RESEARCH
R. L. Mann listens to an exposition of a key point in the structural determination of hygromycin, a new antibiotic. Says D . O. Woolf, a hexose is attached by a glycosidic link at the 4-hydroxyl position of 3,4-dihydroxy-a-methylcinnamic acid
Are M a n - M a d e Antibiotics Coming? First finding of a mono-aminocyclitol in two antibiotics renews hope for tailor-made disease killers Simultaneous discovery of an unusual carbohydrate amine, neoinosarnine - 2 , in two apparently different broadspectrum antibiotics holds promise for design of "tailor-made" antibiotics t o treat specific diseases. Heretofore, presence of this inosamine was not even suspected among this class of biologically produced drugs. J. B. Patrick of American Cyanamid and R. L. Mann of Eli Lilly told t h e Division of Carbohydrate Chemistry during a symposium on the chemistry and biochemistry of cyclitols that they made their discoveries independently with experimental product 1703-18 B and hygromycin, respectively. Both scientists isolated a cinnamic acid d e rivative from their compounds. Both turned up a sugar also but Mann went a step further by characterizing his as 5-keto-6-deoxy-D-arabohexose—a new sugar. k. "TnJlnr-Mode" Antibiotics. Discovery of the inosamine and determination of its exact chemical structure from 4756
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t w o independent sources is a step forward in unraveling the little understood connection between antibiotics, vitamins, and other essential biological functions, says the Cyanamid researcher. Since in the past dimosamines have been uncovered in the antibiotics streptomycin and neomycin, this recent work is confirmation of a strange phenomenon, for aminocyclitols are rare among natural products. The aminocyclitols, like amino sugars, have been considered the basis for a transport mechanism that gets antibiotics into the body's disturbed cells. But mosamines have no biological activity, so it is assumed the acid and the sugar part of these compounds contain the disease killing fragments, namely the acid and the sugar. However, the ones isolated from hygromycin and 1703-18 B are not biologically active, although oxidation of the acid brings on some activity. Hence, the activity secret of these and other available antibiotics could well He in the way they are linked together chemically. In terms of chemical constitution, these discoveries hold a vast potential
area of interest for organic chemists. If the structure and biological activity of these and other antibiotics were known, say the Lilly and Cyanamid chemists, it would then be possible to isolate the molecular fragment or fragments responsible for the drug's disease killing power. In turn, this could lead t o simplified synthesis and, naturally, simple antibiotics based on the active portion of present day biologically produced ones. • Cyanamid's Role. Cyanamid research division scientists R. P* Williams. C. W. Waller, B. L. Hutchings, and Patrick isolated the inosamine and showed it optically inactive and not racemic. This means the compound is one of eight possible meso-inosamine configurations. Derivative studies snow all hydroxyl groups as well as the nitrogen in cis configuration. This identified the compound as neo-inosamine-2. Just what part this and other carbohydrate components play in the biological activity of the parent antibiotic is still questionable. There are certain similarities between 1703 and puromycin discovered several years ago. More work will b e done in the future t o establish positively this relationship, concludes Patrick. • Lilly's Role. While Cyanamid workers were unfolding mysteries of their experimental antibiotic, Lilly researchers R. L. Mann and D . O. Woolf were simultaneously doing the same thing with their new antibiotic called hygromycin. M a u i says the structure of this biologically produced compound was determined by piecing together molecular fragments obtained from mercaptanolysis and also acid and alkali hydrolysis. The acid hydrolysis produced a compound later identified as neo-inosamine-2 (same conventional manner used by the Cyanamid p e o p l e ) . From alkaline hydrolysis came the acid 3,4dihydroxy-a-methyl cinnamic acid. Linking of the cyclitol to the acid was a key question. Infrared spectrum and isolation of an amide after mercaptanolysis of hygromycin proved a carboxamide linkage. • Drugs Not Available. Although providing some interesting chemistry, neither antibiotic is of any clinical importance today. Lilly's has certain toxic properties which would make it harmful if used for human therapy. Of some significance is the fact hygromycin causes a marked increase in growth rate of chicks when placed on a diet containing hygromycin. However, experimental tests are not far enough along to allow drawing of any firm conclusions. Cyanamid's compound 1703-18 B is still in the experimental stage. It is not of any medical importance at the present time. •
