KING, HAROLD

(b. Llanegan, Caernarvonshire, Wales, 24 February 1887; d. Wimbourne, England, 20 February 1956)

organic chemistry, chemotherapy, pharmacology.

King was the first of four children born to Herbert and Ellen Elizabeth Hill King, both originally from Lancashire. From 1891 until their retirement in 1923, King’s parents were head teachers of the St. James’s Church School in Bangor. King’s early education there was followed by five years at the Friars’ Grammar School, Bangor. In 1905 he entered University College, Bangor, on two scholarships. The teaching of K. J. P. Orton led King to chemistry, and in 1909 he graduated with first-class honors. With additional university support he remained for two more years at Bangor, training for research in Orton’s laboratory.

In 1911 King received an industrial bursary and took an appointment in the analytical laboratory of the Gas Light and Coke Company’s Tar and Ammonia Products Works at Beckton. Seeing no prospects for serious research, he moved six months later (1912) to a temporary post in the Wellcome Physiological Research Laboratories at Herne Hill. Here, in the environment created by Henry Hallett Dale and George Barger, and in collaboration with A. J. Ewins, King found an exhilarating research atmosphere in which biology and chemistry were brought together to mutual advantage. Six months later King accepted a position in the experimental department of the Welcome Chemical Works at Dartford. In Frank Lee Pyman’s laboratory he worked on the glycerophosphates and improved his experimental technique.

During World War I, King contributed to Wellcome’s urgent efforts to create a British synthetic drug industry. In Pyman’s laboratory he carried out research on hyoscine that expanded his knowledge of alkaloidal chemistry, an interest already stimulated by his association with Ewins. In 1919 King accepted a position as chemist on the scientific staff of the Medical Research Council, which was then establishing an institute for laboratory work. He remained with the Medical Research Council, at the National Institute for Medical Research, until his retirement in 1950, concentrating his research in areas where organic chemistry might inform medicine or biology; chemotherapy, alkaloidal chemistry, and the structure of steroids. In 1923 King married Elsie Maud Croft; they had one son.

King was well suited by temperament and intellect to the life of a research institute. Quiet and retiring, he thrived on long hours at the laboratory bench and on freedom from teaching or administrative responsibilities. He found sufficient intellectual stimulus in his own curiosity and in contacts with colleagues. Though personally reserved, he readily shared his knowledge with associates, and his interest in work proceeding in other laboratories of the institute prompted him on several occasions to initiate fruitful collaborative efforts.

An active member of the Chemical Society, King served on both its Council (1928–1931) and its Publication Committee. He was a member of the Alkaloids Committee and the Chemical Revision Committee of the Pharmacopoeia Commission. For the Medical Research Council he prepared Chemotherapy Abstracts, served as chemical secretary of the Chemotherapy Committee, and during World War II was secretary of the Committee on the Synthesis of Penicillin. Apart from his work as a chemist, King had a serious amateur interest in entomology, a recreation to which he devoted the six years of his retirement.

King owed his position with the Medical Research Council in part to the council’s interest in chemotherapy in the wake of Paul Ehrlich’s success with Salvarsan, and chemotherapy remained a central focus of his research throughout his career. In his first publications after joining the council, King reported his isolation of the principal impurity in commercial preparations of Salvarsan, a substance responsible for part of the drug’s toxic side effects. Organic arsenicals also figured in King’s next project. Through the 1920’s and early 1930’s he attempted to produce an arsenical drug analogous to suramin (Bayer 205, a compound similar to the dye trypan red). The idea was to combine the antitrypanosomal therapeutic power of the arsenicals with the longlasting therapeutic effect of suramin. No clinically useful drug came out of this effort, but another set of investigations on the thioarsenites, formed by the reaction between arsenious oxide derivatives and thiol compounds, yielded insights into the mode of action of arsenical drugs on spirochetes and trypanosomes.

