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HxTfA 4 is a fluorescent analog of a potent cytotoxic and antimalarial agent, TfA 3 , which is currently being investigated for the development of an antimalarial vaccine, PlasProtect®. HxTfA contains a p-anisylbenzimidazole or Hx moiety, which is endowed with a blue emission upon excitation at 318 nm; thus enabling it to be used as a surrogate for probing the cellular fate of TfA using confocal microscopy, and addressing the question of nuclear localization. HxTfA exhibits similar selectivity to TfA for A-tract sequences of DNA, alkylating adenine-N3, albeit at 10-fold higher concentrations. It also possesses in vitro cytotoxicity against A549 human lung carcinoma cells and Plasmodium falciparum. Confocal microscopy studies showed for the first time that HxTfA, and by inference TfA, entered A549 cells and localized in the nucleus to exert its biological activity. At biologically relevant concentrations, HxTfA elicits DNA damage response as evidenced by a marked increase in the levels of γH2AX observed by confocal microscopy and immunoblotting studies, and ultimately induces apoptosis. [ABSTRACT FROM AUTHOR]

Abstract: A novel diamino/dicationic polyamide f-Im ∗ PyIm (5) that contains an orthogonally positioned aminopropyl chain on an imidazole (Im ∗ ) moiety was designed to target 5′-ACGCGT-3′. The DNA binding properties of the diamino polyamide 5, determined by CD, ΔTM, DNase I footprinting, SPR, and ITC studies, were compared with those of its monoamino/monocationic counterpart f-ImPyIm (1) and its diamino/dicationic isomer f-ImPy ∗ Im (2), which has the aminopropyl group attached to the central pyrrole unit (Py ∗ ). The results gave evidence for the minor groove binding and selectivity of polyamide 5 for the cognate sequence 5′-ACGCGT-3′, and with strong affinity (K eq =2.3 × 107 M−1). However, the binding affinities varied according to the order: f-ImPy ∗ Im (2)>f-ImPyIm (1)⩾f-Im ∗ PyIm (5) confirming that the second amino group can improve affinity, but its position within the polyamide can affect affinity. [Copyright &y& Elsevier]