Novel bisnaphthalimidopropyl (BNIPs) derivatives as anticancer compounds targeting DNA in human breast cancer cells

Abstract

Bisnaphthalimidopropyl (BNIP) derivatives are a family of compounds that exert anti-cancer activities in vitro and, according to previous studies, variations in the linker sequence have increased their DNA binding and cytotoxic activities. By modifying the linker sequence of bisnaphthalimidopropyl diaminodicyclohexylmethane (BNIPDaCHM), a previously synthesised BNIP derivative with anti-cancer properties, three novel BNIP derivatives were designed. Bisnaphthalimidopropyl-piperidylpropane (BNIPPiProp), a structural isomer of BNIPDaCHM, bisnaphthalimidopropyl ethylenedipiperidine dihydrobromide (BNIPPiEth), an isoform of BNIPDaCHM with a shorter linker chain, and (trans(trans))-bisnaphthalimidopropyl diaminodicyclohexylmethane (trans,trans-BNIPDaCHM), a stereoisomer of BNIPDaCHM, were successfully synthesised (72.3-29.5% yield) and characterised by nuclear magnetic resonance spectroscopy (NMR) and mass spectrometry (MS). Competitive displacement of ethidium bromide (EtBr) and UV binding studies were used to study the interactions of BNIP derivatives with Calf Thymus DNA. The cytotoxicity of these derivatives was assessed against human breast cancer MDA-MB-231 and SKBR-3 cells by MTT assay. Propidium iodide (PI) flow cytometry was conducted in order to evaluate the cellular DNA content in both breast cancer cell lines before and after treatment with BNIPs. The results showed that all novel BNIPs exhibit strong DNA binding properties in vitro, and strong cytotoxicity, with IC values in the range of 0.2-3.3 μM after 24 hours drug treatment. Two of the novel BNIP derivatives, BNIPPiEth and trans,trans-BNIPDaCHM, exhibited greater cytotoxicity against the two breast cancer cell lines studied, compared to BNIPDaCHM. By synthesising enantiopures and reducing the length of the linker sequence, the cytotoxicity of the BNIP derivatives was significantly improved compared to BNIPDaCHM, while maintaining DNA binding and bis-intercalating properties. In addition, cell cycle studies indicated that trans,trans-BNIPDaCHM, the most cytotoxic BNIP derivative, induced sub-G1 cell cycle arrest, indicative of apoptotic cell death. Based on these findings, further investigation is under way to assess the potential efficacy of trans,trans-BNIPDaCHM and BNIPPiEth in treating human breast cancer.

A Benzylideneacetophenone Derivative Induces Apoptosis of Radiation-Resistant Human Breast Cancer Cells via Oxidative Stress

“…The MTT solution was removed, and formazan crystals were solubilized in DMSO. The plates were shaken for 20 min at room temperature, and absorbance was measured at 560 nm (Maria et al ., 2016). …”

Novel lead compounds in pre-clinical development against African sleeping sickness

“…Bisnaphthalimidopropyl compounds have been evaluated as agents against cancer, bacteria, and Leishmania infections. [80][81][82][83] The application of 32 was extended to the kinetoplast-holding T. b. brucei, showing an IC 50 value of 2.35 nM (Fig. 15).…”

Novel Synthetic Approaches for Bisnaphthalimidopropyl (BNIP) Derivatives as Potential Anti-Parasitic Agents for the Treatment of Leishmaniasis

“…Beside targeting the sirtuins, BNIP derivatives strongly interact with DNA-a property of naphtalimides [21]-which makes them a good drug candidate as an anticancer agent [16,[22][23][24][25][26][27]. Naphthalimide planar aromatic rings of BNIP intercalate between DNA base pairs and distort the DNA backbone conformation by interfering with DNA-protein interactions [28,29].…”

“…Particular analogues may also inhibit topoisomerase II activity directly, exert post DNA damage effects on ataxia telangiectasia-mutated activated DNA damage signaling pathways, or induce lysosomal permeability [25,[30][31][32]. Cell cycle arrest and apoptosis occur as a result of BNIP's anticancer effect, as verified in different in vitro cell models [22,27,[32][33][34][35].…”