NOVEL SMALL MOLECULES, GAMBOGIC ACID ANALOGUES, AS ANTICANCER AGENTS

CHALLENGE:
The Garcinia genus of tropical plants has yielded a structurally intriguing family of natural products that have interesting anticancer activities and a documented value in traditional Asian medicine.
Natural products of this family have been pursued as anticancer agents but are difficult to isolate and cannot be synthesized using existing methods.

SOLUTION/TECHNOLOGY DESCRIPTION:
Through a new method of synthesis, UCSD researchers have developed small molecules that maintain the basic structural motif and the biological proprieties of the more structurally complex natural products of this family (gambogic acid).
At low concentrations, these new natural analogues are inducers of apoptosis, activators of caspases, and inhibitors of cancer cell growth in a variety of tumor cell lines, including T-cell acute lymphoblastic leukemia (the most sensitive), promyelocitic leukemia, melanoma, colon, and lung cells.
In addition, these molecules are not affected by the mechanisms of multidrug resistance, typical of relapsed cancers and thus represent a new and potent pharmacophore.
Moreover, while the natural gambogic acid shows some toxicity, the new analog molecule developed by UCSD shows no significant toxicity in a mouse model.

BENEFITS:

• Potential cancer therapy that may be effective in the treatment of multidrug resistant cancers
• New chemical synthetic strategy to produce analogues to the anticancer natural product that until now could not be synthesized

FEATURES:

• Simplified analogues of the natural parent structures
• Anti cancer activity at low concentrations in solid and non-solid tumor cell lines
• No significant toxicity in mouse model

MARKET POTENTIAL/APPLICATIONS:
The compounds developed by UCSD may represent new anticancer molecules.

There are approximately 300,000 cases of leukemia in the world* and an estimated 44,240 new cases of leukemia have been diagnosed only in the United States in 2007**.

Moreover, the new molecules may have therapeutic potential in relapsed cancers typically resistant to standard chemotherapeutic agents.
The resistance of tumor cells to several unrelated drugs after exposure to a single chemotherapy drug (multidrug resistance) represents the single most important reason for therapeutic failure in the clinical management of cancer***.

*International Agency for Research on Cancer (IARC); **National Cancer Institute; ***Scitizen.

DEVELOPMENT STATUS:
The synthetic route to these compounds allows further optimization of the structures.

UCSD RESEARCHER:
Dr. Theodorakis is Professor of Chemistry at Department of Chemistry & Biochemistry at UCSD.

TECHNOLOGY-RELEVANT PAPERS AND WEB LINKS:
Batova A, Lam T, Wascholowski V, Yu AL, Giannis A, Theodorakis EA. Synthesis and evaluation of caged Garcinia xanthones. Org Biomol Chem. 2007 Feb 7; 5(3): 494-500.

Tisdale EJ, Slobodov I, Theodorakis EA. Unified synthesis of caged Garcinia natural products based on a site-selective Claisen/Diels-Alder/Claisen rearrangement. Proc Natl Acad Sci U S A. 2004 Aug 17; 101(33): 12030-5.

http://chem-faculty.ucsd.edu/theodorakis/

Key Words: cancer, anticancer agents, small molecule, drug development, drug resistance, MDR, synthesis, natural products, Garcinia, xanthone, gambogic acid.

Case No: SD2007-082

Inquiries To:  invent@ucsd.edu