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Total synthesis of tamandarin and didemnin analogs for development of cancer therapeutics and immunosuppressive therapies
Preparation of macrocyclic derivatives of tamandarin and evaluation of biological activity
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.
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 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.
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
Antitumor and antiviral compounds
Enhancer of apoptosis
Inhibitors of protein synthesis and cell growth
Stage of Development:
In vitro biological activity data and proof-of-concept
Adrio J. et al.
J. Org. Chem.
, 2007, 72, p. 5129-5138.
Adrio J. et al.
2006, 8, p. 511-514.
Docket # M2162, N2523, Q3249
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Licensing Officer, SEAS/SAS Licensing Group
University of Pennsylvania
Chemical Processes and Synthesis
Therapeutics & Vaccines
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