含氟唾液酸-石膽酸混合分子作為增強抑制癌細胞轉移能力的唾液酸轉移酶代謝抑制劑

Abstract

含氟唾液酸可以抑制唾液酸轉移酶的活性，以調節唾液酸的生物合成及其補救途徑，加上石膽酸本身也表現出對唾液酸轉移酶的顯著抑制特性。在本篇論文中，我們合成了一系列具有糖苷酯鍵和酯鍵連接的含氟唾液酸-石膽酸混合分子。希望它們可以與唾液酸轉移酶相互作用並協同調控唾液酸的生物合成，以抑制細胞表面唾液酸化的發生。最後，我們合成了一系列混合分子TYW01-TYW12，並進行了初步的生物試驗。令人驚訝的是，TYW01-TYW12對唾液酸轉移酶沒有抑制作用，但對人類三陰性乳癌細胞株MDA-MB-231有輕微的抗轉移作用。其中，TYW10的影響較為顯著，IC50範圍為40 µM至50 µM。需要更進一步的生物實驗和研究來證實這些結果。

Sialyltransferases (STs) activity can be inhibited using a fluorinated sialic acid (3FaxNeu5Ac) to affect/regulate both the de novo synthesis of sialic acid and its salvage pathway. In addition, lithocholic acid (LCA) itself also demonstrated potent inhibitory property toward STs. In this work, we synthesized a series of P-3FaxNeu5Ac-GA-LCA (GA, Glycolic acid) hybrid molecules with glycosidic ester bonds linkage. Hopefully, they can interact with STs and manipulate the biosynthesis of sialic acid synergistically to inhibit/modulate the occurrence of sialylation on cell surface.Finally, we synthesized a series of hybrid molecules TYW01-TYW12 and tested their preliminary biological experiments. Surprisingly, TYW01-TYW12 showed no inhibitory effect toward sialyltransferase, but mild anti-migration effect in MDA-MB-231 cell. Among them, TYW10 has the best effect with IC50 ranging from 40 µM to 50 µM. Further biological experiments and studies are needed to confirm these results.