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  • MTT naphthalimide a well known DNA

    2021-01-09

    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 MTT 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. Once sufficient single-stranded DNA (ssDNA) has been exposed at origins, synthesis of leading and lagging strands is initiated by the DNA polymerase α-primase complex (Pol α). Lagging-strand synthesis requires repeated cycles of Pol α-dependent priming and subsequent primer extension by Pol δ. Pol α first synthesizes 7–12 nucleotide (nt) RNA primers before transferring them to the DNA polymerase domain, where further extension to about 20–25 nt takes place (Pellegrini, 2012). Evidence suggests that Pol α must be functionally recruited to replication forks for efficient lagging-strand primer synthesis: priming on ssDNA by both human (Collins and Kelly, 1991) and yeast Pol α (Taylor and Yeeles, 2018) is inhibited by RPA; repeated lagging-strand priming by yeast Pol α is dependent on template unwinding by CMG (Georgescu et al., 2015). The details of this functional recruitment are yet to be elucidated. The mechanism by which continuous leading-strand replication is primed by Pol α MTT at replication origins is currently unknown. Furthermore, in vivo studies in budding yeast have reached conflicting conclusions regarding the location of leading-strand start sites relative to an origin. For example, one study concluded that the ARS1 origin contains a single leading-strand start site (Bielinsky and Gerbi, 1999). The site was located between the ARS consensus sequence (ACS), which forms part of a high-affinity ORC binding site required for MCM loading (Bell and Labib, 2016, Coster and Diffley, 2017), and the B2 element, a sequence element located downstream of the ACS that enhances origin activity (Chang et al., 2011, Marahrens and Stillman, 1992). However, a second study found that Pol α DNA synthesis peaked just upstream of the ACS, indicating that leading strands might be started outside the origin sequence, potentially from “lagging-strand” primers (Garbacz et al., 2018). Consequently, the relationship between origin sequences and leading-strand start sites is yet to be fully resolved.