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.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Method to Extend Research in Time (MERIT) Award (R37)
Project #
5R37CA028824-27
Application #
6835114
Study Section
Medicinal Chemistry Study Section (MCHA)
Program Officer
Lees, Robert G
Project Start
1980-03-01
Project End
2006-12-31
Budget Start
2005-01-13
Budget End
2005-12-31
Support Year
27
Fiscal Year
2005
Total Cost
$634,010
Indirect Cost
Name
Sloan-Kettering Institute for Cancer Research
Department
Type
DUNS #
064931884
City
New York
State
NY
Country
United States
Zip Code
10065
Wilson, Rebecca M; Danishefsky, Samuel J (2013) A vision for vaccines built from fully synthetic tumor-associated antigens: from the laboratory to the clinic. J Am Chem Soc 135:14462-72
Wang, Ping; Dong, Suwei; Brailsford, John A et al. (2012) At last: erythropoietin as a single glycoform. Angew Chem Int Ed Engl 51:11576-84
Brailsford, John A; Danishefsky, Samuel J (2012) Probing the stability of nonglycosylated wild-type erythropoietin protein via reiterative alanine ligations. Proc Natl Acad Sci U S A 109:7196-201
Wu, Xiangyang; Stockdill, Jennifer L; Park, Peter K et al. (2012) Expanding the limits of isonitrile-mediated amidations: on the remarkable stereosubtleties of macrolactam formation from synthetic seco-cyclosporins. J Am Chem Soc 134:2378-84
Townsend, Steven D; Tan, Zhongping; Dong, Suwei et al. (2012) Advances in proline ligation. J Am Chem Soc 134:3912-6
Wilson, Rebecca M; Stockdill, Jennifer L; Wu, Xiangyang et al. (2012) A fascinating journey into history: exploration of the world of isonitriles en route to complex amides. Angew Chem Int Ed Engl 51:2834-48
Wu, Xiangyang; Park, Peter K; Danishefsky, Samuel J (2011) On the synthesis of conformationally modified peptides through isonitrile chemistry: implications for dealing with polypeptide aggregation. J Am Chem Soc 133:7700-3
Shang, Shiying; Tan, Zhongping; Danishefsky, Samuel J (2011) Application of the logic of cysteine-free native chemical ligation to the synthesis of Human Parathyroid Hormone (hPTH). Proc Natl Acad Sci U S A 108:5986-9
Tan, Zhongping; Shang, Shiying; Danishefsky, Samuel J (2011) Rational development of a strategy for modifying the aggregatibility of proteins. Proc Natl Acad Sci U S A 108:4297-302
Shang, Shiying; Tan, Zhongping; Dong, Suwei et al. (2011) An advance in proline ligation. J Am Chem Soc 133:10784-6

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