Mechanistic and anti-proliferative studies of two novel, biologically active bis-benzimidazoles.
We have previously synthesised a number of novel head-to-head bis-benzimidazole derivatives that are structurally related to the fluorochrome, Hoechst 33258, and which possess strong affinity for A:T sites in the minor groove of duplex DNA. Initial studies revealed these compounds to exhibit potent antiproliferative activity against a range of ovarian cell lines and to inhibit transcription in an in vitro setting. In this study, we have examined their cellular behaviour in detail and have shown that two of these compounds (ABA13 and ABA833) potently inhibit the proliferation of a range of human tumour cell lines, and show some specificity towards breast carcinoma cell lines. In most of the cell lines investigated, ABA833 was the more potent of the two compounds. Flow cytometric analysis revealed that ABA13 and ABA833 (50-500 nM) induced an S phase block and increased the pre-G1 population in MCF-7 and MDA 468 human breast cancer cells. An increase in the pre-G1 population of RKO colon carcinoma cells was seen only at 500 nM with ABA833, reflecting the reduced sensitivity of this cell line to the bis-benzimidazoles in comparison to the breast cancer cell lines. Mechanistic studies revealed that neither ABA13 or ABA833 act as topoisomerase I (topo I) or topoisomerase II (topo II) poisons in plasmid or kinetoplast DNA (kDNA) relaxation assays, but both compounds do inhibit the catalytic activity of these enzymes. Drug uptake studies showed that reduced sensitivity of MCF-7adr and RKO cells compared with MCF-7 to both ABA13 and ABA833 correlated with a markedly reduced intracellular drug accumulation.
The Cancer Centre, The Queen's University of Belfast, U Floor, Belfast City Hospital, Lisburn Road, Belfast BT9 7AB, UK.
A
A
Seaton
C
C
Higgins
J
J
Mann
A
A
Baron
C
C
Bailly
S
S
Neidle
H
H
van den Berg
D000970:Antineoplastic Agents / Q000627:therapeutic use*; D001562:Benzimidazoles / Q000032:analysis* / Q000493:pharmacokinetics / Q000627:therapeutic use; D006690:Bisbenzimidazole / Q000737:chemistry; D002455:Cell Division / Q000187:drug effects; D045744:Cell Line, Tumor; D005434:Flow Cytometry; D006801:Humans; D009369:Neoplasms / Q000188:drug therapy*; D059004:Topoisomerase I Inhibitors; D059005:Topoisomerase II Inhibitors
C480260:ABA13; C480259:ABA833; D000970:Antineoplastic Agents; D001562:Benzimidazoles; D059004:Topoisomerase I Inhibitors; D059005:Topoisomerase II Inhibitors; C009712:bis-benzimidazole; D006690:Bisbenzimidazole