The long term goals of our laboratory involve the achievement of advances in the capabilities in chemical synthesis and the applications of these advances to problems of biological and even medicinal import. At the chemistry level, we select novel and challenging small molecule natural products structures, which will serve to stimulate and exemplify the value of new strategies and new reaction methodologies. In this facet of our """"""""small molecule"""""""" work, we place particular emphasis on conciseness of approach, convergence, and stereocontrol. In parallel we have a program addressed to the chemical synthesis of complex oligosaccharides, in the context of polypeptide or protein like conjugates. In this effort, we place particular emphasis on novel glycosylation protocols and, seek out particular retrosynthetic disconnections and protection strategies which enable conciseness of the synthetic effort. In this program we seek to enlarge upon our capacity to build complex oligosaccharides into the context of substantial polypeptide or even protein settings. For this AI-16943-25-29 grant period, we have identified eight (8) programs for exploration: (1) migrastatin - as its name implies, this compound is reported to prevent tumor cell migration. As such, it might provide the basis for a significant drug candidate in angiogenesis; (2) brasilicardin - an immunosuppressive agent; (3) garsubellin - this compound is exemplary of a fascinating series of non-peptidal small molecules which exhibit neuronal growth factor activity; (4)tashironin - this compound is substantially dissimilar to garsubellin. It also exhibits non-peptidal NGF activity; (5) NG0187 - this compound is a polyoxygenated steroid-like system which also exhibits non-peptidal nerve growth factor activity; (6) Asparagine linked glycopolypeptide constructs which simulate the key structural features of PSA (prostate specific antigen); (7) the synthesis of constructs which simulate the key features of GP120. Aside from the chemical challenge, implicit in this goal is the hope to induce an antibody response which could be of value in progression of the evolution of AIDS disease; (8) A long term goal of the complex glycoconjugate program is the total synthesis of a functional erythropoietin (EPO). ? ?

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA103823-29
Application #
7238850
Study Section
Medicinal Chemistry Study Section (MCHA)
Program Officer
Lees, Robert G
Project Start
1980-03-01
Project End
2008-06-30
Budget Start
2007-06-01
Budget End
2008-06-30
Support Year
29
Fiscal Year
2007
Total Cost
$558,006
Indirect Cost
Name
Sloan-Kettering Institute for Cancer Research
Department
Type
DUNS #
064931884
City
New York
State
NY
Country
United States
Zip Code
10065
Fernández-Tejada, Alberto; Vadola, Paul A; Danishefsky, Samuel J (2014) Chemical synthesis of the ?-subunit of human luteinizing (hLH) and chorionic gonadotropin (hCG) glycoprotein hormones. J Am Chem Soc 136:8450-8
Wang, Ting; Danishefsky, Samuel J (2012) Revisiting oxytocin through the medium of isonitriles. J Am Chem Soc 134:13244-7
Walczak, Maciej A; Danishefsky, Samuel J (2012) Solving the convergence problem in the synthesis of triantennary N-glycan relevant to prostate-specific membrane antigen (PSMA). J Am Chem Soc 134:16430-3
Wang, Ping; Aussedat, Baptiste; Vohra, Yusufbhai et al. (2012) An advance in the chemical synthesis of homogeneous N-linked glycopolypeptides by convergent aspartylation. Angew Chem Int Ed Engl 51:11571-5
Dong, Suwei; Shang, Shiying; Li, Jianfeng et al. (2012) Engineering of therapeutic polypeptides through chemical synthesis: early lessons from human parathyroid hormone and analogues. J Am Chem Soc 134:15122-9
Nagorny, Pavel; Sane, Neeraj; Fasching, Bernhard et al. (2012) Probing the frontiers of glycoprotein synthesis: the fully elaborated ýý-subunit of the human follicle-stimulating hormone. Angew Chem Int Ed Engl 51:975-9
Aussedat, Baptiste; Fasching, Bernhard; Johnston, Eric et al. (2012) Total synthesis of the ýý-subunit of human glycoprotein hormones: toward fully synthetic homogeneous human follicle-stimulating hormone. J Am Chem Soc 134:3532-41
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
Wang, Ping; Li, Xuechen; Zhu, Jianglong et al. (2011) Encouraging progress in the ?-aspartylation of complex oligosaccharides as a general route to ?-N-linked glycopolypeptides. J Am Chem Soc 133:1597-602
Lecomte, Nicolas; Njardarson, Jon T; Nagorny, Pavel et al. (2011) Emergence of potent inhibitors of metastasis in lung cancer via syntheses based on migrastatin. Proc Natl Acad Sci U S A 108:15074-8

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