SCALE-UP SYNTHESIS TECHNOLOGY FOR ANTICANCER DRUGS

主要目标是开发高效的合成技术 公斤量的寡核苷酸和其他潜在的抗癌药物 化合物.第二个目标是将该技术应用于开发 用于抗癌和抗艾滋病的小分子组合文库 药物筛选具体的研究目标是：（1）完成开发 第四阶段设计的自动化合成仪器 （2）选择高负荷、高效率的固体载体基质， 优化合成化学;（3）集成自动化原位合成子 形成/活化和DNA合成;（4）达到可重复性98-99% 在10- 100 g规模下的分步合成效率;（5）开发 工艺规模的分离和纯化方案; (6)合成10- 100克量的几种潜在的抗癌剂， （7）进行体外生物学试验， 有效性和毒性，并与由 （8）效率显著提高， 与目前的方法相比，成本降低;（9）将该系统应用于 小分子（<700 MW）组合文库混合物合成 含有浓度大于100 μ M的组分;和（10） 进行文库混合物的化学分析以确认它们的 适用于基于细胞的和体外药物筛选应用。更 高效经济的合成技术 寡核苷酸、抗癌剂和组合文库将 促进新治疗剂的鉴定和评价。 拟议的商业应用：该项目将扩大规模 合成反义寡核苷酸等技术 用于开发、临床试验的千克量的化合物 和制造具有抗癌和抗- 艾滋病应用。该技术的延伸， 组合文库将加速识别新的 潜在的药剂，通过使非常大量的 不同的材料将被有效地和成本效益地生产， 生物活性筛选程序。

The primary objective is to develop efficient technology for synthesis of kilogram amounts of oligonucleotides and other potential anticancer compounds. A secondary goal is to apply the technology to the development of small-molecule combinatorial libraries for anticancer and anti-AIDS drug screening. Specific research aims are: (1) completing development and construction of the automated synthesis instrument designed in Phase 1; (2) selecting a high-load, high-efficiency solid-support matrix and optimizing synthetic chemistry; (3) integrating automated in situ synthon formation/activation and DNA synthesis; (4) achieving reproducible 98-99% stepwise synthesis efficiency at the 10-100g scale; (5) developing process-scale isolation and purification protocols; (6) synthesizing 10-100g amounts of several potential anticancer agents of pharmaceutical- grade; (7) performing in vitro biological testing for efficacy and toxicity, and for comparison to compounds produced by current methods; (8) demonstrating significant efficiency improvement and cost-reduction compared to current methods; (9) applying the system to the synthesis of small-molecule (<700 MW) combinatorial library mixtures containing components at concentrations greater than 100muM; and (10) performing chemical analysis of the library mixtures to confirm their suitability for cell-based and in vitro drug screening applications. More efficient and economical technology for scale-up synthesis of oligonucleotides, anticancer agents and combinatorial libraries will facilitate the identification and evaluation of new therapeutic agents. PROPOSED COMMERCIAL APPLICATION: The project will develop scale-up technology for synthesizing antisense oligonucleotides and other compounds in kilogram amounts for use in the development, clinical trials and manufacture of new pharmaceutical products with anticancer and anti- AIDS applications. The extension of the technology to the development of combinatorial libraries will accelerate the identification of new potential pharmaceutical agents by enabling very large numbers of different materials to be produced efficiently and cost-effectively for biological activity screening programs.