of cancer. Most of his career was spent in the Lederle Laboratories, a division of American Cyanamid United States. Despite his isolation of ATP, Subbarow (now a division of Wyeth which is owned by Pfizer), af- was denied tenure at Harvard[1] and remained without a ter he was denied a regular faculty position at Harvard. green card throughout his life,[2] though he would lead At Lederle, he developed a method to synthesize folic [4] some of America’s most important medical research dur- acid, Vitamin B9, based on work by Lucy Wills to ing World War II.[3] Subbarow is also credited with the isolate folic acid as a protective agent against anemia. first synthesis of the chemical compounds folic acid and After his work on folic acid and with considerable in- methotrexate. put from Dr. Sidney Farber, he developed the impor- tant anti-cancer drug methotrexate - one of the very first cancer chemotherapy agents and still in widespread clin- 1 Early life and education ical use.[5][6][6][7] Subbarow also discovered the basis for hetrazan which was used by the World health Organiza- tion against filariasis.[8] Under Subbarow, Benjamin Dug- He was born in Bhimavaram, Madras Presidency, now gar made his discovery of the world’s first tetracycline in West Godavari District, Andhra Pradesh in India. He antibiotic, aureomycin, in 1945. This discovery was passed through a traumatic period in his schooling at made as a result of the largest distributed scientific exper- Rajahmundry (due to the premature death of close rel- iment ever performed to that date, when American sol- atives by disease) and eventually matriculated in his third diers who had fought all over the world were instructed attempt from the Hindu High School, Madras. He passed at the end of WWII to collect soil samples from wher- the Intermediate Examination from the Presidency Col- ever they were, and bring the samples back for screening lege and entered the Madras Medical College where his at Lederle Laboratories for possible anti-bacterial agents education was supported by friends and Kasturi Surya- produced by natural soil fungi.[2] narayana Murthy, whose daughter he later married. Following Gandhi's call to boycott British goods he started wearing khadi surgical dress; this incurred the dis- 3 Honors pleasure of M. C. Bradfield, his surgery professor. Con- sequently, though he did well in his written papers, he was awarded the lesser LMS certificate and not a full MBBS Subbarow’s colleague, George Hitchings, who shared degree. Subbarow tried to enter the Madras Medical Ser- the 1988 Nobel Prize in Physiology or Medicine with vice without success. He then took up a job as Lec- Gertrude Elion, said, “Some of the nucleotides isolated turer in Anatomy at Dr. Lakshmipathi’s Ayurvedic Col- by Subbarow had to be rediscovered years later by other lege at Madras. He was fascinated by the healing powers workers because Fiske, apparently, did not let Subbarow’s [9] of Ayurvedic medicines and began to engage in research contributions see the light of the day.” A fungus was to put Ayurveda on a modern footing. The promise of named Subbaromyces splendens in his honor by American [10] support from Malladi Satyalingam Naicker Charities in Cyanamid. Writing in the April 1950 issue of Argosy, [11] Kakinada, and financial assistance raised by his father-in- Doron K. Antrim observed, “You've probably never law, enabled Subbarow to proceed to the U.S. He arrived heard of Dr. Yellapragada Subbarow. Yet because he in Boston on 26 October 1922. lived you may be alive and are well today. Because he lived you may live longer.”[12]

2 Career in United States 4 Publications After earning a diploma from the Harvard Medical School he joined Harvard as a junior faculty member. • Angia, R.B.; Boothe, J.H.; Hutchings, B.L.; Mowat, With Cyrus Fiske, he developed a method for the es- J.H.; Semb, J.; Stokstad, E.L.R.; Subbarow, timation of phosphorus in body fluids and tissues. He Y.; Waller, C.W.; Cosulich, D.B.; Fabrenbach,

