TRIPTYCENE ANALOGS--NOVEL BIFUNCTIONAL ANTICANCER DRUGS

三蝶烯类似物--新型双功能抗癌药物

• 批准号: 6754506
• 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 2006-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6754506
• 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.

三蝶烯（TT）是无活性的，但我们合成了新的TT类似物（代号TT 1至TT 16），在体外具有nM范围内的抗白血病活性。 先导化合物TT双醌（TT 2）不仅能抑制大分子合成，诱导DNA片段化，并像醌类抗肿瘤药物柔红霉素（DAU）一样在体外降低L1210细胞的生长和活力（IC 50：100 nM），而且还能阻断核苷的细胞转运，这是DAU无法做到的。 由于它们对核苷转运和DNA切割具有独特和高度有用的双重作用，这些TT类似物可能对开发一种新型的合成类双功能抗癌药物具有价值。 主要目的是1）证明TT 2在体内的抗癌潜力，2）表征其分子作用机制，3）鉴定更有效的TT 2类似物。 具体目标是：A）确定水溶性TT 2衍生物可抑制体内肿瘤发展并延长用腹水（L1210）或具有转移潜力的实体瘤（刘易斯肺癌和B16 F10黑色素瘤）攻击的小鼠的存活。B）阐明TT 2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/滞留/催化、细胞周期分析、半胱天冬酶-8和-3活化、细胞凋亡、抗代谢作用的增强以及在P-糖蛋白阳性和阴性多药耐药（MDR）细胞中的有效性）。C）合成新的TT 2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。 由于核苷转运的抑制是不寻常的DNA损伤醌类抗肿瘤药物，使用双功能TT 2类似物在体外的抗白血病活性在nM范围内可能提供了相当大的优势，在多化疗，以加强抗代谢物的作用和敏感MDR肿瘤细胞。

项目成果

Antitumor triptycene analogs induce a rapid collapse of mitochondrial transmembrane potential in HL-60 cells and isolated mitochondria.

抗肿瘤三蝶烯类似物可诱导 HL-60 细胞和分离线粒体中线粒体跨膜电位的快速崩溃。

• 发表时间: 2006
• 期刊: International journal of oncology.
• 作者: Wang,Yang;Perchellet,ElisabethM;Ward,MaryM;Lou,Kaiyan;Zhao,Huiping;Battina,SrinivasK;Wiredu,Bernard;Hua,DuyH;Perchellet,Jean-PierreH
• 通讯作者: Perchellet,Jean-PierreH

Antileukemic activity of synthetic daunomycinone derivatives bearing modifications in the glycosidic moiety.

糖苷部分修饰的合成道诺霉素酮衍生物的抗白血病活性。

• 发表时间: 2001
• 期刊: Anticancer research.
• 作者: Perchellet,EM;Sperfslage,BJ;McIlvain,CJ;Aligiannis,N;Pouli,N;Marakos,P;Skaltsounis,AL;Perchellet,JP
• 通讯作者: Perchellet,JP

Induction of poly(ADP-ribose) polymerase-1 cleavage by antitumor triptycene bisquinones in wild-type and daunorubicin-resistant HL-60 cell lines.

• DOI: 10.1016/s0304-3835(02)00493-7
• 发表时间: 2002-12
• 期刊: Cancer letters
• 影响因子: 9.7
• 作者: Yang Wang;E. Perchellet;M. Tamura;D. Hua;J. Perchellet

Antiproliferative and proapoptotic activities of pyranoxanthenones, pyranothioxanthenones and their pyrazole-fused derivatives in HL-60 cells.

• 发表时间: 2006-07
• 期刊: Anticancer research
• 影响因子: 2
• 作者: E. Perchellet;M. M. Ward-M.;A. Skaltsounis;I. Kostakis;Nicole Pouli;P. Marakos;J. Perchellet

Among substituted 9,10-dihydro-9,10-[1,2]benzenoanthracene-1,4,5,8-tetraones, the lead antitumor triptycene bisquinone TT24 blocks nucleoside transport, induces apoptotic DNA fragmentation and decreases the viability of L1210 leukemic cells in the nanomol

在取代的 9,10-二氢-9,10-[1,2]苯蒽-1,4,5,8-四酮中，主要抗肿瘤药物三蝶烯双醌 TT24 可阻断核苷转运，诱导细胞凋亡 DNA 断裂并降低 L1210 白血病细胞的活力

• DOI: 10.1097/00001813-200207000-00003
• 发表时间: 2002
• 期刊: Anti-cancer drugs
• 影响因子: 2.3
• 作者: Perchellet,ElisabethM;Sperfslage,BonnieJ;Wang,Yang;Huang,Xiaodong;Tamura,Masafumi;Hua,DuyH;Perchellet,Jean-Pierre
• 通讯作者: Perchellet,Jean-Pierre