| Summary: | 碩士 === 國立中央大學 === 化學研究所 === 96 === Part I:
Synthesis of modified lithocholic acids: coumarin, nitro-2,1,3-benzoxadiazole and other functional groups as effective anticancer agents and biological probes.
Overexpression of sialyltransferase is a vital biological process, which plays a role in various physiological and pathological events, such as cell-cell adhesion, tumor cell metastasis and invasions. To increase the inhibitory potency of sialyltransferase, we prepared the coumarin, NBD (7-nitro-2,1,3-benzoxadiazole) and other functional derivatives of lithocholic acid based on our previous studies. Some of these compounds, 5-25, represent the first examples of nanomolar range sialyltransferase inhibitors with cell permeability which had been demonstrated by the experiment of wound healing and the detection of fluorescence imaging of cells incubated with coumarin or NBD derivative of lithocholic acid. Except the property of antimetastasis in wound healing assay, compounds 5-25 also slightly displayed inhibition of the proliferation of breast cancer cells with the inhibitory percentages ranging from 4~40% under the compound dose at 20 ?M.
To investigate the capability of lithocholic acid derivatives attracting the sialyltransferase proteins in vitro and in vivo, nanoparticle-based sialyltransferase inhibitors, 32-36, were prepared to tackle this problem.
Part II:
Analogues of Malyngamide 1 and Isomalyngamide A as inhibitors of sialyltransferases: A structure activity relationship study of chain-length and functional dependence.
Malyngamide 1 and Isomalyngamide A are natural products from Marine and display the significant cytotoxic activity against breast cancer cells at the low micromolar level (IC50 = 12.7 and 2.8 μM). Meanwhile, one of them also inhibited alpha-2,3-sialyltransferase activity at micromolar concentration (IC50 = 66 μM). To find out the pharmacophore, several substructures of malyngamide 1 were synthesized, and their inhibitory properties of sialyltransferase and cytotoxic activities against breast cancer cells were also studied.
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