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Cytotoxic Action of Adenosine Nucleoside and Dialdehyde Analogues on Murine Neuroblastoma in Tissue Culture: Structure-Activity Relationships¹

Division of Clinical Pharmacology, Departments of Pediatrics, Pharmacology, and Biochemistry, University of Minnesota, Health Sciences Center, Minneapolis, Minnesota 55455

A series of purine nucleoside and dialdehyde analogues was studied to determine their potency as inhibitors of C-1300 murine neuroblastoma cell growth in tissue culture. Tumor cells were incubated with each analogue for 72 h, and the number of viable cells was determined at 24, 48, and 72 h. Dose-response curves were generated (concentration range, 10^-8 to 10^-3 M), and the drug concentration producing 50% inhibition of cell growth was calculated for each analogue. The 50% inhibitory concentrations, in ascending order of potency, were as follows: adenosine (inactive); S-adenosylhomocysteine (inactive); methylfuryladenine (5.6 x 10^-1 M); adenosine 5'-carboxylic acid (2.0 x 10^-1 M); 5'-chloro, 5'-deoxy-ara-adenosine (3.0 x 10^-2 M); sinefungin (1.7 x 10^-3 M); 5'-deoxyadenosine (2.2 x 10^-4 M); 5'-chloro, 5'-deoxyadenosine (2.1 x 10^-4 M); 3',5'-dichloro, 2',3',5'-trideoxyadenosine (1.3 x 10^-4 M); 3-deazaadenosine (5.6 x 10^-5 M); and adenosine dialdehyde (1.5 x 10^-6 M).

Oxidation of the pentose to a dialdehyde increased, whereas reduction of the dialdehyde or substitution of adenine with either hypoxanthine, guanine, uracil, or cytosine decreased the inhibitory potency. The analogues 4',5'-anhydroadenosine dialdehyde and 5'-deoxyadenosine dialdehyde, which cannot be phosphorylated at the 5' position, had 50% inhibitory concentrations of 9.1 x 10^-6 and 7.6 x 10^-6 M, respectively.

These data suggest that the inhibitory action and potency of nucleoside dialdehydes on neuroblastoma growth are independent of their capacity to undergo a kinase-mediated phosphorylation at the 5' position.

¹ This investigation was supported by Grants NS17194, National Institute of Neurological and Communicable Diseases and Stroke, and GM 33776, National Institute of General Medical Science.

² To whom requests for reprints should be addressed, at Division of Clinical Pharmacology, University of Minnesota, Health Sciences Center, Mayo Building, Box 87, 420 Delaware Street S.E., Minneapolis, MN 55455.

Received 10/24/86. Revised 3/30/87. Accepted 4/16/87.