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Glycoamino Acid Analogues of the Thomsen–Friedenreich Tumor-Associated Carbohydrate Antigen: Synthesis and Evaluation of Novel Antiproliferative Factor Glycopeptides
ACS Omega ( IF 4.1 ) Pub Date : 2017-09-08 00:00:00 , DOI: 10.1021/acsomega.7b01018
Maqbool A. Siddiqui 1 , Shailesh Ambre 1 , Susan K. Keay 2, 3 , Jeffrey M. Rhyne , Chen-Ou Zhang , Joseph J. Barchi 1
Affiliation  

Glycoamino acid analogues of the Thomsen–Friedenreich antigen disaccharide, where the 4′ and 4″ hydroxyl groups were substituted with fluorine or hydrogen, were synthesized and incorporated into the asialylated antiproliferative factor (as-APF), a biologically active form of APF, a glycopeptide found in the urine of patients with interstitial cystitis. Various strategies were employed to incorporate the fluorine atom at the 4-positions of either the galactose or N-acetylgalactosamine unit of the disaccharide antigen, based on stereochemistry and reactivity. These glycopeptides were evaluated in antiproliferative assays on both primary normal bladder epithelial cells and T24 bladder carcinoma cells. Unlike many previously published substitutions to APF, mono-4′-fluorination of the GalNAc residue did not affect the activity, whereas fluoro-derivatives of the galactose 4″-position or both 4′ and 4″ hydroxyls showed a reduced potency relative to the monosubstituted GalNAc derivative. A fourth compound where the 4″ position of galactose was deoxygenated showed a lower potency than the parent and monosubstituted compounds. These results suggest that specific substitutions in the sugar moieties in the APF can be tolerated, and the glycomimetic design of APF analogues can include fluorine in the GalNAc sugar of the disaccharide.

中文翻译:

Thomsen–Friedenreich肿瘤相关糖抗原的糖氨基酸类似物:新型抗增殖因子糖肽的合成与评价

合成了Thomsen–Friedenreich抗原二糖的糖氨基酸类似物,其中4'和4''羟基被氟或氢取代,并掺入了脱唾液酸化的抗增殖因子(-APF)中,这是APF的一种生物活性形式,间质性膀胱炎患者尿液中发现糖肽。采用了各种策略在半乳糖或N的4位上掺入氟原子基于立体化学和反应性的二糖抗原的-乙酰半乳糖胺单元。这些糖肽在原代正常膀胱上皮细胞和T24膀胱癌细胞的抗增殖试验中进行了评估。与许多以前发表的替代APF的方法不同,GalNAc残基的单4'-氟化不影响活性,而半乳糖4”-位或4'和4”羟基的氟衍生物相对于APF则显示出降低的效价。单取代的GalNAc衍生物。将半乳糖的4''位置脱氧的第四种化合物显示出比母体和单取代的化合物更低的效力。这些结果表明,可以耐受APF中糖部分的特定取代,
更新日期:2017-09-08
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