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    Aryl-urea fatty acids that activate the p38 MAP kinase and down-regulate T multiple cyclins decrease the viability of MDA-MB-231 breast cancer cells☆
    Yassir Al-Zubaidia,1, Curtis Pazderkab,1, Nooshin Koolajia, Md Khalilur Rahmana, Hassan Choucaira, Bala Umashankara, Kirsi Bourgeta, Yongjuan Chena, Tristan Rawlingb, Michael Murraya,
    a Pharmacogenomics and Drug Development Group, Discipline of Pharmacology, School of Medical Sciences, Sydney Medical School, University of Sydney, NSW 2006, Australia b School of Mathematical and Physical Sciences, Faculty of Science, University of Technology, Sydney, Ultimo, NSW 2007, Australia
    Anti-proliferative agents
    Proapoptotic agents
    p38 MAP kinase
    Breast cancer
    Cyclin-dependent kinases 
    We recently developed a novel aryl-urea fatty 6NBDG (CTU; 16( [4-chloro-3-(trifluoromethyl)phenyl]carbamoyl amino)hexadecanoic acid) that impaired the viability of MDA-MB-231 breast cancer cells in vitro and in mouse xenograft models in vivo. At present there is a deficiency of information on the structural requirements for the activity of CTU. Our initial study suggested that electron withdrawing groups were required on the aryl ring, and in this study we further evaluated the influence of the electronic properties of aromatic substitution on the capacity of CTU analogues to decrease MDA-MB-231 breast cancer cell viability. Analogues that contained strong electron-withdrawing groups in the meta- and para-positions of the aryl ring exhibited improved activity over CTU. Effective analogues down-regulated the cyclins D1, E1 and B1, and the cyclin-dependent kinases (CDKs) 4 and 6, that form complexes to coordinate cell cycle progression. Active CTU analogues also stimulated the phosphorylation and activation of the p38 MAP kinase signalling pathway in cells and both decreased proliferation (5-bromo-2′-deoxyuridine (brdU) incorporation) and activated apoptosis (executioner caspase-3/7 activity). These agents offer a new approach to target the cell cycle at multiple phases in order to efficiently prevent cancer cell expansion. Inclusion of the present structural information in drug design approaches could enhance the development of optimal analogues of aryl-urea fatty acids as potential anti-cancer agents.
    1. Introduction
    Drugs that act by novel mechanisms to decrease the viability of breast cancer cells are important for the development of new anti-cancer ther-apeutics and to overcome resistance to established anti-cancer agents. A range of studies have suggested that ω-3 polyunsaturated fatty acids (PUFA), such as eicosapentaenoic acid (EPA; ω-3 C20:5), decrease the development of breast tumours while their ω-6 PUFA counterparts pro-mote tumour development (Rose and Connolly, 1999; Maillard et al., 2002; Simopoulos, 2002; Thiébaut et al., 2009). These actions of ω-3 PUFA could be utilized in novel drug development programs.
    Evidence is increasing that eicosanoid metabolites mediate many of the cellular actions of ω-3 PUFA (Murray et al., 2015). Whereas cyto-chromes P450 (CYPs) have been studied more extensively for their roles
    in drug and xenobiotic oxidation (Hollenberg, 1992; Guengerich, 2001; Stupans et al., 2001; Murray et al., 1987), PUFA are also important CYP substrates that are converted to epoxides that modulate cell viability. Thus, CYPs oxidize the ω-6 PUFA arachidonic acid (AA) to epox-yeicosatrienoic acids that activate cell proliferation, whereas the CYP-derived ω-3-17,18-epoxide of EPA (ω-3-17,18-epoxy-EPA) selectively inhibits proliferation (Cui et al., 2011; Potente et al., 2002).
    The cell cycle is a coordinated sequence of events that regulate cell proliferation (Vermeulen et al., 2003). Non-cycling cells are in G0 phase and are stimulated by mitogens to enter the cell cycle in G1 phase, where they increase in size. DNA is then replicated in S-phase and in G2 phase the cell prepares for division, which occurs in M-phase (mitosis). Cell cycle progression is controlled by regulatory cyclins and the cyclin-dependent kinases (CDKs) that are activated at specific stages
    ☆ Names of compounds: arachidonic acid; N,N‑carbonyldiimidazole; 16( [4-chloro-3-(trifluoromethyl)phenyl]carbamoyl amino)hexadecanoic acid; ω-3-17,18-epoxyeicosanoic acid; epoxyeicosapentaenoic acid.
    Corresponding author at: Discipline of Pharmacology, Sydney Medical School, University of Sydney, NSW 2006, Australia. E-mail address: [email protected] (M. Murray).
    1 These authors contributed equally.
    Available online 29 December 2018
    Fig. 1. Chemical structures of the epoxide metabolite of EPA, ω-3-17,18-epoxy-EPA, and synthetic compounds ω-3-EEA and CTU.
    throughout the cell cycle (Walker and Assoian, 2005). For example, cyclin D1 is activated by mitogens at the point of cell cycle entry and forms a complex with CDK4 to regulate the G1 to S-phase transition (Stacey, 2003). Epoxyeicosatrienoic acids derived from ω-6 AA have been shown to increase cyclin D1 expression and accelerate cell cycle progression by activating the ERK mitogen-activated protein kinase (MAP kinase)-linked proliferative pathway (Potente et al., 2002). In contrast, ω-3-17,18-epoxy-EPA (Fig. 1) decreased cyclin D1/CDK4 ex-pression and arrested the cell cycle in S-phase by activating the p38 MAP kinase pathway (Cui et al., 2011). Thus, activation of the p38 MAP kinase may well be advantageous in the development of novel anti-proliferative agents for use in cancer chemotherapy.