ONCOGENE DIRECTED SYNTHESIS OF CEPHALOSTATIN CANCER DRUG

癌基因定向合成抗癌药物头孢他汀

• 批准号: 6456877
• 负责人: PHILIP L FUCHS
• 金额: $ 6.49万
• 依托单位: PURDUE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1996
• 资助国家: 美国
• 起止时间: 1996-08-09 至 2005-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6456877
• 关键词: affinity labeling; antineoplastics; drug design /synthesis /production; folate; geranyl compound; nucleobase analog; oncogenes; pyrazines; steroid analog; steroid biosynthesis; vinyl ether

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.

描述：（主要研究者的摘要）本提案有七个 药用/生物学目标：（1）合成多达7个北1和南1 “略微简化的”六环甾体螺缩酮亚基。转换这些 南-吡嗪-北十三环吡嗪类化合物 用我们的方法合成了不对称吡嗪，并比较了它们 抗肿瘤活性与头孢菌素1（1.2nM avg. NCI面板）。(2)研究 通过测试中心芳烃部分对抗癌活性的贡献 对不对称的环状吡啶衍生自最好的简化 六环甾体亚基。(3)构造并评估一个 设计了一种新的称为头孢菌素的跨部门药物， 评估所述香叶基香叶基部分是否为识别元件。（四） 制备并测试新试剂与叶酸的共价缀合物， 测定用于治疗约40 过量表达（10的4次方）叶酸的癌症的百分比 受体的(5)使用来自拟定新制剂试验的生物学数据 材料，以完成最小药效团的映射 头孢菌素类抗肿瘤药。(6)确定生物学机制 （7）制备2-5g所述物质， 其最佳地结合了高活性和适宜的合成，以提供一组 新的生物工具以及产生足够的试剂来启动临床 审判 七个六环螺缩酮的合成预计需要9-16 手术（相比之下，我们的“第一代”手术为29-31例 合成）。为了实现医学/生物学目标，高效的新 化学是必需的。(A)利用活跃的交互式计算 不断评估合成方法和生物试验的方法 数据(B)一种新的三氟甲磺酸锍试剂的立体专一性试验 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 自我毁灭性的去保护(D)开发一种新型的非对称环 通过分子内aza-Horner反应从3-酮甾体衍生出吡啶环。 (E)南半球的产生需要羟基化 在甾体CD环连接处的未活化的角甲基。这将 通过系统地探索以前的潜力来实现 未知的β-羟基酮的立体特异性差向重排， β-羟基内酯来完成这种转化。