Date Approved

2-9-2018

Embargo Period

2-9-2018

Document Type

Thesis

Degree Name

MS Pharmaceutical Sciences

Department

Chemistry and Biochemistry

College

College of Science & Mathematics

First Advisor

Moura-Letts, Gustavo

Second Advisor

Jonnalagadda, Subash

Third Advisor

Caputo, Gregory A.

Subject(s)

Organic compounds--Synthesis; Drug development

Disciplines

Chemistry | Pharmacy and Pharmaceutical Sciences

Abstract

Semi-synthetic compounds are an important part of the therapeutic drug discovery process. The goals of the project were to synthesize different generations of matrine analogues in order to gain many opportunities to manipulate the core structure. The long-term goal was, by manipulating the structure, the possibility to increase the biological activity of the original compound while also decreasing the toxicity. The first-generation matrine analogue allows for a synthesis similar to the Striker reaction producing aminonitriles. An alkyne coupling reaction was also possible with the modification, producing propargyl-amines. Both of the reactions resulted in the addition of a triple bond substituent to the final products; increasing complexity and making the products not easily metabolized in the body, therefore able reach the target of interest. The second-generation matrine derivative was reacted with epoxides to produce amino alcohols. Aminonitriles, propargyl-amines, and amino alcohols are known to be backbones of therapeutic drug compounds. The compounds synthesized were later experimented on chronic myeloid leukemia (CML) cells, also in combination with the manufactured drug Imatinib, in order to inhibit the BCR-ABL kinase activity in the CML cell lines E255K and T315I.

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