Potential antitumor agents. 50. In vivo solid-tumor activity of derivatives of N-[2-(dimethylamino)ethyl]acridine-4-carboxamide

Abstract

The synthesis, physicochemical properties, and antitumor activity of a series of N-[2-(dialkylamino)alkyl]-acridine-4-carboxamides are reported. The compounds bind to DNA by intercalation, but exist under physiological conditions as monocations due to the weakly basic acridine chromophore (pKa = 3.5-4.5). The acridine-4-carboxamides show very broad structure-activity relationships (SAR) for antileukemic activity, with substituents at nearly all acridine positions proving acceptable. The compounds also show remarkable activity against the Lewis lung solid tumor in vivo, with several analogues capable of effecting 100% cures of the advanced disease. The broad SAR and high solid-tumor activity of the 9-acridine-4-carboxamides imply they should be considered as a completely new class of antitumor agent.

Phase I and pharmacokinetic study of DACA (XR5000): a novel inhibitor of topoisomerase I and II

“…It is, however, highly active against Lewis lung carcinoma in mice (Atwell et al, 1987;Finlay and Baguley, 1989), the murine 16/C tumour and Colon 11 A and Colon 38 tumours (Baguley et al, 1995). In preclinical pharmacology studies the unbound fraction of DACA in mouse plasma was 15.8%.…”

Considerations for Treatment Development in Rhabdomyosarcoma: In Vitro Assessment of Novel DNA Binding Drugs

“…N-[2-(dimethyl)aminoethyl]-acridine-4-carboxamide (DACA), a dual topoisomerase I/II poison and the parent compound from this class of agents, was unsuccessfully taken into phase II clinical trial in patients with non-small cell lung carcinoma, advanced ovarian cancer, recurrent glioblastoma and advanced colorectal cancer (Twelves et al, 2002;Caponigro et al, 2002). 9-amino derivatives of DACA, however, have greater cytotoxic and dose potencies, and modifications in the 5-position, such as the methyl sulphone group in AS-DACA, promote solid tumour activity (Atwell et al, 1987). In contrast to DACA, 9-amino-DACA and AS-DACA appear to be more specific poisons for topoisomerase II (Bridewell et al, 2001) with AS-DACA, a less lipophillic derivative (Haldane et al,1999) also known to have a wide spectrum of activity in solid tumours (Atwell et al,1987).…”

“…In contrast, its dicationic derivative, 9-amino-DACA, which binds to DNA 6-fold more tightly than DACA and is only weakly active as a topoisomerase I poison (Finlay et al, 1996), is 10 times more potent in all RMS cell lines, making its activity comparable to that of doxorubicin and mitoxantrone (Figure 2). Although the extra charge on the chromophore of 9-amino-DACA enhances cytotoxic potency and antileukaemic activity in mouse tumour models (Atwell et al, 1987), it diminishes solid tumour activity as a consequence of poor tumour penetration due to its elevated DNA affinity. Electron withdrawing substituents in the acridine 5-position lower the chromophore pK, and AS-DACA, bearing a 5-methylsulphone, has a neutral chromophore at physiological pH, binds DNA with an affinity between that of DACA and 9-amino-DACA, and is intermediate between these two agents with respect to topoisomerase selectivity (Finlay et al, 1996).…”

“…Electron withdrawing substituents in the acridine 5-position lower the chromophore pK, and AS-DACA, bearing a 5-methylsulphone, has a neutral chromophore at physiological pH, binds DNA with an affinity between that of DACA and 9-amino-DACA, and is intermediate between these two agents with respect to topoisomerase selectivity (Finlay et al, 1996). These characteristics make it generally more cytotoxic than DACA, and endow it with widespread solid tumour activity (Atwell et al, 1987). In the RMS panel it returns a differential response, strongly reminiscent of topotecan, with JR1 and RH30 cells being sensitive, but the remaining three cell lines have IC 50 s above 1mM (Figure 2).…”

Molecular modeling study of intercalation complexes of tricyclic carboxamides with d(CCGGCGCCGG)2 and d(CGCGAATTCGCG)2

“…Some are potent topoisomerase poisons with widespread antitumor efficacy, for example, N-[2-(dimethylamino)ethyl]acridine-4-carboxamide (DACA), which is a DNA-intercalating agent capable of inhibiting both topoisomerases I and II [7][8][9][10] and is in phase II clinical trial. For the 9-aminoacridine class of these compounds, the parent of which is 9-amino-DACA, there are tight correlations between ligand structure, cytotoxicity and DNA-binding kinetics [11][12][13][14][15].…”