1 2 4 PUBLICATIONS

M.J.; Hultquist, M.E.; Erwin, K.U.H.; Northey, • Bernstein, S.; Sax, K.J.; Subbarow, Y. (1948). “7- E.H.; Seeger, D.R.; Sickels, J.P.; Smith Jr, J.M. Dehydrocholesteryl chloride and bromide”. Jour- (1946). “The structure and synthesis of the liver nal of Organic Chemistry 13 (6): 837–842. L. casei factor”. Science 103 (2683): 667–669. doi:10.1021/jo01164a009. doi:10.1126/science.103.2683.667. • Boothe, J.H.; Mowat, J.H.; Hutchings, B.L.; Ang- • Angier, R.B.; Boothe, J.H.; Hutchings, B.L.; ier, R.B.; Waller, C.W.; Stokstad, E.L.R.; Semb, J.; Mowat, J.H.; Semb, J.; Stokstad, E.L.R.; Sub- Gazzola, A.L.; Subbarow, Y. (1948). “Pteroic acid baRow, Y.; Waller, C.W.; Cosulich, D.B.; Fahren- derivatives. II. Pteroyl-γ-glutamylglutamic acid and bach, M.J.; Hultquist, M.E.; Kuh, E.; Northey, E.H.; pteroyl-γ-glutamyl-γ-glutamylglutamic acid”. Jour- Seeger, D.R.; Sickels, J.P.; Smith Jr, J.M. (1945). nal of the American Chemical Society 70 (3): 1099– “Synthesis of a compound identical with the L. casei 1102. doi:10.1021/ja01183a068. factor isolated from liver”. Science 102 (2644): • 227–228. doi:10.1126/science.102.2644.227. Boothe, J.H.; Semb, J.; Waller, C.W.; Angier, R.B.; PMID 17778509. Mowat, J.H.; Hutchings, B.L.; Stokstad, E.L.R.; Subbarow, Y. (1949). “Pteroic acid derivatives. • Angier, R.B.; Mowat, J.H.; Boothe, J.H.; Waller, III. Pteroyl-γ-glutamylglutamic acid and pteroyl-γ- C.W.; Semb, J.; Hutchings, B.L.; Stokstad, E.L.R.; glutamyl-γ-glutamylglutamic acid”. Journal of the Subbarow, Y. (1948). “The preparation of 2-amino- American Chemical Society 71 (7): 2304–2308. 4-hydroxy-6-keto-5,5-dichlorodihydropyrimidine”. doi:10.1021/ja01175a010. Journal of the American Chemical Society 70 (3): • 1274–1275. doi:10.1021/ja01183a502. Boothe, J.H.; Waller, C.W.; Stokstad, E.L.R.; Hutchings, B.L.; Mowat, J.H.; Angier, R.B.; Semb, • Angier, R.B.; Stokstad, E.L.R.; Mowat, J.H.; J.; SubbaRow, Y.; Cosulich, D.B.; Fahrenbach, Hutchings, B.L.; Boothe, J.H.; Waller, C.W.; Semb, M.J.; Hultquist, M.E.; Kuh, E.; Northey, E.H.; J.; SubbaRow, Y.; Cosulich, D.B.; Fahrenbach, Seeger, D.R.; Sickels, J.P.; Smith Jr, J.M. (1948). M.J.; Hultquist, M.E.; Kuh, E.; Northey, E.H.; “Synthesis of pteroylglutamic acid. IV”. Journal Seeger, D.R.; Sickels, J.P.; Smith Jr, J.M. (1948). of the American Chemical Society 70 (1): 27–28. “Synthesis of pteroylglutamic acid. III”. Journal