SCIENCE/TECHNOLOGY
New Anticancer Antibiotic Acts Through Diradical Rearrangement Duyne and supported by the Na tional Institutes of Health, Clardy thought to bind via DNA determined the structure by x-ray crystallography. intercalation; offers chemists Performing x-ray studies turned out to be far from trivial because of another way to explore difficulties in finding a phase model site-specific drug delivery to fit the data. In addition to diffrac tion patterns, the Ithaca chemists Chemists at Bristol-Myers Squibb had to know the phases in which xCo. and Cornell University have rays arrived at the detector—crests, found and characterized an antican troughs, or any variations in be cer antibiotic, dynemicin A, that tween. may be the fourth of a series of anti Further complications arose from biotics that act by metabolic rear the crystallization of the compound rangement to a diradical [/. Am. in pairs of two conformations. So Chem. Soc, 112, 3715 (1990)]. while the triacetate was C36H25If true, diradical precursors may N 0 1 2 , the Cornell workers had to represent an antibiotic strategy that solve the structure of an object that has evolved widely in nature. And, was C72H50N2O24. there may be many more anticancer On solving the phase problem, antibiotics awaiting discovery. Also, Clardy and Van Duyne found a the unique internal trigger that structure with a 3-ene-l,5-diyne seems to set off the dynemicin rear bridge reminiscent of those found in rangement gives chemists a new un the anticancer agents calicheamicin derstanding of how these com and esperamicin (C&EN, June 8, pounds work. If, indeed, the anthra 1987, page 17). The Konishi and Clar quinone nucleus in dynemicin A dy groups have suggested a mecha binds by intercalation between nism by which dynemicin A works. strands of DNA as is now thought, The first step is a bioreduction of chemists will learn more about how the anthraquinone nucleus. This to deliver drugs to specific sites. leads to a reorganization of electron Dynemicin A was discovered at density to form a quinodimethide the Bristol-Myers Research Institute and open an epoxide ring. Reaction in Tokyo by associate director Masa- of the quinodimethide with water taka Konishi, chemists Hiroaki restores the anthraquinone nucleus Ohkuma and Takashi Tsuno, and in and replaces the epoxide with a vicstitute president Toshikazu Oki. diol overall. Opening the epoxide They isolated it from fermentation ring eases the strain in the whole broths of Micromonospora chersina. system and lets the multiple bonds This mold, cultured from soil sam of the 3-ene-l,5-diyne bridge move ples from Gujarat State on the north closer together. Cyclization of these west coast of India, is in the same bonds forms a p-phenylene diradi family as Streptomycetes. cal. The diradical abstracts protons The Tokyo team converted the from a deoxyribose unit in DNA, compound to the more soluble triac initiating strand breakage. etate and sent a sample of that to or This mechanism finds support in ganic chemistry professor Jon C. the isolation of other dynemicins in Clardy at Cornell. Working with M. chersina cultures. These other postdoctoral fellow Gregory D. Van compounds have bridging phenyl-
Antibiotic, dynemicin A,
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May 28, 1990 C&EN
Anthraquinone nucleus intercalates with DNA and undergoes bioreduction..
OH
Ο
OH
. . . quinodimethide formed, opens epoxide...
DH
OH
OH
. . . releasing the strain holding ene-diyne bridge.
