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Total synthesis of tamandarin and didemnin analogs for development of cancer therapeutics and immunosuppressive therapies

Description:

Preparation of macrocyclic derivatives of tamandarin and evaluation of biological activity

 

Inventor

Madeleine M. Joullié, Professor of Chemistry

 

Problem

Plants and marine organisms have become excellent sources of novel compounds that can be used therapeutically in humans.  Tamandarins and didemnins are cyclodepsipeptides that are natural products, harvested from marine organisms.  These molecules have been found to be potent immunosuppressants and inhibitors of tumor cell growth at nM and fM levels.  The unwanted side effects of didemnins, however, have limited their utility as therapeutics.  Importantly, it has been found that side chain modification of the didemnins can improve their efficacy at killing tumor cells and as immunosuppressants and simultaneously reduce negative side effects.

 

Solution

Researchers in the Joullié lab have developed a novel synthetic route to generate Tamandarin A and B in high yield that both eliminates the need to harvest the molecule from marine organisms and allows the production of a wide range of analogues that can be assayed for their utility as therapeutics.  A number of tamandarin analogues have been interrogated in high-throughput screens at the National Cancer Institute (NCI) for the ability to kill tumor cells, and several were found to be effective against breast, colon, non-small cell lung, and prostate cancer cell lines.  Initial mode of action studies have been performed for some compounds, and the results suggest that they achieve their cytotoxic effects by inhibiting protein synthesis.   

 

Advantages

•       Optimization of synthetic route

•       Production of gram quantities, as opposed to mg from natural sources

•       Range of derivatives and analogs

•       Fewer side effects and higher potency in vitro than Didemnin B

•       NCI testing indicates efficacy of tamandarin analogs against breast, colon, prostate, and non-small cell lung cancers

 

Applications

•       Antitumor and antiviral compounds

•       Immunosuppressive compounds

•       Enhancer of apoptosis

•       Inhibitors of protein synthesis and cell growth

 

 

Stage of Development

•       In vitro biological activity data and proof-of-concept

 

Intellectual Property

USSN 6,509,315

USSN 7,122,519

USSN 7,737,114

USSN 7,064,105

USSN 7,651,997

USSN 8,030,279

 

Reference Media

Adrio J. et al.  J. Org. Chem., 2007, 72, p. 5129-5138.

Adrio J. et al.  Org. Lett., 2006, 8, p. 511-514.

 

Desired partnerships

License

Co-development

 

 

Download PDF

 

Docket #  M2162, N2523, Q3249 


Patent Information:
For Information, Contact:
Pamela Beatrice
Director, SEAS/SAS Licensing Group
University of Pennsylvania
215-573-4513
beatricp@upenn.edu
Inventors:
Madeleine Joullie
Keywords: