CYTOTOXICITY OF BORON-CONTAINING DIPEPTIDE ANALOGS

This work is an extension of our previous work (Hall et al., 1993) on the synthesis and cytotoxic activity of boronated peptides. The aim of this work was to carry out structural modifications of the amine term inal in compounds 1 and 2, to increase water solubility, and its effec t on the cytotoxicity to tumor cell lines. Surprisingly, only compound s 4, 7 and 8 were more water soluble than the parent compounds. With t he exception of compound 4, the new derivatives were generally less ef fective than the parent compounds (1 and 2). There was no apparent cor relation between structure and activity. Cytotoxic effect was more pro nounced in single cell suspended cells. The growth of solid tumor cell lines was not significantly reduced. The most active derivative, thyl )-2-methylamino-2-oxoethyl]amino]carboxy]boron (4), inhibited DNA, RNA , and protein synthesis in Tmolt(3) cells. Enzymsttic activities, e.g. , DNA polymerase alpha, m-RNA polymerase, PRPP amidotransferase, carba myl phosphate synthetase, TMP-kinase, TDP-kinase, dihydrofolate reduct ase, and ribonucleoside reductase were reduced after 60 min incubation with 4. d(TTP) and d(CTP) pool levels were also reduced by 60 min inc ubation with 4.