ONCOGENE DIRECTED SYNTHESIS OF CEPHALOSTATIN CANCER DRUG

描述：（主要研究者的摘要）该提案有七个 医学/生物学目标：(1) 合成最多七个 North 1 和 South 1 “稍微简化”的六环甾体螺缩酮亚基。转换这些 原料南--吡嗪--北十三环（十三环）吡嗪 使用我们的方法进行不对称吡嗪合成并比较它们 头孢菌素 1 的抗癌活性（平均 1.2nM。NCI 组）。 (2) 研究 通过测试发现中心芳烃部分对抗癌活性的贡献 衍生自最佳简化的不对称环状吡啶对 六环类固醇亚基。 (3) 构建并评估一个成员 设计了称为头孢呋辛的新型叶间药物 评估香叶基香叶基部分是否是识别元件。 (4) 制备并测试新药物与叶酸的共价结合物 测定增强（靶向）活性以治疗约 40 叶酸过度表达（十的四次方）的癌症百分比 受体。 (5) 使用拟议新产品测试中的生物学数据 材料来完成最小药效团的绘制 头孢他汀类抗肿瘤药。 (6)确定生物学机制 三十环吡嗪的作用； (7)准备2-5g该材料 它最好地将高活性与方便的合成结合起来，提供一组 新的生物工具以及产生足够的药物来启动临床 试验。 七种六环螺缩酮的合成预计需要 9-16 操作（与我们的“第一代”中的 29-31 个操作相比） 合成）。为了实现医学/生物学目标，高效的新 需要化学。 (A) 利用强有力的交互式计算 不断评估合成方法和生物测试的方法 数据。 (B) 测试新型硅氧基锍三氟甲磺酸盐试剂以实现立体定向 乙烯基醚的烯丙基氧化。 (C) 调查结果 用于化学特异性离子对的邻甲硫基苯基二甲基甲硅烷基醚 自焚脱保护。 (D) 开发一种新的不对称环化 通过分子内氮杂霍纳反应从 3-酮类固醇生成吡啶环。 (E) 南半球的生成需要羟基化 类固醇 CD 环连接处未激活的角甲基。这将 通过系统地探索先前的潜力来完成 β-羟基酮的未知立体特异性二异重排和 β-羟基内酯来完成这种转变。

DESCRIPTION: (Principal Investigator's Abstract) This proposal has seven medicinal/biological goals: (1) Synthesize up to seven North 1 and South 1 'slightly simplified' hexacyclic steroidal spiroketal subunits. Convert these materials to South--pyrazine--North trisdecacyclic (thirteen rings) pyrazines using our method for unsymmetrical pyrazine synthesis and compare their anticancer activity to cephalostain 1 (1.2nM avg. NCI panel). (2) Study the contribution of the central arene moiety to anticancer activity by testing pairs of unsymmetrical annulated pyridines derived from the best simplified hexacyclic steroidal subunits. (3) Construct and evaluate one member of a designed new class of inter-phylal agents termed the cephalofurthins to evaluate whether the geranyl geranyl moiety is a recognition element. (4) Prepare and test covalent conjugates of the new agent(s) with folic acid to assay for enhanced (targeted) activity for the treatment of the around 40 percent of cancers which over-express (ten to the 4th power) the folate receptor. (5) Use the biological data from testing of the proposed new materials to complete the mapping of the minimum pharmacophore for the cephalostatin class of antieoplastics. (6) Determine the biological mechanism of action of the trisdecacyclic pyrazines; and (7) Prepare 2-5g of the material which best combines high activity with expedient synthesis to provide a set of new biological tools as well as generating enough agent to initiate clinical trials. Synthesis of the seven hexacyclic spiroketals are projected to require 9-16 operations (compared with 29-31 operations in our 'first generation' synthesis). To accomplish the medicinal/biological goals, efficient new chemistry is required. (A) Utilize a vigorous interactive calculational approach to constantly evaluate synthetic approaches and biological testing data. (B) Test a new siloxysulfonium triflate reagent to effect stereospecific allylic oxidation of a vinyl ether. (C) Investigate the resulting ortho-methylthiophenyldimethylsilyl ether for chemospecific ion-pair self-immolative deprotection. (D) Develop a new annulation of unsymmetrical pyridine rings from 3-ketosteroids via an intramolecular aza-Horner reaction. (E) Generation of the Southern hemispheres requires hydroxylation of the unactivated angular methyl group at the steroidal CD ring junction. This will be accomplished by systematic exploration of the potential of a previously unknown stereospecific dyatropic rearrangement of beta-hydroxyketones and beta-hydroxy lactones to accomplish this transformation.