SYNTHESIS/TUMOR DNA TARGETING OF CARBORANYL POLYAMINES

碳烷基多胺的合成/肿瘤 DNA 靶向

• 批准号: 2414461
• 负责人: ALBERT H SOLOWAY
• 金额: $ 16.12万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1996
• 资助国家: 美国
• 起止时间: 1996-05-15 至 1999-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2414461
• 关键词: CHO cells; DNA binding protein; analog; boron; brain neoplasms; chemical binding; chemical structure function; cytotoxicity; drug design /synthesis /production; drug metabolism; drug screening /evaluation; laboratory rat; neoplasm /cancer chemotherapy; neoplasm /cancer radionuclide therapy; neoplastic cell; neutron radiation; nonhuman therapy evaluation; pharmacokinetics; polyamines; putrescine; spermidine; spermine; thymidine

DESCRIPTION: There are eight specific aims; 1) To develop fully the chemical methodology of synthesizing a variety of different carborane-containing polyamines. 2) To synthesize specific analogues related to putrescine, spermidine, spermine and pentamines with potential tumor DNA-binding properties. 3) To assess their DNA-binding properties in vitro by the displacement of ethidium bromide from DNA. 4) To correlate chemical structure and physiochemical properties with DNA binding activity in order to improve drug design. 5) To determine the in vitro uptake, persistence, and subcellular distribution of boronated polyamines in glioma, melanoma and normal cells. 6) To optimize the hydrophilic/lipophilic properties of compounds in order to enhance tumor cell penetration and DNA binding. 7) To evaluate the in vivo pharmacokinetics and tumor-localizing properties in brain tumor-bearing rats of compounds demonstrating the requisite selectivity and persistence in vitro. 8) To determine the therapeutic efficacy of BNCT in rat models of human glioblastoma and melanoma metastatic to the brain.

描述：有八个具体目标； 1）充分发展 合成各种不同不同的化学方法论 含卡堡的多胺。 2）合成特定的 与perrescine，Permidine，Apermine和 具有潜在肿瘤DNA结合特性的戊胺。 3）评估 通过位移，它们的DNA结合特性在体外 DNA的溴化乙锭。 4）将化学结构和 具有DNA结合活性的理化特性以改善 药物设计。 5）确定体外摄取，持久性， 胆汁胶质瘤中的硼酸多胺的亚细胞分布， 黑色素瘤和正常细胞。 6）优化 化合物的亲水/亲脂性特性以增强 肿瘤细胞穿透和DNA结合。 7）评估体内 脑肿瘤的药代动力学和肿瘤定位特性 大鼠的大鼠表明了必要的选择性和 体外持久性。 8）确定BNCT的治疗功效 在人类胶质母细胞瘤和黑色素瘤转移的大鼠模型中 脑。