Michael P. Pollastri
Frank G. Favaloro, Graham B. Jones
Date of Award
Master of Science
Department or Academic Unit
College of Science. Department of Chemistry and Chemical Biology.
chemistry, pharmaceutical sciences, aldehyde, diol, macrocycle, polyketide, reductive amination
Macrocyclic compounds - Synthesis
Chemistry | Pharmacy and Pharmaceutical Sciences
Ensemble Therapeutics, a biotechnology company in Cambridge, MA, bases its research on a new class of compounds known as Ensemblins. Ensemblins are synthetically engineered macrocycles that lie within the structural gap between small-molecule drugs and biological drugs. Ensemblins possess the biophysical properties of small-molecule drugs but the unique macrocyclic structure of Ensemblins allows for high levels of affinity and specificity for targets that are currently only addressable with biological drugs. Ensemble Therapeutics utilizes a technology known as DNA-programmed chemistry to efficiently synthesize large, diverse libraries of Ensemblins.
Constantly striving to further diversify their libraries, and using design features from naturally occurring macrocycles where possible, Ensemble's latest endeavor is inspired by Jasplakinolide, a natural product of the sea sponge Jaspis johnstoni. Jasplakinolide is cell permeable and induces apoptosis in a number of tumor cell lines, including those related to renal, prostate, and breast cancer. Ensemble Therapeutics finds Jasplakinolide interesting not only because it is a biologically-active natural product, but also because of its structure. Jasplakinolide is a macrocycle that it incorporates not only a peptidic region (a feature of all of Ensemblin libraries at Ensemble Therepeutics), but also a polyketide-derived region, which the company had yet to explore in its libraries.
The newest library at Ensemble Therapeutics, Ensemble Library E, incorporates a polyketide-derived region utilizing reductive amination, a novel chemistry for Ensemblin libraries. The production of a pilot library of ELE-type macrocycles simultaneously verifies the intended chemistry for the ELE library and optimizes the synthetic route for these macrocycles on solid-phase.
Snedeker, Cheri, "The synthesis of novel synthetic macrocycles containing both peptidic and polyketide-like domains" (2012). Chemistry Master's Theses. Paper 23. http://hdl.handle.net/2047/d20002533
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