NOVEL APPROACHES TO ANTITUMOR AND ANTIVIRAL AGENTS

抗肿瘤和抗病毒药物的治疗重要性需要 继续努力定义更好的综合战略。选择 以生物活性著称的一类化合物作为靶标，这 该项目开发了新的化学原理，可能演变为 创造这样的分子结构的前所未有的策略。 利用手性钯催化剂的不对称诱导提供了许多 实现不对称诱导的方法。鉴别对映体 离开集团开启了核苷新范式的前景 由呋喃合成。探索多种构造类型 其中杂环碱、C-5侧链和2-和3- 可以变化的取代基将被检查以确定有效性 这一新概念的灵活性。实用的不对称合成 如AZT、DDI、DDDC、司他夫定、法扎拉滨、 秀多霉素、卡地霉素、奎宁、辛福金、多毒素和 菊花可能会导致这种结果。一种新的影响分子的方法 相关抗肿瘤药物星形孢菌素需要认可 和K252a可以得到这些化合物的简单合成。 考虑到前手性烯丙基酯的络合概念 提供了一种合成吲哚生物碱的策略 抗病毒药物优地沙星E以亲核型为基础 可以用在这样的合成中，提出了形成 具有不寻常氨基酸的环肽可以利用 如抗肿瘤药物所示的大环化的效率， 滑膜结合蛋白。 创造了一系列新的反应，源于 金属催化的分子间和分子内加成反应导致 几个新的战略见解。基于Ru催化的烯型化合物 反应，逆合成分析了越来越多的一类 高活性试剂，乙酰基元，可以在一个高度 收敛、高效、简约的时尚。AN的环异构化反应 使用Pd或Ru的烯类型提供了一种常见的 发现以皂苷内酯为代表的结构。展期 烷基化烯炔环化的概念为非常 表鬼臼毒素的短合成。机械方面的考虑导致 到另一个维度的创造--一种烯--分解 为新型桥式双环抗肿瘤药物创造机会 以玫瑰红素为代表，更重要的是紫杉醇。一种新型的 涉及末端炔的金属催化加成反应导致 创建核苷的不同范式--以griseolic为例 酸。榄香烯类抗肿瘤药物的高灵敏功能 就像三重命名法A和B一样，A和B成为这种 方法论。合成方法的真正勇气是无法判断的 直到它在“战场”--一个复杂的合成靶子--进行测试。 抗肿瘤和抗病毒药物所带来的挑战的多样性 代理代表着对其使用的高度有意义的测试。同样 重要的、新的途径来改变这些核心周围的结构 建立结构-活动关系，目的是创造更好的 治疗剂变得可用。

The therapeutic importance of antitumor and antiviral agents requires a continued effort to define better synthetic strategies. Choosing classes of compounds known for their biological activity as targets, this project develops new chemical principles that may evolve into unprecedented strategies for creating such molecular architectures. Asymmetric induction utilizing a chiral Pd catalyst offers a number of ways to effect asymmetric induction. Differentiating enantiotopic leaving groups opens the prospect of a new paradigm for nucleoside synthesis from furan. Exploration of a variety of structural types wherein the heterocyclic base, the C-5 side chain, and the 2- and 3- substituents can be varied will be examined to establish the validity and flexibility of this new concept. Practical asymmetric syntheses of such diverse systems as AZT, DDI, DDDC, stavudine, fazarabine, showdomycin, cadequomycin, queuosine, sinefugin, polyoxins, and chryscandin may result. A novel way to effect the molecular recognition required for the related antitumor agents staurosporine and K252a can result in simple syntheses of these compounds. Considering the concept of complexation of prochiral allyl esters can provide a strategy for the synthesis of indole alkaloids represented by the antiviral agent eudistomin E. Building upon the type to nuclephile that can be used in such a synthesis, suggests a new thrust for forming cyclic peptides possessing unusual amino acids to capitalize on the efficiency of macrocyclizations as illustrated by the antitumor agents, the glidobactins. Creation of a family of new reactions derived from the concept of metal catalyzed inter- and intramolecular addition reactions leads to several new strategic insights. Based upon a Ru catalyzed ene type reaction, retrosynthetic analysis of a number of a growing class of highly active agents, the acetogenins, may be broached in a highly convergent, efficient and simple fashion. A cycloisomerization of an ene type using either Pd or Ru provides an approach to a commonly found structure as represented by the saponaceolides. Extension of the concept to an alkylative enyne cyclization sets the stage for a very short synthesis of epipodophyllotoxin. Mechanistic considerations led to the creation of another dimension-an enyne metathesis-which creates opportunities to the novel bridge bicyclic antitumor agents represented by roseophilin and, more significantly, taxol. A new type of metal catalyzed additions involving terminal alkynes leads to a different paradigm for creation of nucleosides as illustrated by griseolic acids. The highly sensitive functionality of ynediene antitumor agents like tricholomenym A and B become natural targets for such methodology. The true mettle of synthetic methods cannot be judged until it is tested in "the field of battle"-a complex synthesis target. The diversity of the challenges posed by the antitumor and antiviral agents represent highly meaningful tests of their use. Equally important, new avenues to vary structure around these cores in order to establish structure-activity relationships with the aim to create better therapeutic agents become available.