The bis(adenosin-N6-yl) alkanes, a family of potential dinucleoside polyphosphate analogue precursors. Mechanism of growth inhibition and suppression of adenosine toxicity in lymphoid cells.

Abstract

The potential diadenosine polyphosphate analogue precursor, bis(adenosin-N6-yl)dodecane (A[CH2]12A) (Chen, H. & McLennan, A. G. (1993) Eur. J. Biochem. 213, 935-944.) is equally toxic to both wild-type and adenosine-kinase-deficient BHK cells at concentrations up to 100 microM; at higher concentrations, wild-type cells are more sensitive, as are cells over-expressing adenosine kinase. Thus both the nucleoside and its nucleotide products are toxic. In contrast to adenosine toxicity, the toxicity of A[CH2]12A to S-49 T-lymphoma cells could not be reversed by uridine or by L-homocysteine thiolactone. A[CH2]12A and all its shorter chain bis(adenosin-N6-yl)alkane homologues could relieve the toxicity of low adenosine concentrations (< 20 microM) to S-49 cells, mainly through inhibition of adenosine kinase, while relief of the toxicity of high adenosine concentrations (> 20 microM) required the longer chain homologues. A[CH2]12A at 10 microM completely eliminated adenosine toxicity. Deoxyadenosine toxicity could also be relieved, but only that due to low concentrations (< 4 microM). A[CH2]12A had only a slight stimulatory effect on S-adenosylhomocysteine-hydrolase activity.