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: 6633174
• 负责人: PHILIP L FUCHS
• 金额: $ 35.78万
• 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/6633174
• 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：（首席研究员摘要）本提案有七个部分