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50多万人死亡。在目前的治疗方法下，这些患者中有三分之一是通过局部手术或放射治疗治愈的；但在其余病例中，需要进行全身化疗。目前，化疗对许多形式的癌症提供的是姑息性治疗，而不是根治性治疗，从而暂时消除癌症的症状和体征。因此，迫切需要开发更新、更有效、毒性更低的化疗药物来治疗癌症。几种抗生素，如阿霉素、丝裂霉素、虫草素、五抑素和奈普诺星，已被用作抗癌药物和/或作为新化合物设计的“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使其具有很强的抗癌活性。例如，在抗生素neplan ocin A中，其碳环部分存在一个具有战略意义的双键(pi电子云)，这是其有效抗肿瘤活性的重要结构特征。以奈普罗星为“先导结构”，我们建议设计新的芳香族碳环奈普诺菌素类似物，其中奈普诺菌素A的环戊烯碳环被合理取代的双键富芳环(pi电子云丰富)取代，以模拟和加强所需的电子性质，从而更强地与靶和非靶向大分子结合，从而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)设计和综合一系列合理的 取代的芳香族奈普罗星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个具有抗癌特性的化合物。在这个项目中获得的信息不仅对确定这类新化合物的结构-活性-关系(SAR)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。

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.