TRIPTYCENE ANALOGS--NOVEL BIFUNCTIONAL ANTICANCER DRUGS

三蝶烯类似物--新型双功能抗癌药物

• 批准号: 6514600
• 负责人: Jean-Pierre H Perchellet
• 金额: $ 19.64万
• 依托单位: KANSAS STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-07-01 至 2005-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6514600
• 关键词: DNA damage; DNA replication; DNA topoisomerases; antineoplastics; apoptosis; cell cycle; chemical structure function; combination chemotherapy; cysteine endopeptidases; drug design /synthesis /production; drug metabolism; drug screening /evaluation; enzyme activity; laboratory mouse; lung neoplasms; melanoma; membrane transport proteins; multidrug resistance; neoplasm /cancer chemotherapy; nonhuman therapy evaluation; nucleic acid probes; purines; pyrimidines; quinones

Triptycene (TT) is inactive but we synthesized new TT analogs (code names TT1 to TT16) that have antileukemic activity in the nM range in vitro. The lead compound, a TT bisquinone (TT2), not only inhibits macromolecule synthesis, induces DNA fragmentation, and decreases the growth and viability (IC50: 100 nM) of L1210 cells in vitro like the quinone antitumor drug daunomycin (DAU) but can also block the cellular transport of nucleosides, an effect which DAU cannot do. Since they have unique and highly useful dual effects on nucleoside transport and DNA cleavage, these TT analogs might be valuable to develop a novel synthetic class of bifunctional anticancer drugs effective in polychemotherapy. The major objectives are 1) to demonstrate the anticancer potential of TT2 in vivo, 2) to characterize its molecular mechanism of action, and 3) to identify more potent TT2 analogs. The specific aims are: A) To establish that water-soluble TT2 derivatives can inhibit tumor development in vivo and prolong the survival of mice challenged with ascites (L1210) or solid tumors with metastatic potential (Lewis lung carcinoma and B16F10 melanoma). B) To elucidate the molecular mechanisms by which TT2 interacts with nucleoside transport (effects on equilibrative and Na+-dependent transporters, bidirectional fluxes of purines and pyrimidines, competition with nucleoside transport probes), DNA (binding, intercalation, strand breakage and crosslinks, topoisomerase activities), and tumor cells (drug uptake/retention/catabolism, cell cycle analysis, caspase-8 and -3 activation, apoptosis, potentiation of antimetabolite action, and effectiveness in P-glycoprotein-positive and -negative multidrug-resistant (MDR) cells). C) To synthesize new TT2 analogs and screen them in vitro to clarify structure-activity relationships for drug uptake, nucleoside transport/DNA synthesis, DNA fragmentation, and cell growth/viability. Because inhibition of nucleoside transport is unusual among DNA-damaging quinone antitumor drugs, the use of bifunctional TT2 analogs with antileukemic activity in the nM range in vitro might provide a considerable advantage in polychemotherapy to potentiate the action of antimetabolites and sensitize MDR tumor cells.

Triptycene (TT) 没有活性，但我们合成了新的 TT 类似物（代号 TT1 至 TT16），其在体外具有 nM 范围的抗白血病活性。 先导化合物 TT 双醌 (TT2) 不仅能像醌类抗肿瘤药物道诺霉素 (DAU) 一样在体外抑制大分子合成、诱导 DNA 断裂并降低 L1210 细胞的生长和活力 (IC50: 100 nM)，而且还可以阻断核苷的细胞运输，这是 DAU 无法做到的。 由于它们对核苷转运和 DNA 切割具有独特且非常有用的双重作用，因此这些 TT 类似物对于开发一种在多化疗中有效的新型合成双功能抗癌药物可能有价值。 主要目标是 1) 证明 TT2 的体内抗癌潜力，2) 表征其分子作用机制，3) 鉴定更有效的 TT2 类似物。 具体目标是：A) 确定水溶性 TT2 衍生物可以抑制体内肿瘤发展并延长腹水 (L1210) 或具有转移潜力的实体瘤（刘易斯肺癌和 B16F10 黑色素瘤）小鼠的生存期。 B) 阐明 TT2 与核苷转运相互作用的分子机制（对平衡和 Na+ 依赖性转运蛋白的影响、嘌呤和嘧啶的双向通量、与核苷转运探针的竞争）、DNA（结合、嵌入、链断裂和交联、拓扑异构酶）活性）和肿瘤细胞（药物摄取/保留/分解代谢、细胞周期分析、caspase-8 和 -3激活、凋亡、抗代谢作用的增强以及 P-糖蛋白阳性和阴性多药耐药 (MDR) 细胞的有效性）。 C) 合成新的 TT2 类似物并在体外对其进行筛选，以阐明药物摄取、核苷转运/DNA 合成、DNA 片段化和细胞生长/活力的构效关系。 由于核苷转运的抑制在 DNA 损伤性醌类抗肿瘤药物中并不常见，因此使用具有 nM 范围体外抗白血病活性的双功能 TT2 类似物可能会在联合化疗中提供相当大的优势，以增强抗代谢药物的作用并使 MDR 肿瘤细胞敏感。