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Abstract
Grant Number: 2R37CA028824-24 Project Title: Synthesis of Antitumor Natural Products
PI Information: Name Title DANISHEFSKY, SAMUEL J. sjd15@columbia.edu Abstract: The mission of our laboratory is to serve as a resource for the advancement of organic synthesis directed to relatively complex targets. As we pursue these goals, the chemistry we develop is brought to bear on multidisciplinary problems with implications for human health. The ability of our laboratory to function in problems if this sort arises from its demonstrated capacity to attract chemists who are already well versed or anxious to become well versed in gaining the capability to deal with goal systems of considerable complexity. Our problem selection process focuses on natural product targets which carry considerable biological interest, and reflects our confidence that with appropriate imagination and persistence, the desired systems can be assembled in amounts suitable for studying their biological ramifications. We consider not only traditional phytochemical, microbial and coral metabolites, but also complex cell surface glycoconjugates (particularly glycopeptides and glycoprotein constructs) corresponding to tumor associated antigens. Our program for CA28824 24-28 will involve a large effort in fashioning and optimizing second and third generation carbohydrate based antitumor vaccines (project i). There is a particular urgency in pursuing these matters since Phase I studies conducted with fully synthetic single carbohydrate based antigens produced quite favorable serological results. We feel that it is now possible for us to obtain a glycoprotein by full chemical synthesis. This goal will involve merging the technology of N-(asparagine) linked glycopeptide synthesis with protein ligation (project ii). We also deal with important issues in the 12,13-desoxyepothilone area. Our goal is to use total synthesis to generate non-prodrug, water soluble epothilones. We will be drawing on our recently completed total synthesis of 12, 13-desoxyepothilone F (project iii). In addition, we will be seeking to accomplish the total synthesis of several interesting of several interesting natural products. These include pinnaic acid (a PLA2 inhibitor; project iv), radicicol (an Hsp-90 inhibitor; project v), merrilactone A (a non peptidal small molecule neurotrophic factor; project vi) spiroxin (a DNA cleaving agent; project vii) and TMC-95A (which targets proteosomal proteolysis; project viii). In summary, our projected program will feature issues in organic synthesis at the perimeter of feasibility. These efforts will be linked to questions of significant biological concern, particularly in the anticancer field.
Public Health Relevance:
This Public Health Relevance is not available.Thesaurus Terms:
antineoplastic, drug design /synthesis /production
asparagine, enzyme inhibitor, glycoprotein, heat shock protein, neurotrophic factor, phospholipase A2, synthetic tumor antigen
chemical synthesis
Institution: SLOAN-KETTERING INSTITUTE FOR CANCER RES 1275 YORK AVE NEW YORK, NY 10065 Fiscal Year: 2002 Department: Project Start: 01-MAR-1980 Project End: 31-DEC-2006 ICD: NATIONAL CANCER INSTITUTE IRG: MCHA