doi:10.1021/ja01181a009. of the American Chemical Society 70 (1): 25–26. • doi:10.1021/ja01181a008. Fiske, C.H.; Subbarow, Y. (1927). “The nature of the “inorganic phosphate” in vol- • Angier, R.B.; Waller, C.W.; Boothe, J.H.; Mowat, untary muscle”. Science 65 (1686): 399. J.H.; Semb, J.; Hutchings, B.L.; Stokstad, E.L.R.; doi:10.1126/science.65.1686.401. PMID Subbarow, Y. (1948). “Pteridine chemistry. I”. 17807679. Journal of the American Chemical Society 70 (9): • 3029–3031. doi:10.1021/ja01189a058. Fiske, C.H.; Subbarow, Y. (1929). “Phosphorus compounds of muscle and liver”. Science 70 (1816): • Angier, R.B.; Waller, C.W.; Hutchings, B.L.; 381–382. doi:10.1126/science.70.1816.381-a. Boothe, J.H.; Mowat, J.H.; Semb, J.; SubbaRow, • Y. (1950). “Pteroic acid derivatives. VI. Unequiv- Harned, B.K.; Cunningham, R.W.; Halliday, S.; ocal syntheses of some isomeric glutamic acid pep- Vessey, R.E.; Yuda, N.N.; Clark, M.C.; Hine, C.H.; tides”. Journal of the American Chemical Society 72 Cosgrove, R.; Subbarow, Y. (1948). “Studies on (1): 74–77. doi:10.1021/ja01157a021. the chemotherapy of filariasis. VI. Some phar- macopynamic properties of 1-diethylcarbamyl-4- • Baker, B.R.; Querry, M.V.; Bernstein, S.; Safir, methylpiperazine hydrochloride, Hetrazan”. The S.R.; Subbarow, Y. (1947). “Biotin. IV. A sec- Journal of Laboratory and Clinical Medicine 33 (2): ond synthesis of 2-(Œ¥-carboxybutyl)-thiophane- 216–235. 3,4-dicarboxylic acid”. Journal of Organic Chem- • istry 12 (1): 167–173. doi:10.1021/jo01165a021. Hewitt, R.I.; Kushner, S.; Stewart, H.W.; White, E.; Wallace, W.S.; SubbaRow, Y. (1947). • Baker, B.R.; Querry, M.V.; McEwen, W.L.; Bern- “Experimental chemotherapy of filariasis. III. stein, S.; Safir, S.R.; Dorfman, L.; Subbarow, Y. Effect of 1-diethylcarbamyl-4-methylpiperazine (1947). “Biotin. VI. Synthesis of biotin and epi- hydrochloride against naturally acquired filarial allobiotin”. Journal of Organic Chemistry 12 (1): infections in cotton rats and dogs”. The Journal 186–198. doi:10.1021/jo01165a023. of Laboratory and Clinical Medicine 32 (11): 1314–1329. • Bernstein, S.; Binovi, L.J.; Dorfman, L.; Sax, K.J.; Subbarow, Y. (1949). “7-Dehydrocholesterol”. • Hewitt, R.I.; Wallace, W.S.; White, E.; SubbaRow, Journal of Organic Chemistry 14 (3): 433–446. Y. (1947). “Experimental chemotherapy of filar- doi:10.1021/jo01155a015. iasis. I. Experimental methods for testing drugs 3

