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  • Organometallic compounds exhibited remarkable potential

    2019-10-22

    Organometallic compounds exhibited remarkable potential for the development of new cancer drugs not only due to the direct cytotoxicity but also to the drug targeting and active anticancer immune response ability [4]. Among the organometallic compounds, ferrocene is one of the most well-known compounds in many areas of science, especially in medicinal chemistry. It attracted great attention on account of the high stability, lipophilicity, low toxicity, easy functionalization and mild reversible redox property [5]. Hence, ferrocenyl group conjugated nature products or drugs were synthesized and exhibited kinds of biological activities, including antitumor, antimalarial and antibacterial activity [6]. In the development of ferrocene based drugs, the two most successful examples were ferrocifen and ferroquine. The last one entered the clinical trials and would be completed in 2019 [7]. The two compounds represent one type of ferrocene derivatives, in which the ferrocenyl group replaced a portion of the lead compound [8]. And in another type, the ferrocenyl group directly attached to the lead compound, which is a promising strategy to enhance the anticancer efficiency by attaching ferrocenyl group to a DNA intercalator [5a]. Ferrocene appended intercalators were reported to exhibit far more cytotoxicity or better selectivity towards cancerous Doripenem than the single intercalators [9]. 1,8-naphthalimide, a well-known DNA intercalator, has been extensively investigated in the development of antitumor agents [10]. Some of the naphthalimide derivatives, such as amonafide, elinafide and bisnafide (Fig. 1), have entered into phase II clinical trials stage [10]b), [11]. Among them, elinafide and bisnafide were typical bis-intercalator which constructed by a polyamine linker and two naphthalimide groups. Such a strategy was helpful to enhance the DNA binding ability and anticancer activity of the intercalator [12]. In our previous work, some bis-aryl compounds were designed and synthesized according to the strategy [13]. And the DNA binding and cytotoxicity activity of the bis-aryl compounds were systematically studied, which displayed significant advantage over the mono-aryl ones.
    Materials and methods
    Results and discussion
    Conclusions Herein, some ferrocene appended naphthalimide derivatives were synthesized and characterized to evaluate the synergistic effect of the ferrocene group in anticancer activity of napthalimide derivatives. And according to the results of EB display, UV–visible spectrophotometry and viscosity studies, the ferrocene appended naphthalimide derivatives exhibited partial-intercalation binding mode with DNA duplex. Ferrocenyl group was helpful to enhance the DNA binding ability of bis-naphthalimide derivative. Hybrid compound 6 was 6.45–17.62 times more toxicity than the reference compound 5 and control drug amonafide on tested cancer cell lines. The synergistic effect of ferrocene group played an important role to enhance the cytotoxicity of bis-naphthalimide derivative. And the cytotoxicity of compound 6 was relate to the DNA damage in cancer cells.
    Acknowledgments This work was financially supported by the National Natural Science Foundation of China (Nos. 21362026, 21867016), Young Talent Program of NingXia medical University and Ningxia Medical University Key Project (XZ2018002).
    Introduction Bidirectional DNA replication is initiated from specific regions of the genome, termed origins. In eukaryotes, assembly of the DNA replication machinery (replisome) begins in the G1 phase of the cell cycle when the ATP-dependent motor component of the replicative helicase, the hexameric Mcm2–7 complex (MCM), is loaded at origins by the origin recognition complex (ORC), Cdc6 and Cdt1 (Bell and Kaguni, 2013, Bell and Labib, 2016). The MCM complex is assembled around double-stranded DNA (dsDNA) as an inactive double hexamer with the N-terminal domains of each hexamer facing one another (Evrin et al., 2009, Remus et al., 2009). Replication commences when double hexamers are activated in S phase to form two Cdc45-MCM-GINS helicases (CMG helicases), around which the replisome is built (Heller et al., 2011, Yeeles et al., 2015). CMG assembly and activation require multiple “firing factors” and are coupled to the initial untwisting and subsequent unwinding of duplex DNA at the replication origin (Douglas et al., 2018). Activated CMG translocates 3ʹ-5ʹ along the leading-strand template in an N-terminus-first orientation (Douglas et al., 2018, Georgescu et al., 2017, Moyer et al., 2006), and consequently, the two CMG complexes must pass one another before extensive template unwinding and DNA synthesis can occur.