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    • gap 26 In our previous report we synthesized derivatives wit

    2023-12-12

    In our previous report, we synthesized derivatives with some straight chain residues on the 2-position of the 3-cyanopyridine ring of compound 1. In this time we tried to introduce aromatic ring on the chain of the 2-position. Namely, we replaced the hydroxyl-alkylamino group in the position 2 of the 3-cyanopyridine ring of compound 1 with aryloxyethylamino groups or pyridyloxy-2-ethylamino groups. The substitution reaction (Scheme 1) of the chlorine gap 26 of compound 2 with nucleophiles such as aryloxyethylamines or pyridyloxyethylamines in DMSO in the presence of NaHCO3 at 100°C delivered compounds 3a–3j (Table 1). As shown in the (3a–3f) data, 3-pyridyloxyethyl derivative (3d) gave good results in terms of inhibitory activity against Aurora A kinase and HCT116 cells proliferation (HCT116 is a cancer cell which expresses aurora A and B, so this test is also useful for supposing cell membrane permeability of aurora kinase inhibitors), and physiochemical properties. The pharmacokinetic (PK) profile of compound 3d was very good after po administration in rats. However, compound 3d showed strong inhibition against Cyp (3A4) enzyme. We presumed that one of the reasons was rapid metabolism of the pyridine residue of the 2-substituent of the 3-cyanopyridine. Therefore we substituted the non-substituted pyridine with alkyl-pyridine (3g–3j). After doing so, the Cyp inhibition profiles were markedly improved. The optimized compound in the alkyl-pyridyloxy-2-ethylamino series was compound 3g (Fig. 2) which inhibited Aurora A and B kinase with a Ki value of 0.004μM and 0.010μM respectively (Table 2). It inhibited the proliferation of HCT116 cells with an IC50 value of 0.001μM (Table 1). As mentioned above, this means that compound 3g showed good cell membrane permeability. The inhibitory activities against 66 other typical kinases were tested, and Ki values against 60 kinases were over 1.0μM. Ki values against the remaining 6 kinases are shown in Table 2. Ki/Km values are shown because the Km values of the kinases were different in each other. Compound 3g exhibited good kinase selectivity to Aurora A and B kinases. The phosphorylation of Ser10 of histone H3 was inhibited by compound 3g in vitro. Furthermore, surprisingly tubulin polymerization was inhibited by compound 3g in vitro. Compound 3g showed a good PK profile; Cmax value was 19.6μg/mL (Tmax=0.25h) and AUC was 14.6μg/mL at 30mg/kg po in rats. Then compound 3g was tested for antitumor activity. In HCT-116 subcutaneous Xenograft model in mouse, compound 3g was administrated at 30mg/kgpoqd. Tumor growth was inhibited by 81.9% after 14days. Compound 3g was also effective in another antitumor mouse model (PC-3 and CT26 subcutaneous Xenograft model) at a dose of 30mg/kgpoqd for 14days with 85.0% and 47.8% inhibition respectively. With Taxol, which was selected as a positive control, growth inhibitions (25mg/kgipqd) after 14days were 24.8% in the case of the CT26 model. In subcutaneous Xenograft model in rat, compound 3g, which was given in intermittent oral administrations, significantly inhibited growth of HCT-116 (Fig. 3). Therefore, compound 3g is a good candidate for anticancer therapy.
    Acknowledgements
    Introduction Aurora kinases are the members of serine/threonine kinases and have attracted significant attention as promising anticancer targets up to date. Both Aurora A and B are commonly overexpressed in human tumor cells and play important roles in various organ tumors including the colon, breast, pancreatic, gastric, and prostate cancer. The overexpression of Aurora A causes aberrant phosphorylation of normal cell cycle targets and cytoplasmic targets, leading to chromosomal instability, oncogenic transformation, tumor progression, and development of chemoresistance. Similarly, the overexpression of Aurora B increases the phosphorylation of histone H3, forming more aggressive tumors in transgenic mouse models. Mechanistically, Aurora kinases (A, B, and C) are regulatory proteins and play key roles in the mitotic events of cell division. Aurora A associates with the spindle poles and regulates centrosome duplication, maturation, and mitotic spindle assembly; Aurora B is involved in chromatin remodeling, phosphorylation of histone H3 at Ser-10, centrosome separation, chromosome segregation, and cytokinesis; the third isozyme, Aurora C is believed to have overlapping function with Aurora B and similar localization patterns; however, its function is not yet clearly understood.