against naturally acquired filarial infections in cot- white mice”. The Journal of Laboratory and Clini- ton rats and dogs”. The Journal of Laboratory and cal Medicine 33 (10): 1249–1253. Clinical Medicine 32 (11): 1293–1303. • Mowat, J.H.; Boothe, J.H.; Hutchings, B.L.; Stok- • Hewitt, R.I.; White, E.; Wallace, W.S.; Stew- stad, E.L.R.; Waller, C.W.; Angier, R.B.; Semb, J.; art, H.W.; Kushner, S.; SubbaRow, Y. (1947). Cosulich, D.B.; SubbaRow, Y. (1948). “Erratum: “Experimental chemotherapy of filariasis. II. Effect The structure of the liver L. casei factor (Journal of of piperazine derivatives against naturally acquired the American Chemical Society (1948) 70, (14))". filarial infections in cotton rats and dogs”. The Jour- Journal of the American Chemical Society 70 (12): nal of Laboratory and Clinical Medicine 32 (11): 4275. doi:10.1021/ja01192a622. 1304–1313. • Mowat, J.H.; Boothe, J.H.; Hutchings, B.L.; Stok- • Hultquist, M.E.; Germann, R.P.; Webb, J.S.; Wright stad, E.L.R.; Waller, C.W.; Angier, R.B.; Semb, Jr, W.B.; Roth, B.; Smith Jr, J.M.; Subbarow, J.; Cosulich, D.B.; SubbaRow, Y. (1948). “The Y. (1951). “N-heterocyclic benzenesulfonamides”. structure of the liver L. casei factor”. Journal Journal of the American Chemical Society 73 (6): of the American Chemical Society 70 (1): 14–18. 2558–2566. doi:10.1021/ja01150a042. doi:10.1021/ja01181a005. • Hultquist, M.E.; Kuh, E.; Cosulich, D.B.; Fahren- • Mowat, J.H.; Gazzola, A.L.; Hutchings, B.L.; bach, M.J.; Northey, E.H.; Seeger, D.R.; Sick- Boothe, J.H.; Waller, C.W.; Angier, R.B.; Semb, els, J.P.; Smith Jr, J.M.; Angier, R.B.; Boothe, J.; Subbarow, Y. (1949). “Pteroic acid derivatives. J.H.; Hutchings, B.L.; Mowat, J.H.; Semb, J.; IV. Pteroyl-α,γ-glutamyldiglutamic acid”. Journal Stokstad, E.L.R.; SubbaRow, Y.; Waller, C.W. of the American Chemical Society 71 (7): 2308– (1948). “Synthesis of pteroylglutamic acid (liver 2310. doi:10.1021/ja01175a011. L. casei factor) and pteroic acid. II”. Journal of the American Chemical Society 70 (1): 23–24. • Mowat, J.H.; Hutchings, B.L.; Angier, R.B.; Stok- doi:10.1021/ja01181a007. stad, E.L.R.; Boothe, J.H.; Waller, C.W.; Semb, J.; Subbarow, Y. (1948). “Pteroic acid deriva- • Hutchings, B.L.; Stokstad, E.L.R.; Bohonos, N.; tives. I. Pteroyl-Œ±-glutamylglutamic acid and Sloane, N.H.; SubbaRow, Y. (1948). “The isola- pteroyl-α,γ-glutamyldiglutamic acid”. Journal of tion of the fermentation Lactobacillus casei factor”. the American Chemical Society 70 (3): 1096–1098. Journal of the American Chemical Society 70 (1): 1– doi:10.1021/ja01183a067. 3. doi:10.1021/ja01181a001. • Safir, S.R.; Bernstein, S.; Baker, B.R.; McEwen, • Hutchings, B.L.; Stokstad, E.L.R.; Mowat, J.H.; W.L.; Subbarow, Y. (1947). “Biotin. IX. A synthe- Boothe, J.H.; Waller, C.W.; Angier, R.B.; Semb, sis of dl-dehydrobiotin”. Journal of Organic Chem- J.; SubbaRow, Y. (1948). “Degradation of the istry 12 (3): 475–482. doi:10.1021/jo01167a017. fermentation L. casei factor. II”. Journal of the American Chemical Society 70 (1): 10–13. • Safir, S.R.; Kushner, S.; Brancone, L.M.; Sub- doi:10.1021/ja01181a004. barow, Y. (1948). “Experimental chemother- • Kushner, S.; Dalalian, H.; Cassell, R.T.; San- apy of trypanosomiasis. II. The preparation jurjo, J.L.; McKenzie, D.; Subbarow, Y. of compounds related to p-phenylenediguanidine”. (1948). “Experimental chemotherapy of tu- Journal of Organic Chemistry 13 (6): 924–932. berculosis. I. Substituted nicotinamides”. Jour- doi:10.1021/jo01164a024. nal of Organic Chemistry 13 (6): 834–836. • Sanders, M.; Subbarow, Y.; Alexander, R.C. doi:10.1021/jo01164a008. (1948). “An effective antiviral synthetic”. Texas re- • Little, P.A.; Oleson, J.J.; SubbaRow, Y. (1948). ports on biology and medicine 6 (3): 385–395. “The effect of nutrition on the tumor response in • Semb, J.; Boothe, J.H.; Angier, R.B.; Waller, Rous chicken sarcoma”. The Journal of Laboratory C.W.; Mowat, J.H.; Hutchings, B.L.; Sub- and Clinical Medicine 33 (9): 1139–1143. barow, Y. (1949). “Pteroic acid derivatives. • Little, P.A.; Sampath, A.; SubbaRow, Y. (1948). V. Pteroyl-α-glutamyl-α-glutamylglutamic acid, “The use of antagonists of pteroylglutamic acid in pteroyl-γ-glutamyl-α-glutamylglutamic acid, controlling Rous chicken sarcoma”. The Journal pteroyl-α-glutamyl-γ-glutamylglutamic acid”. of Laboratory and Clinical Medicine 33 (9): 1144– Journal of the American Chemical Society 71 (7): 1149. 2310–2315. doi:10.1021/ja01175a012. • McKenzie, D.; Malone, L.; Kushner, S.; Oleson, • Stewart, H.W.; Turner, R.J.; Denton, J.J.; Kushner, J.J.; SubbaRow, Y. (1948). “The effect of nico- S.; Brancone, L.M.; McEwen, W.L.; Hewitt, R.I.; tinic acid amide on experimental tuberculosis of Subbarow, Y. (1948). “Experimental chemotherapy 4 5 REFERENCES

