Natural feedstocks for diversity oriented synthesis

Promiliad Biopharma, Inc., Alberton MT

Investigators

Linked publications & trials

Abstract

DESCRIPTION (provided by applicant): This STTR application requests funds to support the transfer of specific synthetic expertise and methodologies from the Wright Group at Dartmouth College to investigators at Promiliad Biopharma in an effort to reduce Promiliad's REBACS strategy to the level of practice. These efforts will focus on the use of a high-complexity feedstock, nonactic acid, as the point of departure for diversity oriented synthesis. Nonracemic (+) and (-) nonactic acid will be produced at Promiliad through a process involving fermentation, recombinant biochemical and chemical technologies. Preparative amounts of these compounds will be provided to the Wright group for conversion to specific compounds that will be examined as new pharmaceutical leads at Promiliad. The main focus will relate to the synthesis of a new class of macrolides known as the nonactolides. These compound have been designed with the express purpose of mimicing the structure of the macrolide antibiotics in an attemp to identify new lead antibiotics that target the bacterial ribosome. First generation compounds will be prepared by the Dartmouth workers and provided to Promiliad for testing. A second, parallel effort, will focus on the conversion of nonactic acid to a new class of beta-turn mimetics known as ketide amino acids. These compounds are designed to mimic specific structural features common to bioactive peptides for use in peptidomimetic-based drug discovery. These compound will be similar to the currently employed sugar amino acids but offer specific advantages in cost effectiveness and synthetic flexibility. The final initiative in this proposal is to develop chemical methodoogies to amplify the diversity inherently present in nonactic acids. These basic studies will focus on methods to incorporate additional sites of reactive functionality into the natural scaffold. Integration of these diversity-expanded building blocks into the previously discussed designs will greatly increase the diversity and magnituted of the compound we will be able to use in our lead discovery program.