The guanine, inosine, adenine and cytidine deoxyriboside cyanoboranes proved to be cytotoxic and possess in vivo antineoplastic activity against murine and human single cells and cultured cells derived from solid tumor lines. The agents preferentially inhibited DNA synthesis in Tmolt3 leukemic cells. The enzyme sites of drug inhibition of two active derivatives were DNA polymerase-alpha and de novo purine synthesis at the regulatory sites, PRPP amido transferase and IMP dehydrogenase. Moderate inhibition by the agents of TDP kinase and ribonucleoside reductase activities also occurred. Kinetic studies showed that IMP dehydrogenase activity was inhibited the earliest of all of the enzymes affected by the drugs. The d(ATP) pools were also reduced by drug treatment. DNA strand scission was evident after 24 hr incubation at 100 microM of drug. The 14C-cytidine-cyanoborane drug was rapidly taken up over 6 hr and most effective uptake was shown by rapidly dividing cells. The drug was bound to DNA, RNA and protein in Tmolt3 leukemic cells.

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PubMedDate not supplied

Antineoplastic activity of boron-containing thymidine nucleosides in Tmolt3 leukemic cells.

The sugar boronated thymidine nucleoside, 5' -0-[(triphenylphosphine-boryl) carbonyl]-3'-0-acetyl thymidine 1, and the boron-modified nucleoside phosphotriester, 5'-(diethylphosphite- cyanoborane)-3'-acetylthymidine 2, were successfully synthesized. Both compounds demonstrated differential activity when tested against eight cell lines, with significant cytotoxic activity against the growth of human Tmolt3 leukemia, colon adenocarcinoma, HeLa S3 uterine carcinoma, and osteosarcoma cells. In in vivo studies these agents were found to be active against the growth of Ehrlich ascites carcinoma at 8 mg/kg/day I.P. and to be marginally active against the growth of L1210 and Lewis lung cancers in mice. The mode of action of these thymidine derivatives in Tmolt3 cells was the inhibition of DNA and protein synthesis. Compound 2 was highly effective in inhibiting DNA polymerase alpha and m-RNA, r-RNA and t-RNA polymerase activities. Both compounds inhibited ribonucleoside reductase activity. The de novo purine pathway appeared to be the major site of inhibition of the agents, with IMP dehydrogenase, PRPP amido transferase, and dihydrofolate reductase activities being significantly inhibited. In the pyrimidine pathway, carbamyl phosphate synthetase and aspartate transcarbamylase activities were inhibited by 1. As expected, d[NTP] levels were significantly reduced by treatment with the agents. DNA strand scission was evident after incubating Tmolt3 cells for 24 hr with the agents.

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