BORONIC ACID ANALOGS OF NUCLEOSIDE-5'-PHOSPHATES

使用核苷磷酸作为抗病毒和抗肿瘤药物的主要问题是， 抗肿瘤药物的缺点是它们不能穿透细胞膜。 此外，核苷磷酸对磷酸酶敏感， 核酸酶，这减少了它们的体内寿命。 更换 带电荷的磷酸基团与不带电荷的含硼部分应 不仅增强了它们的细胞通透性，而且新的类似物 预期对磷酸酶和核酸酶具有抗性。 本项目的长期目标是合成硼化 核苷磷酸作为正常或糖修饰的核苷的类似物。 这些化合物可以通过两种方法制备：1）通过直接修饰 或2）通过将经修饰的糖部分连接到核苷上， 基地 第一阶段的工作将主要集中在综合一个 阿昔洛韦单磷酸类似物，并开发可以 用于合成其他核苷磷酸类似物 第二阶段。 将测试新合成的化合物的效果 对某些酶的作用及其潜在的抗肿瘤和抗病毒活性。 硼化核苷酸可以以多种方式使用，包括： 1)作为研究酶作用机制的工具 2)作为抗病毒剂和抗肿瘤剂，和 3)作为硼中子俘获治疗的硼-10载体。

A major problem with the use of nucleoside phosphates as antiviral and antitumor drugs has been their inability to penetrate cell membranes. Additionally, nucleoside phosphates are susceptible to phosphatases and nucleases, which reduce their in vivo life time. Replacement of the charged phosphate group with uncharged boron containing moieties should not only enhance their cell permeability, but the new analogs are expected to be resistant to phosphatases and nucleases. The long term objective of this project is to synthesize boronated nucleoside phosphates as analogs of normal or sugar modified nucleosides. These compounds may be prepared by two methods: 1) by direct modification of a nucleoside or 2) by attachment of a modified sugar moiety to the base. The Phase I effort will mainly concentrate on the synthesis of an analog of acyclovir monophosphate and to develop methods that may be utilized for the synthesis of analogs of other nucleoside phosphates in Phase II. The newly synthesized compound will be tested for its effect on certain enzymes and its potential antitumor and antiviral activity. The boronated nucleotides may be useful in a number of ways including: 1) as tools for studying mechanism of action of enzymes 2) as antiviral and antitumor agents, and 3) as carriers of boron-10 for boron neutron capture therapy.