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Phorboxazole compounds as potent anti-tumor agents

Description:

 

Problem: Phorboxazoles are naturally occurring compounds that have been isolated from the marine sponge Phorbas, endemic to the western coast of Australia.  Previous screens of phorboxazoles against the National Cancer Institute human cell line panel indicated the most potent cytotoxicity assayed.  While the mechanism of action in vivo is unknown, phorboxazole arrests the cell cycle at S phase without interfering with microtubule stability.  Because of the antimitotic bioactivity, structural complexity, and extreme natural scarcity of the compound, efforts have been underway for the total synthesis of this natural product.

 

Solution: Researchers in the Smith lab in the Department of Chemistry have completed the total synthesis of phorboxazole compounds and derivatives.  The Petasis-Ferrier rearrangement was utilized to construct two tetrahydropyran rings in the phorboxazole macrolide ring, along with an extension of the Julia olefination and application of a novel bifunctional oxazole linchpin.  This sequence gave an overall yield of 3-6% in a stereocontrolled, highly convergent Stille coupling to unite the macrocycle with the sidechain.  Structure-activity relationship studies on phorboxazole analogs and initial biological screening in leukemia, breast cancer, and brain tumor cell lines have demonstrated extremely potent anticancer activity.

 

 

Advantages:

·         Anti-proliferative activity

·         Antifungal and antibiotic activity

·         Synthetic scheme does not rely on use of restricted marine sponge

·         High yield and stereoselectivity compared to previously demonstrated synthesis of phorboxazoles

 

Applications:

·         Potential pharmaceuticals and therapeutics for cancer, inhibiting cancer cell division or inducing apoptosis in malignant cells

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Stage of Development:

·         Proof-of-principle and in vitro testing

 

Intellectual Property:

USSN 7,485,631

 

 

 

 

Reference Media:

Smith AB et al.  Tetrahedron, 2011, 67, p. 5069-5078.

Smith AB et al.  J. Org. Chem., 2008, 73, p. 1201-1208.

Smith AB et al.  J. Org. Chem., 2008, 73, p. 1192-1200.

Smith AB et al.  Org. Lett., 2006, 8, p. 797-799.

Smith AB et al.  JACS, 2001, 123, p. 10942-10953.

Smith AB et al.  JACS, 2001, 123, p. 4834-4836.

 

 

Desired Partnerships:

1.    License

2.    Co-development

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TLO:

            Sarah Johnson

            johnsa@upenn.edu

            215-746-7253

 

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Patent Information:
For Information, Contact:
Joshua Jeanson
Associate Director, SEAS/SAS Licensing Group
University of Pennsylvania
jeanson@upenn.edu
Inventors:
Amos Smith
Keywords:
Cancer