Novel Avrainvillamide-like Compounds with Anti-proliferative Properties

Summary Avrainvillamide and stephacidin B, (a dimer of avrainvillamide) have been identified in culture media from various strains of the fungus Aspergillus. Both compounds demonstrate anti-proliferative activity, and avrainvillamide is reported to exhibit antimicrobial activity against multidrug-resistant bacteria. A common barrier to the use of avrainvillamide and stephacidin in the clinic is the inability to produce sufficient quantities of the compounds in bulk. This problem stems, in part, from the cost and manufacturing limitations required to generate appropriate clinical volume. An additional barrier to market has been the lack of a full understanding of the avrainvillamide and stephacidin mechanisms of action. They are believed to function as alkylating agents, but to date there has been no evidence explaining this action. In order to improve yield, cost, and efficacy, scientists must not only find novel synthetic routes to these compounds, but also decipher their specific antiproliferative properties.

Professor Andrew Myers has developed a novel and robust platform for synthesis of avrainvillamide, stephacidin B, key intermediates, and analogs. The compounds generated as a result of this synthetic platform include a novel 3-alkylidene-3H-indole 1-oxide functional group, which is capable of reversible covalent bond formation with heteroatom-based nucleophiles, such as nucleic acids. Functional groups, such as 3-alkylidene-3H-indole 1-oxides, that bond covalently to active-site nucleophiles frequently form the basis for the design of potent and selective enzyme inhibitors, which are especially valuable in pharmaceutical development.

Applications This synthetic platform is cost-efficient and yields significantly more avrainvillamide and stephacidin than by isolation methods from Aspergillus culture media. The generation of avrainvillamide and stephacidin analogs also limits chemical space and improves antiproliferative activity as compared to their bulky natural product counterparts. The 3-alkylidene-3H-indole 1-oxide functional group provides the first insight into the compounds modes of action; hence further studies can build and refine this chemistry into less toxic and more efficacious lead compounds.

Avrainvillamide and stephacidin analogs are lead compounds for treatment of cancer and multi-drug resistant bacteria. They may be used as pharmaceutical agents alone or as foundations in designing new pharmaceutical formulations. The synthetic machinery is in place to generate libraries of antiproliferative compounds for research and identification of biological pathways for potential targets..

Publications: Andrew G. Myers and Seth B. Herzon. Identification of a Novel Michael Acceptor Group for the Reversible Addition of Oxygen- and Sulfur-Based Nucleophiles.

Andrew G. Myers and Seth B. Herzon. Synthesis and Reactivity of the 3-Alkylidene-3H-indole 1-Oxide Function of Avrainvillamide., J. Am. Chem. Soc. 2003, 125, 12080.

Patent: Pending. For Further Information Please Contact the Director of Business Development Laura Brass Email: [email protected] Telephone: (617) 495-3067

Inventor(s): Myers, Andrew G

Type of Offer: Licensing



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