Aromatic Neplanocin Analogues for Cancer Chemotherapy

用于癌症化疗的芳香族奈普兰菌素类似物

• 批准号: 6727045
• 负责人: Shashikant K Phadtare
• 金额: $ 11.14万
• 依托单位: XAVIER UNIVERSITY OF LOUISIANA
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-04-01 至 2008-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6727045
• 关键词: antineoplastic antibiotics; cell line; chemical synthesis; cytoprotection; drug design /synthesis /production; drug screening /evaluation; enzyme inhibitors; esters; neoplasm /cancer chemotherapy; nucleoside analog; pharmacokinetics; prodrugs; thiophosphate

Next to the heart disease, cancer is the major cause of death in the USA, causing over 500,000 fatalities annually. With present methods of treatment, one-third of these patients are cured with local surgery or radiation therapy; however, in the remaining cases a systemic approach of chemotherapy is required. At present, chemotherapy provides palliative rather than curative therapy for many forms of cancer resulting in temporary clearing of the symptoms and signs of cancer. Therefore, there is a critical need for the development of newer more potent and less toxic chemotherapeutic classes of drugs for the treatment of cancer. Several antibiotics such as doxorubicin, mitomycin, cordycepin, pentostatin and neplanocin, have been used as anticancer agents and/or as "lead structures" for the design of new compounds. Our approach to uncover new structural "leads" is to explore these antibiotics, especially nucleoside analogues, wherein the unique electronic properties in their chemical structure has resulted in their potent anticancer activity. For example in antibiotic neplanocin A, presence of a strategically placed double bond (pi electron cloud) in its carbocycle moiety is a structural feature important for its potent antitumnor activity. Using neplanocin as the "lead structure", we propose to design new aromatic carbocyclic neplanocin analogues wherein the cyclopentene carbocycle of neplanocin A is replaced with a rationally substituted double bond rich aryl ring (pi electron cloud rich) to mimic and strenghthen the required electronic properties for stronger binding to both target and nontarget macromolecules for improved therapeutic actions of the drug. To test this hypothesis, we propose to conduct the following studies: a) design and synthesize a series of rationally substituted aromatic neplanocin A analogues, c) evaluate them for in-vitro anticancer activity at the National Cancer Institute, and c) conduct the DNA binding studies to establish their mechanism of action. Preliminary studies on some designs proposed in this project have already yielded several compounds with anticancer properties. The information gained in this project will be valuable not only in determining the structure-activity-relationship (SAR) of this new class of compounds, but may also result in the development of new potent and selctive anticancer agents.

癌症是美国仅次于心脏病的第二大死因，每年造成超过 50 万人死亡。根据目前的治疗方法，三分之一的患者可以通过局部手术或放射治疗治愈；然而，在其余情况下，需要采用全身化疗方法。目前，化疗为许多形式的癌症提供姑息性而非治愈性治疗，从而暂时消除癌症的症状和体征。因此，迫切需要开发更新的更有效且毒性更小的化疗药物来治疗癌症。几种抗生素，例如阿霉素、丝裂霉素、虫草素、喷司他丁和奈普拉诺星，已被用作抗癌剂和/或作为新化合物设计的“先导结构”。我们发现新结构“先导”的方法是探索这些抗生素，特别是核苷类似物，其中 其化学结构中独特的电子特性使其具有强大的抗癌活性。例如，在抗生素 neplanocin A 中，其碳环部分中战略性放置的双键（π 电子云）的存在是对其有效抗肿瘤活性非常重要的结构特征。使用奈普拉菌素作为“先导结构”，我们建议设计新的芳香族碳环奈普拉菌素类似物，其中奈普拉菌素A的环戊烯碳环被合理取代的富含双键的芳环（富含π电子云）取代，以模拟和增强所需的电子特性，以更强地结合目标和非目标大分子 改善药物的治疗作用。为了检验这一假设，我们建议进行以下研究：a）设计并综合一系列合理的 取代的芳香族奈普兰菌素 A 类似物，c) 在国家癌症研究所评估它们的体外抗癌活性，以及​​ c) 进行 DNA 结合研究以确定其作用机制。对该项目中提出的一些设计的初步研究已经产生了几种具有抗癌特性的化合物。该项目中获得的信息不仅对于确定此类新型化合物的结构活性关系（SAR）很有价值，而且还可能导致新的有效和选择性抗癌药物的开发。