Synthesis and antitumor activity of boronated dipeptides containing aromatic amino acids.
N-[(Trimethylamine-boryl-carbonyl]-L-tryptophan methyl ester and N[(trimethylamine-boryl)-carbonyl]-L-histidine methyl ester were obtained by synthesis using triphenyl-phosphine/carbon tetrachloride or dicyclohexyl-carbodiimide as coupling agents, respectively. Both agents reduced L1210 lymphoid leukemia DNA, RNA, and protein syntheses with the largest reductions occurring in DNA synthesis. Reductions in DNA synthesis appear to be mediated by inhibition of key enzyme activities (i.e., DNA polymerase a, IMP dehydrogenase, and PRPP amido transferase). These agents had little effect on in vitro L1210 DNA topoisomerase II activity at 100 microM but were able to cause synergistic increases in protein-linked DNA breaks when combined with etoposide (VP16). It was shown that these agents significantly reduced protein kinase C mediated phosphorylation of human topoisomerase II in vitro. Thus, inhibition of topoisomerase II phosphorylation may be a mechanism by which these agents and VP-16 are synergistic in causing protein-linked DNA breaks.
Miller
M C
MC
Division of Medicinal Chemistry and Natural Products, School of Pharmacy, University of North Carolina, Chapel Hill 27599-7360, USA.
Sood
A
A
Spielvogel
B F
BF
Hall
I H
IH
D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis*; D001896:Boron Compounds / Q000494:pharmacology*; D004273:DNA, Neoplasm / Q000378:metabolism; D004151:Dipeptides / Q000138:chemical synthesis*; D006639:Histidine / Q000737:chemistry; D006801:Humans; D007939:Leukemia L1210; D051379:Mice; D009363:Neoplasm Proteins / Q000378:metabolism; D011493:Protein Kinase C / Q000378:metabolism; D012334:RNA, Neoplasm / Q000378:metabolism; D014364:Tryptophan / Q000737:chemistry; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D001896:Boron Compounds; D004273:DNA, Neoplasm; D004151:Dipeptides; D009363:Neoplasm Proteins; D012334:RNA, Neoplasm; D006639:Histidine; D014364:Tryptophan; D011493:Protein Kinase C