Λ> OH
OH
CH 3
OH
.. .which cyclizes to a phenylene diradical
J ÎH 3 OH
Ο
OH
Ο
ΗΝμη\\\*Γ 1 Ύ
OH
Q Ν
ΟΗ
ene groups in place of the 3-ene-l,5diyne bridge and vic-diol or chlorohydrin functions in place of the ep oxide ring. Thus they may be end products of the cascade. Other research groups have ex plored such cascades of reactions leading to p-phenylene diradicals not only in calicheamicin and esperamicin but also in 25-year-old neocarzinostatin (now called zinostatin). Dynemicin A may bring the number of such compounds to four. In addition to providing a redox trigger for dynemicin A, the anthraquinone nucleus may be the part of the molecule that intercalates be tween guanine and cytosine base pairs in double-stranded DNA. In this way, the dynemicin A molecule could bind to DNA like a limpet mine to the hull of a ship before go ing off. Intercalation is the function of anthraquinone nuclei in antican cer drugs daunomycin (now called
daunorubicin) and adriamycin (now called doxorubicin). A naphthoate ester group in neocarzinostatin may serve the same purpose. Calicheamicin and esperamicin lack polynuclear aromatic groups for intercalation with DNA. But other workers have found that sugar mol ecules attached to them are very spe cific for binding to DNA. Now that the Konishi and Clardy groups have solved the structure of dynemicin A, other workers have swung into action to investigate the compound. Clardy sent the x-ray structure to organic chemistry pro fessor Paul A. Wender at Stanford University, who has applied com puter-guided molecular modeling to it. He finds such modeling matches the structure of one of the two conformers in the crystal. Wender will go on to model the interaction of such a molecule with DNA. Stephen Stinson
Evidence mounts for dietary solublefiberbenefits Oat bran has become popular in re cent years as a food ingredient, notes Peter J. Wood, of Agriculture Canada's Food Research Centre, Ot tawa, because of its reported effec tiveness in lowering elevated cho lesterol levels. Oat bran's effective ness has b e e n a t t r i b u t e d to its soluble fiber content, Wood says, but definitive proof is lacking. Nev ertheless, evidence is accumulating. Current findings on oat bran's ef fectiveness were discussed at a sym posium on β-glucans, held at the re cent national meeting of the Ameri can Chemical Society in Boston. Wood points out the soluble fiber from oat bran is, like starch or cellu lose, a polysaccharide composed en tirely of glucose units. Specifically, it's composed of 70% 4-O-linked and 30% 3-O-linked /3-D-glucopyranosyl units. Because of the way the glu cose units are joined, this material is neither digestible, like starch, nor a water insoluble material of great tensile s t r e n g t h , like cellulose. Structurally it's like cellulose, Wood says, but with "kinks" that make it water-soluble and viscous. Numerous studies in animals and humans have shown viscous poly saccharides exert specific physiolog-
ical effects, Wood says. In humans, for example, materials such as guar gum cause a reduction in glucose ab sorption rates, resulting in reduced levels of blood glucose and insulin after meals. The lowered absorption may be a result of resistance to dif fusion at the surface of the small in testine and decreased mixing in the small intestine. Both effects are re lated to intestinal viscosity, Wood notes. Recently, the presumed active in gredient in oats has been obtained as oat gum—a concentrate contain ing about 80% oat 0-glucan—in quantities sufficient to allow clinical studies, Wood says. Glucose was fed to healthy volunteers in the pres ence or absence of oat and guar gum. After-meal blood glucose and insulin rises were both significantly reduced, to a similar extent, by both gums. In "more realistic" tests, oat gum was added to wheat porridge and compared w i t h w h e a t p o r r i d g e alone and also with a specially pre pared, β-glucan-rich oat bran por ridge. The blood sugar rise follow ing intake of the oat bran porridge was "significantly lower" than with the wheat porridge. However, add
ing oat gum to wheat porridge re sulted in a glycémie response almost identical to that of oat bran. Such results, Wood concludes, demonstrate a physiological effect of oat bran that can be attributed to its soluble fiber β-glucan component. Wood's presentation stressed the relationship between soluble fiber and glucose response, rather than oat bran's effect on serum cholester ol levels. However, nutritionist Rosemary K. Newman of Montana State University addressed the latter topic. "Contrary to recent media atten tion to a research report which chal lenged the cholesterol-lowering ability of oat bran, there is a substan tial body of long-standing scientific evidence to support the oat bran theory," Newman says. However, she adds, soluble dietary fiber from sources o t h e r t h a n oats is also known to be effective in lowering serum cholesterol in hypercholesteremic animals and humans. Barley does, for example. Like oats, Newman notes, barley contains β-glucans. She cites two studies in volving humans that confirm bar ley's ability to lower serum choles terol levels as much as 15% in hypercholesterolemic individuals. Newman lists three reasons for barley's ability to lower serum cho lesterol. First, the β-glucans and oth er soluble fiber components create a viscous solution in the intestine that hinders absorption of fats and cho lesterol. Second, the fiber tends to bind bile acids, thus removing them from the cycle of cholesterol synthe sis, with a net effect of lowered available cholesterol. Normally that would stimulate cholesterol synthe sis. But barley also contains certain fat-soluble substances, tocotrienols, that suppress the synthesis of new cholesterol in the liver, so there is a net reduction of serum cholesterol. In that respect, barley has an advan tage over other grains, Newman as serts. Chemist Asaf A. Qureshi of Ad vanced Medical Research, Madison, Wis., cited other studies in a variety of avian and mammalian systems suggesting substances other than soluble fiber—specifically, toco trienols—may also contribute to lowering hypercholesteremia. AcMay 28, 1990 C&EN
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