烯烴基 (C11-C12) 石膽酸類似物為唾液酸轉移酶抑制劑的合成與初步活性研究
Abstract
根據研究指出唾液酸轉移酶的異常表現量與許多癌症有所關連。因此，發展能調控唾液酸轉移酶活性的抑制劑，進而抑制或減緩疾病的生理過程之藥物引起我們高度興趣。
本文所合成之藥物主要是以石膽酸結構中的C-ring (C-11/C-12) 嵌入雙鍵作為基底藥物 (化合物EY-22)。以脫氧石膽酸作為起始物，先將C24位置的羧酸和C3位置的羥基進行保護，然後將C12位置的羥基進行mesylation。而為了得到雙鍵而進行demesylation時，發現產物與異構物的比例為1:1，因此改變不同反應條件來找到適當的反應條件，使異構物的比例大幅地減少。最後，將保護基都去除掉，成功得到化合物EY-22。
參考本實驗室先前合成具有活性的石膽酸衍生物中，挑選出抑制效果較好的官能基 (如：aspartic acid、NBD和4-Nitrobenzoic acid等) 作修飾，成功合成出化合物EY-36、EY-37、EY-39、EY-43、EY-45和EY-46。同時為了探討在C-ring上有無羥基或帶有雙鍵結構，它們對於抑制α2,3-唾液酸轉移酶效果的差異性，因此設計合成C-ring上具有羥基的化合物DX-5。最後，將所有合成的化合物對乳癌細胞MDA-MB-231作細胞傷口癒合的活性測試，以定性實驗的方式來觀察到化合物EY-36、EY-39和EY-45有抑制轉移的潛力。
Aberrant expressions of sialyltransferases (STs) have been reported to positively correlate with many cancers. Therefore, we interest that the development of sialyltransferase inhibitors to modulate sialyltransferase activity and thus alleviate or inhibit physiological processes (e.g., alteration of sialylation in cell surface and sialylation of glycoproteins/glycolipids) caused by sialyltransferases. In this thesis, we initially designed a potential STs’ inhibitor containing an olefin moiety within C-ring (C-11/C-12) of the lithocholic acid as a parent skeleton (compound EY-22). Synthesis of EY-22 was carried out from deoxycholic acid as the starting material. First, both the carboxylic acid at C-24 and the hydroxyl group at C-3 of deoxycholic acid were selectively protected. The protected deoxycholic acid was esterified to yield the required mesylate ester (mesylation of the hydroxyl group at C-12), which was subsequently converted to the protected lithocholic acid with an olefin at C-11 by the method of demesylation. However, demesylation resulted in a mixture compounds with the presence of desired product and steroidal rearrangement compound in the ratio of 1:1. Efficient formation of demesylation product was obtained from modification of reaction conditions. The final product EY-22 was accomplished after removal of the remaining protecting groups. A series of EY-22 based derivative, EY-36、EY-37、EY-39、EY-43、EY-45 and EY-46 (containing Asp, Glu, NBD and 4-nitrobenzoic acid moieties), were successful prepared according to the procedure described previously. Interestingly, effective disruption of wound closure was observed for cells cultured in the presence of derivatives EY-36、EY-39 and EY-45 compared to deoxycholic acid and DX-5. Assays of sialyltransferase inhibition are underway.
Aberrant expressions of sialyltransferases (STs) have been reported to positively correlate with many cancers. Therefore, we interest that the development of sialyltransferase inhibitors to modulate sialyltransferase activity and thus alleviate or inhibit physiological processes (e.g., alteration of sialylation in cell surface and sialylation of glycoproteins/glycolipids) caused by sialyltransferases. In this thesis, we initially designed a potential STs’ inhibitor containing an olefin moiety within C-ring (C-11/C-12) of the lithocholic acid as a parent skeleton (compound EY-22). Synthesis of EY-22 was carried out from deoxycholic acid as the starting material. First, both the carboxylic acid at C-24 and the hydroxyl group at C-3 of deoxycholic acid were selectively protected. The protected deoxycholic acid was esterified to yield the required mesylate ester (mesylation of the hydroxyl group at C-12), which was subsequently converted to the protected lithocholic acid with an olefin at C-11 by the method of demesylation. However, demesylation resulted in a mixture compounds with the presence of desired product and steroidal rearrangement compound in the ratio of 1:1. Efficient formation of demesylation product was obtained from modification of reaction conditions. The final product EY-22 was accomplished after removal of the remaining protecting groups. A series of EY-22 based derivative, EY-36、EY-37、EY-39、EY-43、EY-45 and EY-46 (containing Asp, Glu, NBD and 4-nitrobenzoic acid moieties), were successful prepared according to the procedure described previously. Interestingly, effective disruption of wound closure was observed for cells cultured in the presence of derivatives EY-36、EY-39 and EY-45 compared to deoxycholic acid and DX-5. Assays of sialyltransferase inhibition are underway.
Description
Keywords
唾液酸, 唾液酸轉移酶, 唾液酸轉移酶抑制劑, sialic acid, sialyltransferase, sialyltransferase inhibitors