title: 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 IC50values 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.
authors.affiliation: School of Pharmacy and Life Sciences, Robert Gordon University, Garthdee Road, Aberdeen, AB10 7GJ, Scotland, UK. m.goua@rgu.ac.uk.
authors.forename: Maria
authors.initials: M
authors.lastname: Kopsida
authors.affiliation: School of Pharmacy and Life Sciences, Robert Gordon University, Garthdee Road, Aberdeen, AB10 7GJ, Scotland, UK. m.goua@rgu.ac.uk and Centre for Obesity Research and Education (CORE), Faculty of Health and Social Care, Robert Gordon University, Garthdee Road, Aberdeen, AB10 7GJ, Scotland, UK.
authors.forename: Gemma A
authors.initials: GA
authors.lastname: Barron
authors.affiliation: Centre for Obesity Research and Education (CORE), Faculty of Health and Social Care, Robert Gordon University, Garthdee Road, Aberdeen, AB10 7GJ, Scotland, UK.
authors.forename: Giovanna
authors.initials: G
authors.lastname: Bermano
authors.affiliation: School of Pharmacy and Life Sciences, Robert Gordon University, Garthdee Road, Aberdeen, AB10 7GJ, Scotland, UK. m.goua@rgu.ac.uk.
authors.forename: Paul
authors.initials: P
authors.lastname: Kong Thoo Lin
authors.affiliation: School of Pharmacy and Life Sciences, Robert Gordon University, Garthdee Road, Aberdeen, AB10 7GJ, Scotland, UK. m.goua@rgu.ac.uk.
authors.forename: Marie
authors.identifier: http://orcid.org/0000-0003-1609-4366
authors.initials: M
authors.lastname: Goua
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use; D001943:Breast Neoplasms / Q000188:drug therapy / Q000473:pathology*; D002417:Cattle; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D003514:Cyclohexylamines / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use; D004247:DNA / Q000378:metabolism*; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D058990:Molecular Targeted Therapy; D053644:Naphthalimides / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use
chemical_list: D000970:Antineoplastic Agents; D003514:Cyclohexylamines; D053644:Naphthalimides; C000607203:bisnaphthalimidopropyl diaminodicyclohexylmethane; D004247:DNA; C427203:calf thymus DNA