Finally this study described that
Finally, this study described that the lead CPI-169 (1) acted as an efficient alkylating agent for the G4 structure in addition to the previously reported T-T mismatch structure. The shortcoming of probe (1) is the lack of a structure selectivity, but that can be overcome by changing the acridine scaffold to a more selective binder to G4 or the T-T mismatch. Efforts for improving the structure selectivity and alkylation effectivity are under active investigation.
Materials and methods
Acknowledgements This work was supported by a Grant-in-Aid for Scientific Research on Innovative Areas ‘‘Middle Molecular Strategy” (No. JP15H05838) from the Japan Society for the Promotion of Science (JSPS). This work was also supported in part by the research program of “Dynamic Alliance for Open Innovation Bridging Human, Environment and Materials”. The lead author gratefully acknowledges scholarship support throughout master’s degree from Sato Yo International Scholarship Foundation (SISF).
Introduction Sporadic colorectal cancers (CRC) are the majority of cases of CRC and result from gene–environment interactions. Diet is an important contributing factor for cancer risk due on one hand to the presence of food mutagens and on the other to its composition in anticarcinogenic compounds (Goldman and Shields, 2003, Jagerstad and Skog, 2005). Among the most potent food mutagens (that do not result from microbial contamination) are the polycyclic aromatic hydrocarbons (PAHs), the N-nitrosamines and the heterocyclic amines (HACs), compounds that result from the high temperature cooking or present in cured foods (Jagerstad and Skog, 2005). These mutagens induce several types of DNA damage, such as oxidative, alkylating lesions and mutagen–DNA adducts that may cause coding errors upon DNA replication if repair mechanisms do not remove them (Goldman and Shields, 2003). Alkylation of DNA can be an important initial step in cancer formation. High levels of alkylating damage have been found in human colorectal DNA where high incidence of tumours has been observed (Povey et al., 2000). Alkylating agents are able to react with nucleophilic sites (such as N and O) covalently binding with DNA. A wide spectrum of DNA adducts in double-stranded DNA (dsDNA), including N-alkylated adducts (more than 80% of alkylated bases), and O-alkylated adducts (<10% of total alkylated bases) can be formed by these agents. Methyl methanesulfonate (MMS) is a monofunctional alkylating agent that binds to the most nucleophilic site (N7 position of guanine) and reacts via SN2 reaction (Drablos et al., 2004). Maintenance of genomic integrity is complex due to the great diversity of damage that can occur in DNA. Deleterious consequences of damage accumulation may be avoided by a variety of DNA repair pathways, each recognizing and repairing specific types of DNA damage. Base excision repair (BER), nucleotide excision repair (NER), mismatch repair (MMR), homologous recombination (HR), non-homologous end-joining repair (NHEJ), single strand breaks repair (SSBR) and direct damage reversal repair are some of the most important pathways involved in the repair of oxidative and alkylating DNA damage (Kondo et al., 2010). The genus Hypericum contains a large number of sps that are widespread throughout Europe, West Asia, North Africa and North America. Hypericum sps. are widely used in traditional medicine due to their beneficial properties in the digestive and neurologic systems. Several biological activities, namely, antioxidant, antiproliferative, proapoptotic, anti-inflamatory, hepatoprotective and antidepressant activities have been attributed to some species of genus Hypericum (Savikin et al., 2007, Valentao et al., 2002, Xavier et al., 2012). Recently, Rainha and collaborators (Rainha et al., 2012) reported the phenolic composition of the aqueous extracts of some Hypericum species. The main constituents of H. perforatum (HP) are rutin (R), hyperoside, isoquercitrin, chlorogenic acid (Ch) and quercetin (Q). In H. androsaemum (HA), the main phenolic compound is Ch, followed by 3-caffeoylquinic acid, hyperoside, quercetin 3-sulfate, kaempferol, isoquercitrin, caffeoylquinic acid, R and Q that are less abundant. The major phenolic compounds present in the aqueous extract of H. undulatum (HU) are hyperoside, isoquercitrin, 3-caffeoylquinic acid, Ch and Q.