A by–product of King’s work on arsenicals was his study of the constitution of sulfarsphenamine and neoarsphenamine, published between 1933 and 1935. In the late 1930’s and 1940’s King investigated the effects of structural modifications of the cinchona alkaloids on their antiplasmodial action in malaria. Identifying the traits of the molecules essential for biological activity, he was able to synthesize several analogues of these alkaloids, one of which had marked antiplasmodial action. Although no clinically useful drug emerged immediately from these studies, King’s work found an important place in the U. S. wartime search for synthetic antimalarials. In the 1940’s King, working with E. M. Lourie and Warrington Yorke, demonstrated that long aliphatic straight–chain diguanidines, diisothioureas, and diamidines showed antitrypanosomal activity, a result that led to the development by A. J. Ewins of stilbamidine for the treatment of kala-azar. King’s finding, with James Walker and C. H. Andrewes, also in the 1940’s, that p-sulfonamidobenzamidine had antirickettsial activity was the first indication that rickettsial infections were vulnerable to chemotherapy.

King’s early work with A. J. Ewins and then F. L. Pyman on alkaloidal chemistry opened to him a second field of lifelong research that yielded significant results for chemistry, pharmacology, and therapeutics. Of greatest importance was his work on curare, prompted by Dale’s work on chemical transmission of nerve impulses and the resulting interest within the institute in substances affecting neuromuscular transmission. In studies that he began to publish in 1935, King succeeded in isolating a specific alkaloid, d-tubocurarine chloride, from the South American arrow poison tube curare, and in showing that it was the active principle. He went on to demonstrate its botanical origin and to determine its chemical constitution. Access to the pure alkaloid was an immediate boon to surgeons, who could safely control its dosage for use as a muscle relaxant. Consideration of the structure of d-tubocurarine chloride prompted King to attempt synthesis of simpler molecules that might reproduce its effects. This work, done in King’s laboratory by Eleanor Zaimis, did yield such a compound, decamethonium iodide. Still more important medically was the unexpected finding that other members of the series of methonium compounds acted as powerful sympathetic blocking agents, producing a drop in blood pressure. Follow-up of this derivative result of King’s curare studies resulted in the first effective drugs for treatment or hypertension.

More theoretical was King’s proposal, with institute colleague Otto Rosenheim, of new structural formulas for cholesterol and the bile acids. Existing formulas in the early 1930’s suffered from several problems, including failure to conform to J. D. Bernal’s X-ray crystallographic studies. Beginning in 1932, King and Rosenheim published a series of papers arguing that the ring structure of the sterols consisted of four fused six-membered rings. Quickly accepted in slightly modified form—one of the rings was shown to have five members—this proposal was of major significance in that it opened up many opportunities for investigation in the biologically important field of steroids.

The value of King’s work was well recognized by the scientific community. Elected fellow of the Royal Society in 1933, he received the Hanbury Medal of the Pharmaceutical Society in 1941, and the Addingham Gold Medal of the William Hoffman Wood Trust (Medical) in 1952. In 1950, the year of his retirement, King was appointed C. B. E. in consideration of his work for the Medical Research Council.

BIBLIOGRAPHY

I. Original Works. King’s publications are listed at the end of C. R. Harington, “Harold King, 1887–1956,” in Biographical Memoris of Fellows of the Royal Society, 2 (1956), 157–171. Representative of his work in chemotherapy is “Trypanocidal Action and Chemical Constitution,” published with various collaborators in Journal of the Chemical Society, 125 (1924), 2595–2611; 127 (1925), 2632–2651, 2701–2714; 129 (1926), 817–831, 1355–1370; 91927), 1049–1060, 3068–3097; (1928), 2426–2447; (1930), 669–694; (1931) 3043–3056, 3236–3257; and (1932), 2505– 2510, 2866–2872. The main work on curare was published in “Curare Alkaloids,” in Journal of the Chemical Society (1935), 1381–1389; (1936), 1276–1279; (1937 (, 1472–1482; (1939), 1157–1165; (1940), 737–746; (1947), 936–937; (1948), 265–266, 1945–1949; and 91949) 955–958, 3263–3271. King’s principal joint publication with Otto Rosenheim was “The Ring-System of Sterols and Bile Acids,” in Journal of the Society of Chemical Industry, 51 91932), 464–466, 954–957; 52 (1933), 299–301; and 53 (1934), 91–92, 196– 200. King’s biographical notice on Otto Rosenheim includes remarks on their collaboration: “Sigmund Otto Rosenheim, 1871–1955,” in Biographical Memoirs of Fellows of the Royal Society, 2 (1956), 257–267.

II. Secondary Literature. The fullest availabe biographical source is C. R. Harington (see above). See also T. S. Work, “Dr, Harold King, C. B.E., F.R.S.,” in Nature, 177 91956) 604–605.

John E. Lesch