As a continuous research for the discovery of trehalose-based anti-invasive agents, we developed a convenient synthetic approach for the preparation of 6,6'-dideoxy-6,6'-bis(acylamino)-α,α-D-trehaloses. A series of trehalose-based amides were prepared through the trityl protection of the two primary hydroxyls of α,α-D-trehalose, benzoylation, the removal of the trityl protective group, mesylation, azidation, catalytic hydrogenation in the presence of hydrochloride, coupling reaction with a variety of acids, and subsequent debenzoylation and deacetylation in some cases. Compound 8b, 6,6'-dideoxy-6,6'-bis(2-hydroxybenzamide)-α,α-D-trehalose, was just as potent as the natural brartemicin against the invasion of murine colon 26-L5 cells. It exhibited no cytotoxicity on human breast adenocarcinoma MDA-MB-231 and murine colon 26-L5 cells. It can significantly inhibit the migration and invasion of the MDA-MB-231 cells. The anti-invasive effect of 8b was possibly related to its inhibitory activity on MMP-9, its suppression on the expression of MMP-9 and VEGF, and its deactivation of Akt.
Progress in identifying and understanding the molecular and cellular causes of cancer has led to the discovery of anomalies that characterize cancer cells and that represent targets for the development of cancer therapeutics. One such target is the epidermal growth factor receptor (EGFR), a transmembrane protein that is frequently dysregulated in cancer cells and associated with the development, progression and aggressiveness of a number of malignancies. Inhibition of EGFR signaling has thus been identified as an attractive strategy in control of tumor proliferation, and over a decade of intense activity in the field has culminated in the discoveries and subsequent approvals of gefitinib and erlotinib for the treatment of non-small cell lung cancer. However, the drug's resistance to gefitinib and erlotinib has been clinically observed. Therefore, intensive efforts have been made in the discovery of novel potent and selective EGFR inhibitors. This review will focus on the developments of small molecule EGFR inhibitors based on the quinazoline core scaffolds in recent 5 years. Diverse EGFR inhibitors are classified as 4-anilinoquinazolines and 4-nonanilininoquinazolines, their biological data are described, and the structure-activity relationships (SARs) are discussed.
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