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.
Brartemicin is a trehalose-based inhibitor of tumor cell invasion produced by the actinomycete of the genus Nonomuraea. In order to find more potent anti-invasive agents and study the structure-activity relationships, a series of 19 brartemicin analogs were prepared via two synthetic routes from α,α-D-trehalose and evaluated for their anti-invasive activities. Compound 4f, 6,6'-bis(2,3-dimethoxybenzoyl)-α,α-D-trehalose, was more potent than the natural brartemicin. It inhibited the invasion of murine colon 26-L5, colon carcinoma SW620, melanoma B16-BL6 and breast MDA-MB-231 cells with IC50 values of 0.15, 2.35, 4.12 and 2.61 μM, respectively. Analog 4p, 6,6'-bis(3,4-dimethoxycinnamoyl)-α,α-D-trehalose, was as potent as brartemicin against invasion of murine colon 26-L5 carcinoma cells in vitro. The structure-activity relationships of these novel trehalose-based compounds were summarized.
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