This proposal weaves together three themes with a view toward producing modalities of value in regards to cancer. The first is that synthetic organic chemistry has made major advances, such as to render it a usable resource in the discovery of new modalities in medicine. The second theme is that a class of structurally diverse, biologically active molecules, in most cases with respect to cancer targets, known as SMNPs (small molecule natural products), have a remarkable record in producing new drugs. This may take the form of SMNPs themselves, chemical derivatives of SMNPs, or synthetic intermediates derived through the process of molecular editing. The third notion is that synthesis has reached the stage where biologicals, including oligosaccharides and glycopeptides of high complexity and value, can be assembled in the laboratory. The proposal is divided into 11 programs. Eight use SMNPs as springboard for new discoveries in therapy. Three others are focused on synthetic biologicals which are directed to immune system targets - one against HIV and two against prostate cancer, either via improved prospects for diagnosis or as a means of creating a prostate cancer-directed vaccine. The SMNP-based programs center around: (1) Migrastatin, which finds potentially critical application against tumor metastasis. We have found, through a sequence of synthesis, diverted total synthesis, and molecular editing, a series of simplified migrastatins that virtually block colonization of primary tumors to other target organs;(2) Maoecrystal, a complex terpenoid-like structure which is about 50 times more potent against certain cancer cell lines than cis-platin;(3) Cortistatin, a potent anti-angiogenesis agent of complex molecular architecture;(4) Platensimycin, a gram-positive antibacterial, whose target is cell wall biosynthesis;(5) Aplykurodinone, a stereochemically challenging terpene-like structure, and a member of a family of cytotoxic agents;(6) Hyperforin, a complex polyprenyloid which induces apoptosis in cancer cells;(7) Actinophyllic Acid, an alkaloidal submicromolar inhibitor of carboxypeptidases;and (8) Piperazimycin, a complex depsipeptide, containing two difficultly installable piperazic acids, which is active against a panel of cancer cell lines at 100 nM. In addition, three programs will be directed to the synthesis of biological level molecules. Program 9 contemplates an anti-HIV vaccine based on the carbohydrate sector of the gp120 antigen. Program 10 involves assembling a PSA-based construct using the very complex carbohydrate domain to differentiate between highly aggressive and less aggressive prostate cancers, thereby providing additional calibration of conventional PSA readings. Program 11 entails the synthesis and evaluation of a complex vaccine against prostate cancer, based on the membrane-localized PSMA. In summary, we foresee a program which integrates chemistry, cell biology, immunology, and development for chemical evaluation with a view to advancing synthesis and medicine.

Public Health Relevance

The proposal brings to bear the resources of target directed organic synthesis to create complex molecular entities with opportunities for translation to medicine, particularly in the context of cancer and HIV.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA103823-32
Application #
7864113
Study Section
Synthetic and Biological Chemistry A Study Section (SBCA)
Program Officer
Lees, Robert G
Project Start
1980-03-01
Project End
2012-05-31
Budget Start
2010-06-01
Budget End
2011-05-31
Support Year
32
Fiscal Year
2010
Total Cost
$904,868
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
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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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