Emami Saeed, Kumar Piyush, Yang Jennifer, Kresolic Zbigniew, Paproski Robert, Cass Carol, McEwan Alexander Jb, Wiebe Leonard I
Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, Alberta, Canada.
J Pharm Pharm Sci. 2007;10(2):237-45.
Cellular uptake of most azomycin-based radiosensitizers depends on perfusion and diffusion, rather than on active transport. In medical imaging using radioisotopically labeled azomycin nucleosides, image contrast depends on rapid diffusion from normoxic tissues and rapid renal clearance from the central compartment. [18F]FAZA [1-alpha-D-(5-deoxy-18F]fluoroarabinofuranosyl)-2-nitroimidazole], an azomycin nucleoside currently under clinical evaluation as a marker of tissue hypoxia in medical centers world wide, provides high contrast but its uptake is diffusion dependent and therefore low. 1-D-(5-Fluoro-5-deoxyribofuranosyl)-2-nitroimidazole 6 (beta-5-FAZR), a Beta-ribose analog of FAZA, has now been developed to exploit transport across cell membranes to improve absolute uptake in hypoxic regions and high contrast.
Beta-5-FAZR was synthesized by classical sugar base coupling followed by regioselective fluorination. In radiosensitization of hypoxic and normoxic to 60Co x-rays was determined relative to known radiosensitizers. The relative abilities of five human nucleoside transporters (hENT1/2, hCNT1/2/3 to bind the radiosensitizers were determined by quantifying their inhibition of uridine transport by recombinant transporters produced in yeast.
Beta-5-FAZR was synthesized in 44 percent yield. Beta-5-FAZR had moderate radiosensitization effect on human HCT116/100 colorectal carcinoma (OER 1.8). Beta-5-FAZR was a weak inhibitor of uridine transport relative to nonfluorinated 1-beta-D-(ribofuranosyl)-2-nitroimidazole (beta-AZR).
Facile synthesis of beta-5-FAZR was achieved and its activity as a radiosensitizer was confirmed. Substitution of C-5 hydroxyl by fluorine in the ribose moiety greatly reduced interaction with hENT1/2 and hCNT1/2 and moderately reduced interaction with hCNT3 relative to thymidine and beta-AZR.
大多数基于偶氮霉素的放射增敏剂的细胞摄取取决于灌注和扩散，而非主动转运。在使用放射性同位素标记的偶氮霉素核苷的医学成像中，图像对比度取决于从正常组织的快速扩散以及从中枢隔室的快速肾脏清除。[18F]FAZA[1-α-D-(5-脱氧-18F)氟阿拉伯呋喃糖基]-2-硝基咪唑]，一种目前正在全球医疗中心作为组织缺氧标志物进行临床评估的偶氮霉素核苷，提供了高对比度，但其摄取依赖于扩散，因此较低。1-D-(5-氟-5-脱氧核糖呋喃糖基)-2-硝基咪唑6（β-5-FAZR），一种FAZA的β-核糖类似物，现已被开发用于利用跨细胞膜转运来提高缺氧区域的绝对摄取和高对比度。
通过经典的糖基偶联然后区域选择性氟化合成β-5-FAZR。相对于已知的放射增敏剂，测定了β-5-FAZR对缺氧和正常氧合的60Co X射线的放射增敏作用。通过量化它们对酵母中产生的重组转运体的尿苷转运的抑制作用，确定了五种人核苷转运体（hENT1/2、hCNT1/2/3）与放射增敏剂结合的相对能力。
以44%的产率合成了β-5-FAZR。β-5-FAZR对人HCT116/100结肠直肠癌具有中等放射增敏作用（氧增强比1.8）。相对于非氟化的1-β-D-(核糖呋喃糖基)-2-硝基咪唑（β-AZR），β-5-FAZR是尿苷转运的弱抑制剂。
实现了β-5-FAZR的简便合成，并证实了其作为放射增敏剂的活性。与胸苷和β-AZR相比，核糖部分中C-5羟基被氟取代极大地降低了与hENT1/2和hCNT
