ONCOGENE DIRECTED SYNTHESIS OF CEPHALOSTATIN CANCER DRUG

描述：(首席调查员摘要)这项提案有七个 医学/生物学目标：(1)合成最多七个北一南一 “略微简化”的六环螺酮亚基。将这些转换为 南方的原料--吡嗪--北方的三环(十三环)吡嗪 使用我们的方法合成不对称吡嗪，并比较了它们的 头孢菌素1的抗癌活性(平均1.2 nM)NCI面板)。(2)研究 测试中心芳烃部分对抗癌活性的贡献 不对称环状吡啶对衍生自最佳简化 六环类固醇亚基。(3)构造和评估一个成员 设计了一类新的类间药物，称为头孢呋辛 评估香叶基香叶基部分是否为识别元件。(4) 新制剂(S)与叶酸的共价偶联物的制备和试验 治疗约40例患者的增强(靶向)活性的检测 叶酸过度表达(10次方为4次方)的癌症 受体。(5)使用拟议新项目测试中的生物数据 完成最低药效团测绘的材料 头孢他丁类抗肿瘤药物。(6)确定生物机制 以及(7)制备2-5g的材料 它最好地结合了高活性和便利的合成，提供了一套 新的生物工具以及产生足够的试剂来启动临床 审判。 七个六环螺酮的合成预计需要9-16个 运营(与我们第一代的29-31个运营相比) 综合)。为了实现医学/生物学目标，高效的新技术 化学是必修课。(A)利用充满活力的互动计算 不断评估合成方法和生物测试的方法 数据。(B)测试一种新的硅氧基三氟化硫试剂，以影响立体特异性 乙烯基醚的烯丙基氧化。(C)调查由此产生的 化学特异性离子对用邻甲基苯基二甲基硅基醚 自焚的自我保护。(D)开发一种新的不对称环形 通过分子内氮杂-霍纳反应从3-酮类固醇中得到吡啶环。 (E)南半球的产生需要羟化 甾体Cd环结处未活化的角甲基。这将是 是通过系统地探索以前的 β-羟基酮和β-羟基酮的立体特异性营养不良重排 β-羟基内酯来完成这一转化。

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.