Antitumor Polycyclic Acridines. 7. Synthesis and Biological Properties of DNA Affinic Tetra- and Pentacyclic Acridines

Abstract

New synthetic routes to a series of tetra- and pentacyclic acridines related in structure to marine natural products are reported. The novel water-soluble agent dihydroindolizino[7,6,5-kl]acridinium chloride 14 has inhibitory activity in a panel of non-small-cell lung and breast tumor cell lines exceeding that of m-AMSA. The salt inhibited the release of minicircle products of kDNA confirming that disorganization of topoisomerase II partly underlies the activity of the compound. COMPARE analysis of the NCI mean graph profile of compound 14 at the GI(50) level corroborates this conclusion with Pearson correlation coefficients (>0.6) to clinical agents of the topoisomerase II class: however, this correlation was not seen at the LC(50) level. The inhibitory action of 14 on Saccharomyces cerevisiae transfected with human topoisomerase II isoforms showed a 3-fold selectivity against the IIalpha isoform over the IIbeta isoform. Unlike m-AMSA, 14 is not susceptible to P-glycoprotein-mediated drug efflux and retains activity in lung cells with derived resistance to the topoisomerase II inhibitor etoposide.

Apoptosis on the move

“…One of the lead compounds, dihydroindolizino[7,6,5-kl]-acridinium chloride (DS, Fig. 1) displayed growth inhibitory activity at sub-micromolar concentration range in panels of breast and non-small cell lung cancer cell lines [20]. The compound formed a binding ‘hot spot’ in DNA with the planar pyridoacridine moiety intercalating at G–C sequences and the pyrrolidinium fragment occupying minor or major grooves [21].…”

“…1), which is also an acridine derivative, DS was not susceptible to P -glycoprotein-mediated drug efflux and retained activity in lung and breast cancer cells made resistant to the topoisomerase II inhibitors (etoposide and doxorubicin) [20]. In addition, the compound was shown to be more potent than amsacrine and etoposide in breast cancer cells with varying molecular characteristics [20]. Assessment of mode of cell death induced by the compound revealed SKBr-3 breast cancer cells underwent apoptosis, as observed with the aid of scanning electron microscopy (Fig.…”

Mechanism Targeted Discovery of Antitumor Marine Natural Products

“…In COMPARE analysis (NCI), compounds with a Pearson correlation coefficient greater than 0.6 often function though a biochemically related mechanism [157]. The pyridoacridine alkaloids were subjected to COMPARE analysis and showed a correlation pattern consistent with topo II inhibitors [158].…”

Increasing antitumor activity in vivo by enhancing acridine dimer solubility with salt preparations

“…Many approaches by modifying acridine monomer (Antonini et al, 1995;Stanslas et al, 2000;Antonini et al, 2001;Charmantray et al, 2003) or dimer (Antonini et al, 2003;Wakelin et al, 2003;Wang et al, 2007) to increase cancer chemosensitivity have been demonstrated.…”