alpha-Bromoacryloyl derivative of distamycin A (PNU 151807): a new non-covalent minor groove DNA binder with antineoplastic activity

PNU 151807 is a new synthetic alpha-bromoacryloyl derivative of distamycin A. In the present study we investigated the DNA interaction and the mechani sm of action of this compound in parallel with the distamycin alkylating de rivative, tallimustine. PNU 151807 possesses a good cytotoxic activity in i n vitro growing cancer cells, even superior to that found for tallimustine. By footprinting experiments we found that PNU 151807 and tallimustine inte ract non-covalently with the same AT-rich DNA regions. However, differently from tallimustine, PNU 151807 failed to produce any DNA alkylation as asse ssed by Tag stop assay and N3 or N7-adenine alkylation assay in different D NA sequences. PNU 151807, like tallimustine, is able to induce an activatio n of p53, and consequently of p21 and BAX in a human ovarian cancer cell li ne (A2780) expressing wild-type p53. However, disruption of p53 function by HPV16-E6 does not significantly modify the cytotoxic activity of the compo und. Flow cytometric analysis of cells treated with equitoxic concentration s of PNU 151807 and tallimustine showed a similar induction of accumulation of cells in the G2 phase of the cell cycle but with a different time cours e. When tested against recombinant proteins, only the compound PNU 151807 ( and not tallimustine or distamycin A) is able to abolish the in vitro kinas e activity of CDK2-cyclin A, CDK2-cyclin E and cdc2-cyclin B complexes, The results obtained showed that PNU 151807 seems to have a mechanism of actio n completely different from that of its parent compound tallimustine, possi bly involving the inhibition of cyclin-dependent kinases activity, and clea rly indicate PNU 151807 as a new non-covalent minor groove binder with cyto toxic activity against cancer cells.