Jeno Tomasz

Chemical and Enzymatic Incorporation of Boron into DNA

Neutron capture events occurring in the cell nucleus associated with genetic material should be highly lethal.1,2 We and others have prepared a variety of boronated nucleic acid derivatives or DNA binding boronated ligands toward achieving this goal.3 Approaches we have used include synthesis of nucleosides with N-boronated bases4 and (oligo)nucleotides with boronation on the phosphodiester backbone.5 Previously, we reported that the radiolabeled [2-14C]2’-deoxycytidine-N3-cyanoborane was taken up much faster in leukemic Tmolt3 cells than in rapidly dividing non-tumorous human Bg-9 fibroblasts.6 Evidence was also reported for a greater percentage of binding or incorporation into the DNA and RNA of cancer cells than in non-cancer cells.

Boronated pyrimidines and purines as cytotoxic, hypolipidemic and anti-inflammatory agents.

The simple boronated bases, e.g. cytosine, adenine and guanine, containing no sugar residues retained good pharmacological activity as hypolipidemic, anti-neoplastic and anti-inflammatory agents in mice at 8 mg/kg. Their activities were generally identical to their respective nucleoside derivatives. Interestingly the boronated acyclovir derivative was a very potent hypolipidemic agent achieving better activity than clofibrate and lovastatin. The boronated adenine derivatives appeared to have the best anti-inflammatory activity in reducing local edema and analgesic effects. The agents were active against the growth of murine and human leukemias and human HeLa-S3 suspended uterine carcinoma. Only the boronated adenine derivatives were effective in blocking the growth of human SW480 adenocarcinoma and the KB nasopharynx.

Boronated Peptides and Nucleic Acid Components for Nct

We are interested in the synthesis, pharmacological, and neutron capture properties of boron-containing intermediate antimetabolites. These include analogues of amino acids,1 peptides,2 choline3 derivatives, phosphonoacetates4 or boranophosphates,5 and more recently, the boron analogs of nucleosides6 and nucleotides.7

The hypolipidemic activity of boronated nucleosides in male mice and rats.

The boronated nucleosides with varying bases and sugar moieties were shown to be potent hypolipidemic agents in rodents. The 3′– aminocynaoborane dideoxythymidine derivative caused reductions in serum cholesterol and triglyceride levels, tissue lipids, VLDL and LDL cholesterol levels while elevating HDL cholesterol levels in rodents. The agents suppressed rat hepatic acetyl CoA synthetase, HMG-CoA reductase, acyl-CoA cholesterol acyl transferase, phosphatidylate phosphohydrolase and lipoprotein lipase activities while elevating cholesterol-7α-hydroxylase activity from 25 to 100 μM.