of filariasis. IV. The preparation of derivatives of 5 References piperazine”. Journal of Organic Chemistry 13 (1): 134–143. doi:10.1021/jo01159a018. [1] Mukherjee, Siddhartha (16 November 2010). The Em- peror of All Maladies: A Biography of Cancer. Simon and • Stokstad, E.L.R.; Hutchings, B.L.; Mowat, J.H.; Schuster. p. 31. ISBN 978-1-4391-0795-9. Retrieved 6 Boothe, J.H.; Waller, C.W.; Angier, R.B.; Semb, September 2011. Quote: “Any one of these achievements J.; SubbaRow, Y. (1948). “The degradation of the should have been enough to guarantee him a professor- fermentation Lactobacillus casei factor. I”. Jour- ship at Harvard. But Subbarow was a foreigner, a reclu- nal of the American Chemical Society 70 (1): 5–9. sive, nocturnal, heavily accented vegetarian who lived in a doi:10.1021/ja01181a003. one-room apartment downtown, befriended only by other nocturnal recluses”

• Stokstad, E.L.R.; Hutchings, B.L.; SubbaRow, Y. [2] Pushpa Mitra Bhargava (2001). “History of Medicine: (1948). “The isolation of the Lactobacillus casei fac- Dr. Yellapragada SubbaRow (1895-1948) - He Trans- tor from liver”. Journal of the American Chemical formed Science; Changed Lives” (PDF). Journal of the Society 70 (1): 3–5. doi:10.1021/ja01181a002. Indian Academy of Clinical Medicine 2 (1,2): 96_100. [3] Yellapragada SubbaRow Archives OnLine • Subbarow, Y.; Dann, W.J. (1938). “The inactiv- ity of β-aminopyridine in blacktongue”. Journal [4] Farber, S; Cutler, EC; Hawkins, JW; Harrison, JH; Peirce of the American Chemical Society 60 (10): 2565. Ec, 2nd; Lenz, GG (1947). “The Action of Pteroylglu- doi:10.1021/ja01277a506. tamic Conjugates on Man”. Science 106 (2764): 619–21. doi:10.1126/science.106.2764.619. PMID 17831847. • Subbarow, Y.; Dann, W.J.; Meilman, E. [5] Farber et al.'s article, published in the New England Jour- (1938). “The effect of β-aminopyridine in nal of Medicine in 1946, noted Dr Subbarow’s work as a experimental blacktongue”. Journal of the foundation for this landmark paper. The paper remains American Chemical Society 60 (6): 1510–1511. one of the earliest top-cited research articles and is a clas- doi:10.1021/ja01273a505. sic in the field of medicine.

• Subbarow, Y.; Hastings, A.B.; Elkin, M. (1945). [6] Farber, Sidney; Farber S; Diamond LK; Mercer RD et al. “Chemistry of Anti-Pernicious Anemia Substances (1948). “Temporary remissions in acute leukemia in chil- of Liver”. Vitamins and Hormones 3 (C): 237–296. dren produced by folic acid antagonist, 4-aminopteroyl- glutamic acid (aminopterin)". N. Engl. J. Med. 238 (23): doi:10.1016/s0083-6729(08)61114-0. 787–93. doi:10.1056/NEJM194806032382301. PMID 18860765. • Subbarow, Y.; Hitchings, G.H. (1939). “Pantothenic acid as a factor in rat nutrition [7] Miller, DR (2006). “A tribute to Sidney Farber-- [9]". Journal of the American Chemical Society 61 the father of modern chemotherapy”. British journal (6): 1615–1616. doi:10.1021/ja01875a522. of haematology 134 (1): 20–6. doi:10.1111/j.1365- 2141.2006.06119.x. PMID 16803563. • Subbarow, Y.; Jacobson, B.M.; Prochownick, V. [8] WHO Report on Global Filaria Control 2002 (1936). “Studies of the pernicious anemia principle in liver. III. The isolation and properties of a sub- [9] The Hindu : Discoverer of miracle medicines - Y. Subba stance with primary therapeutic activity”. Journal Row (1895-1948) of the American Chemical Society 58 (11): 2234– [10] Taxon ID 50474 2236. doi:10.1021/ja01302a044. [11] “Miracle man of miracle drugs: Dr Yellapragada Sub- • Subbarow, Y.; Rane, L. (1939). “Pantothenic baRow”. Retrieved 10 March 2014. acid as a growth factor for the Dochez NY5 strain of hemolytic Streptococcus [10]". Journal [12] Dr. Yellapragada SubbaRow (1895-1948): The man and the method by Kapur, S. & Gupta, S. P. K. in Indian Jour- of the American Chemical Society 61 (6): 1616. nal of Experimental Biology, 36(11):1087-92 doi:10.1021/ja01875a523.

• Waller, C.W.; Hutchings, B.L.; Mowat, J.H.; Stok- stad, E.L.R.; Boothe, J.H.; Angier, R.B.; Semb, J.; SubbaRow, Y.; Cosulich, D.B.; Fahrenbach, M.J.; Hultquist, M.E.; Kuh, E.; Northey, E.H.; Seeger, D.R.; Sickels, J.P.; Smith Jr, J.M. (1948). “Synthesis of pteroylglutamic acid (liver L. ca- sei factor) and pteroic acid. I”. Journal of the American Chemical Society 70 (1): 19–22. doi:10.1021/ja01181a006. 5

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