From amsacrine to DACA (N-[2-(dimethylamino)ethyl]acridine-4-carboxamide): Selectivity for topoisomerases I and II among acridine derivatives

4β-[4′-(1-(Aryl)ureido)benzamide]podophyllotoxins as DNA topoisomerase I and IIα inhibitors and apoptosis inducing agents

“…27,28 Thus dual inhibitors of topoisomerase-I and topoisomerase-IIα may have advantages and there has been much interest in such compounds in clinical evaluation, including intoplicine and XR 500016. 29,30 In our ongoing research efforts to design and develop new potent anticancer agents, we have been involved for many years in the synthesis and in vitro biological evaluation of podophyllotoxin congeners. [31][32][33][34][35][36][37] In continuation of these efforts, we have undertaken the synthesis of some new analogues of podophyllotoxin by linking it to a urea moiety through an aryl amino spacer at C-4 position of the podophyllotoxin scaffold with a view to combine the pharmacological characteristics of both these chromophores.…”

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

“…Interestingly, this is the inverse selectivity of SN26356, which is inactive in RH30 and JR1, and raises the intriguing question of the potential clinical activity of their use in combination. The novel topoisomerase poisons evaluated are structurally based on the acridine-4-carboxamide chromophore, the parent compound of which, DACA (Figure 1), has been identified as a dual topoisomerase I/II poison (Finlay et al, 1996). Despite its wide solid tumour activity and its clinical evaluation (Twelves et al, 2002;Caponigro et al, 2002;Haldane et al, 1993), it shows poor potency in all RMS cell lines with IC 50 s about 2 to 4 mM.…”

“…SN26871 has an N-methylated monocationic -(CH2)3N(Me)(CH2)3-linker and an 8,9-benzphenazine chromophore ( Figure 1C). ¶ A third class of novel compounds, also structurally based around the acridine-4-carboxamide intercalating chromophore, have previously been identified as topoisomerase poisons (Finlay et al, 1996) and act as monointercalating agents that feature electronwithdrawing moieties in place of a single active side chain ( Figure 1D). 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).…”

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].…”