DNA BINDING-INDEPENDENT ANTIPROLIFERATIVE ACTION OF BENZAZOLO[3,2-ALPHA]QUINOLINIUM DNA INTERCALATORS

The proposed mechanism of action of the antineoplastic drug 3-nitroben zothiazolo[3,2-alpha]quinolinium chloride (NBQ-2) involves its interac tion with DNA by intercalation and inhibition of topoisomerase II acti vity by arresting the enzyme in a covalent cleavage complex. In an att empt to identify some structural determinants for activity and develop a molecular structure/cytotoxicity correlation, four new structural a nalogs of the antitumor NBQ-2 were prepared and their cytotoxic activi ty and DNA binding properties were investigated. The cytotoxic activit y was evaluated against six different human tumor cell lines: U937, K- 562, HL-60, HT-29, HeLa, and A431. The results showed that these new d rugs elicit pronounced cytotoxic effects against U937, K-562, HL-60 an d A431 while HeLa and HT-29 were less sensitive to the new drugs. This apparent selectivity was different to that of m-AMSA, a drug currentl y used for cancer treatment. Since the interaction of NBQ-2 to DNA by intercalation has been proposed as the initial step leading to its ant ineoplastic activity, DNA binding and changes in DNA contour length in duced by the new NBQ-2 structural analogs were also investigated using calf thymus and human DNA. The drug, openyl)-3-nitrobenzimidazolo[3,2 -alpha]quinolinium chloride (NBQ-59) was the most cytotoxic agent of t he analog series (IC50 = 16 mu M for HL-60 cells), however, it demonst rated the weakest binding to DNA (K-int = 0.9 x 10(5) M-1 for calf thy mus DNA). NBQ-59 was also found to be a poor intercalator into the DNA double helix. Therefore, our results suggest that DNA binding is not the primary mechanism of drug action for this family of compounds. In addition structural determinants important for cytotoxicity of the ben zazolo quinolinium chlorides were suggested by our results. In particu lar, the nitro group in the 3 position does not seem to be necessary f or bioactivity, while substitutions in the benzazolo moiety have strik ing effects on the biological activity of the drugs.