RESEARCH

Amino Acids Fight Tooth Decay

Tooth-destroying mouth acids are reduced by a group o f amino acid and peptide derivatives

Biological Chemistry

1 A # 1 A C S New chemicals 1 {^/NATIONAL J"oin t h e b a t t l e • VJL» MEETING against tooth de­

cay. A group of amino acid and peptide derivatives seem to inhibit the

formation of tooth destroying acids found i n the mouth. Phthaloyl phenyl-alanyl compounds seem to do an espe­cially g o o d jobr Saul B. Needleman, Leonard S. Fosdick, and R. Quentin Blackvvell of the Northwestern Univer­sity D e n t a l School told the Division of Biological Chemistry.

According to "generally accepted theory/* says Needleman, dental caries are of ten due to lactic and pyruvic acids formed by enzymes acting on resi­dues of fermentable sugar found in the mouth. These glycolytic enzymes, says Needleman, probably reside in micro­organisms found in the plaque layer covering the tooth surface. Chemicals which eould inhibit any step in this glycolysis should be able to reduce the amount of acid formed and so reduce tooth d e c a y .

Lots of chemicals have been tested as glycolytic inhibitors, including vita­min K, antibiotics, urea, and some com­mon arr*fno acids. Only a few of these bad a n y significant effect on reducing bacterial count or preventing acid for­mation in the rnouth, says Needleman.

• Promising Results. Much more promising are t h e new amino acid and peptide derivatives, says Needleman. A total of 36 were prepared. Among them w e r e phthaloyl amino acids, car-bobenzroxy amino acids, lysine with its «- and e-amino groups blocked with tosyl a n d carbobenzoxyl radicals, and several blocked amino dipeptide esters.

Tests show that phthaloyl phenyl-alanyl compounds inhibit glycolytic en­zymes. Of all the compounds tested, only t h o s e having a free C-terminal car-boxyl g roup vvere active. C-terminal lysine ajnd leucine residues seem to add to the action.

Exactly how or on what these chem­icals a c t isn't known yet. It's difficult

Add another weapon against tooth de­cay. Saul B. Needleman, North­western University Dental School, says some amino acid derivatives inhibit formation of cavity-causing acids

to separate inhibition of the bacteria from the blocking of enzyme action. But the important thing, says Needle­man, is that harmful mouth acids are reduced.

One word of caution: The bacteria in the mouth shouldn't b e totally in­hibited or killed. The aim here, says Needleman, is to repress glycolytic ac­tion only. Going much beyond this could upset the bacterial flora normally present in the mouth.

New Drugs Join Cancer Fight

Fluorinated pyrimidines look good against animal can­cers, may lead to more po­tent cancer drugs

Biological Chemistry

mACS Cancer fighters NATIONAL a r e e d S i n g c l o s e r

MEETING to some answers. A group of new chemicals, fluorin­ated pyrimidines, shows promising

results with tumors in rats and mice. Just as important, work with newly synthesized 5-fluorouridine and 5-fluoro-2'-deoxyuridine has uncovered clues to where these chemicals act, Charles Heidelberger of McArdle

Memorial Laboratory at University of Wisconsin told the Division of Biologi­cal Chemistry.

Fluorinated pyrimidines are now be­ing used in clinical trials on cancers in people, bu t it's too early ye t to evaluate results, says Heidelberger.

Instead of an empirical approach to finding anticancer drugs, a "rational" approach was used, says Heidelberger. Researchers have noticed differences in nucleic acid biosynthesis between tumors and normal tissue. Tests with uracil tagged with carbon-14, for ex­ample, show that some tumors use this pyrimidine more rapidly to make nu­cleic acid than do most normal tissues.

The high biological activity shown by some fluorine-substituted com­pounds made them good bets for a tryout as anticancer chemicals. Sort of put t ing two and two together, Heidelberger, collaborating with Rob­ert Duschinsky from Hoffrnann-La-Roche, synthesized some fluorinated pyrimidines.

• W h e r e They Work. The first of these fluorinated chemicals to be syn­thesized and tested was 5-fluorouracil. Working with C 1 4 tagged material, re­searchers found this chemical selec­tively localized in tumors of mice bear­ing Sarcoma-180. The 5-fluorouracil is incorporated in nucleotide linkage into ribonucleic acid of the cancer cells. It also enters RNA of normal cells but to a much smaller degree. This "fraudulent" ribonucleic acid, says Heidelberger, may damage the tumor.

Digging deeper these researchers found that 5-fluorouracil blocks conver­sion of formate into methyl i n deoxy-nucleic acid thymine. Apparently, says Heidelberger, the primary site of action of the fluorinated pyrimidines is at one of the key reactions in deoxy-nucleic acid synthesis, die methylation of deoxyuridylic acid t o thymidylic acid.

Inhibition of this reaction, says Heidelberger, is higher with the nu­cleoside, 5-fluoro-2'-deoxyuridine, than the free base 5-fluorouracil. Follow­ing this through, the true blocking agent is probably the nucleotide, 5-fluoro-2'-deoxyuridylic acid, says Heid­elberger. This compound h a s been extracted from cancer cells incubated in vitro with 5-fluorouracil.

These studies, says Heidelberger, could provide basic knowledge of tumor metabolism and could lead to more potent anticancer drugs.

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