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  • br Experimental methods br Results and discussion br Conclus

    2019-10-30


    Experimental methods
    Results and discussion
    Conclusion Rational design of highly selective fluorescent probes to detect G-quadruplexes is of profound importance for basic research. On this basis, we designed and synthesized a series of N-alkylated styrylquinolinium dyes Ls-1, Ls-2 and Ls-3. Among these dyes, Ls-2 which carried a sulfonato group at the chain end was chosen as the most promising candidate due to its significant absorbance shift and fluorescence enhancement in the presence of G-quadruplex DNA and insignificant change with non-G-quadruplex structure. The interactions between Ls-2 and G-quadruplex DNA have been investigated in detail. Our results demonstrated that Ls-2 interacted with G-quadruplex DNAs mainly by the groove binding mode without affecting their topologies and exhibited higher binding affinity to parallel G-quadruplexes. Furthermore, we also assessed the behavior of Ls-2 in cellular application. Ls-2 could enter into living topoisomerase inhibitor and mainly locate in cytoplasma with low cytotoxicity. Taken together, this work provides successful example of developing probes for targeting G-quadruplex DNA via the rational structural modification. Further investigations will focus on the work of detection and visualization of G-quadruplex structures in cells.
    Acknowledgements This work was financially supported by the Natural Science Foundation of Jiangsu Province (BK20180857), General Program of Natural Science Foundation of the Higher Education Institutions of Jiangsu Province (17KJB150009) and China Postdoctoral Science Foundation Funded Project (2017M611704).
    Strategic Paths Towards Anticancer Therapy Oncology mainly focuses on patient symptoms, treating hallmarks acquired by normal cells that gradually progress to a neoplastic state, instead of fighting against a still-unknown causal entity responsible for cancer occurrence and progression [1]. Global strategies, namely chemotherapy and radiotherapy (RT), still comprise the mainstay of the treatment of solid tumors by addressing specific mechanisms involved in tumorigenesis. More targeted therapies (see Glossary), such as antiangiogenesis strategies, have been developed with various degrees of success depending on the patient pathogenesis 2, 3. A better insight into the diverse underlying processes, including causes, triggered cellular and molecular pathways, and potential related targets, would definitely help in the development of relevant and effective anticancer treatments. In contrast to the empiricism from animal models that gave rise to alkylating agents or to the rational design emanating from the targeting of pathways altered in tumors, we suggest that rethinking the use of conventional anticancer drugs could make it possible to exploit their full potential. This alternative approach relies on the optimization of an already marketed bioactive drug capable of reaching topoisomerase inhibitor its target in effective concentrations to exert its anticancer activity while limiting adverse side effects. In this context, alkylating agents are old molecules still widely used in the frontline treatment of various solid tumors. Among them, platinum derivatives do not alkylate but rather complex with their nucleophilic targets. Although historically affiliated to alkylating agents, they should therefore rather be referred to as ‘alkylating-like’ agents. Half of cancer patients experience platinum-based drug therapy 4, 5. Thus, the clinical relevance of platinum compounds is key in daily practice. Cisplatin is the oldest platinum drug approved by the FDA. Although alternative platinum derivatives have been developed to improve its therapeutic index, cisplatin remains the leader molecule of platinum complexes and one of the most compelling anticancer drugs, with a pivotal role in the management of solid tumors 6, 7. Therefore, cisplatin will be addressed as a prototypic platinum-based anticancer agent to exemplify paradigms, mechanisms, limitations, and new directions that fall under a broader understanding of the future of alkylating agents and platinum compounds in the clinic.