TRIPTYCENE ANALOGS--NOVEL BIFUNCTIONAL ANTICANCER DRUGS

三蝶烯类似物--新型双功能抗癌药物

• 批准号: 6157638
• 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/6157638
• 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.

三联苯（TT）是不活跃的，但我们合成了新的TT类似物（代码名称TT1至TT16），它们在NM范围内的体外具有抗血清活性。 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. 由于它们对核苷转运和DNA裂解具有独特且非常有用的双重影响，因此这些TT类似物对于开发一种有效的多化学化学疗法的新型合成抗癌药物可能很有价值。 主要目标是1）证明TT2在体内的抗癌潜力，2）以表征其分子的作用机理，以及3）识别更有效的TT2类似物。 具体目的是：a）确定水溶性TT2衍生物可以抑制体内肿瘤的发展，并延长腹水挑战（L1210）或具有转移性潜能的实体瘤的小鼠的存活（Lewis Lung癌癌和B16F10黑色素瘤）。 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，抗代谢物作用的增强以及P-糖蛋白阳性和 - 否耐药性多药物（MDR）细胞的有效性）。 c）合成新的TT2类似物并在体外筛选它们，以阐明药物摄取，核苷转运/DNA合成，DNA片段化和细胞生长/活力的结构活性关系。 由于抑制核苷转运在DNA损伤醌抗肿瘤药物中是不寻常的，因此在NM范围内使用具有抗血清症活性的双功能TT2类似物在体外可能会提供相当大的优势，从而可以增强抗微代剂的作用并敏感MMDR肿瘤细胞。