Abstract
Nucleoside analogues of 5'-deoxy-5'-adenosylcobalamin have been synthesized by reduction of cyanocobalamin with zinc in ammonium chloride, followed by reaction with the 5'-chloro derivatives of inosine, thioinosine (6-mercaptopurine riboside), adenine arabinoside, cytosine arabinoside, 2-fluoroadenosine, homoadenosine, 1,N6-ethenoadenosine, tubercidin, and formycin. These analogues, several alkylcobalamins (CH3-, CCl2F-, CClF2, aminoethyl-, and carboxypentyl-), and adenosyl- and methylcobinamide were tested as inhibitors of the adenosylcobalamin-dependent ribonucleotide reductase (EC 1.17.4.2) from Lactobacillus leichmannii. The fluoroadenosine derivative had full coenzymatic activity (Km = 6.7 x 10-7 M), but all the other cobalamin analogues were inhibitory; most effective were the formycin (Ki, = 1.0 x 10-6 M) and adenine arabinoside (Ki = 3.0 x 10-6 M) analogues. The cobinamides were very weak inhibitors. When tested as inhibitors of the transcobalamin II-mediated transport of vitamin B12 into L1210 cells, all the cobalamins were effective competitors (50% inhibition at analogue to vitamin B12 ratios of less than 10). The cobinamides, however, were poor inhibitors of vitamin B12 transport.
ACKNOWLEDGMENTS The authors are indebted to Lawrence Troxell and Bettie Bowen for expert technical assistance. Dr. R. Reisfeld kindly provided the original L1210 culture.
- Copyright ©, 1975, by Academic Press, Inc.
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