Aromatic Neplanocin Analogues for Cancer Chemotherapy

在美国，癌症是仅次于心脏病的主要死因，每年造成超过50万人死亡。在目前的治疗方法中，三分之一的患者通过局部手术或放射治疗治愈;然而，在其余病例中，需要全身化疗。目前，化学疗法为许多形式的癌症提供姑息疗法而不是治愈疗法，导致癌症症状和体征的暂时清除。因此，迫切需要开发用于治疗癌症的更新的更有效和毒性更小的化学治疗类药物。几种抗生素如阿霉素、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/或用作设计新化合物的“先导结构”。我们发现新的结构“线索”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性质导致其有效的抗癌活性。例如，在抗生素neplanocin A中，在其碳环部分中存在策略性放置的双键（π电子云）是对其有效的抗肿瘤活性重要的结构特征。使用neplanocin作为“前导结构”，我们提出设计新的芳香族碳环neplanocin类似物，其中neplanocin 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，以模拟和加强所需的电子性质，从而更强地结合靶和非靶大分子，以改善药物的治疗作用。为了验证这一假设，我们建议进行以下研究：a）设计和合成一系列合理的 取代的芳香族奈普拉霉素A类似物，c）在国家癌症研究所评估它们的体外抗癌活性，和c）进行DNA结合研究以建立它们的作用机制。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。本项目所获得的信息不仅在确定这类新化合物的构效关系（SAR）方面有价值，而且还可能导致开发新的有效的和选择性的抗癌药物。

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.