DNA binding, anti-tumour activity and reactivity toward cell thiols of acridin-9-ylalkenoic derivatives

Abstract

In this paper, we describe the synthesis, biochemical properties and biological activity of a series of new 9-substituted acridine derivatives with a reactive alkene moiety: 9-[(E)-2-phenylethenyl] acridine (1) and methyl (2E)-3-(acridin-9-yl)-prop-2-enoate (2). The interaction of derivatives 1 and 2 with calf thymus DNA was investigated using UV-Vis, fluorescence and circular dichroism spectroscopy. The binding constants K were estimated as being in the range of 1.9 to 7.1 × 10 5 M −1 , and the percentage of hypochromism was found to be 40-57% (from spectral titration). UV-Vis, fluorescence, and CD measurements indicate that the compounds were effective DNA-intercalating agents. Electrophoretic separation proved that ligands 1 and 2 relaxed topoisomerase I at a concentration of 5 μM. Ester 2 was shown to have a stronger cytostatic effect on leukemia cell line L1210 than alkene 1. The incubation of ligands 1 and 2 with the ovarian carcinoma cell line A2780 confirmed their extensive cytotoxic effects, an effect which was particularly pronounced in the case of ligand 2. Cytotoxicity tests against A2780 cells demonstrate that a conjugate of compound 2 with L-cysteine (3) is less cytotoxic than compound 2, especially at concentrations greater than 10 μM.

Pyronaridine exerts potent cytotoxicity on human breast and hematological cancer cells through induction of apoptosis

“…Our results show that PND was able to increase the intensity of both, the negative and the positive bands, in a concentration dependent manner but with no significant red-shifts in any of them. These results are comparable to previously reported similar compounds, and suggest that PND is able to stabilize the right-handed B form of DNA with no significant conformational changes [ 24 , 26 ]. The fact that the same spectral changes were observed upon 30 minutes and 20 hour incubations suggests that the kind of interaction taking place occurs in a few minutes, confirming the intercalative mode of binding.…”

“…In addition, the Scatchard equation [ 15 , 16 ] was used to determine the binding affinity [8.5 ± 0.7 x 10 5 M -1 ] of PND to CT DNA. All binding data of PND with CT DNA, shown in Fig 6B , are comparable to that of well-known intercalating agents with similar structure [ 23 , 24 ], and indicate that PND is also able to intercalate between the bases of DNA, as suggested by the mobility-shift assay.…”

Unexpected regiospecific formation and DNA binding of new 3-(acridin-9-yl)methyl-2-iminothiazolidin-4-ones

“…The hypochromism observed is caused by DNA binding of the investigated drugs involving a partial unwinding of the DNA double helix and consequent conformational changes. 27 An absence of the isosbestic point in the titration UV-Vis spectra of 5a-d is similar to our previous study of acridin-9-ylalkenoic derivatives interaction with thiols 28 and indicates that non-classical interaction is active. The intrinsic binding constants K b , which we found in the range 0.79×10 5 -2.85×10 5 M −1 (Table 1), correspond well with the data on CT DNA interaction with analogous acridin-9-yl thiosemicarbazones 29 (K b = 1.74×10 4 -1.0×10 6 M −1 ) and 9-benzylamino-2-methoxyacridine (1.42×10 5 M −1 ).…”

“…34 Here, intensity of the positive band increased and showed a small red shift upon increasing the concentration of 5a−d (5 μM, 10 μM, 15 μM) in CT DNA solution similarly to our recent work on interaction of acridin-9-ylalkenoic derivatives. 28 The observation corresponds to a stabilization of DNA by intercalation. 35 Intensity of the negative band decreased (became more positive) with a slight red shift of about 2.0 nm (5a) upon addition of 5a−d ( Figure 5).…”

p-Pyridinyl oxime carbamates: synthesis, DNA binding, DNA photocleaving activity and theoretical photodegradation studies

“…Small organic molecules able to bind DNA provide promises for anticancer activity due to alteration of the structure and function of the genetic material. Amongst a plethora of such binders [1][2][3][4][5][6][7][8], various oxime derivatives were found to show affinity towards DNA [9][10][11][12], whereas others were found to cleave DNA as metal-free artificial nucleases [13,14].…”