SYNTHESIS AND ANTITUMOR-ACTIVITY OF BORONATED DIPEPTIDES CONTAINING AROMATIC-AMINO-ACIDS

N-[(Trimethylamine-boryl-carbonyl]-L-tryptophan methyl ester and N[(tr imethylamine-boryl)-carbonyl]-L-histidine methyl ester were obtained b y synthesis using triphenylphosphine/carbon tetrachloride or dicyclohe xyl-carbodiimide as coupling agents, respectively. Both agents reduced L-1210 lymphoid leukemia DNA, RNA, and protein syntheses with the lar gest reductions occurring in DNA synthesis. Reductions in DNA synthesi s appear to be mediated by inhibition of key enzyme activities (i.e., DNA polymerase a, IMP dehydrogenase, and PRPP amido transferase). Thes e agents had little effect on in vitro L-1210 DNA topoisomerase II act ivity at 100 mu M but were able to cause synergistic increases in prot ein-linked DNA break when combined with etoposide (VP16). It was shown that these agents significantly reduced protein kinase C mediated pho sphorylation of human topoisomerase II in vitro. Thus, inhibition of t opoisomerase II phosphorylation may be a mechanism by which these agen ts and VP-16 are synergistic in causing protein-linked DNA breaks.