Date of Graduation

8-2018

Document Type

Dissertation

Degree Name

Doctor of Philosophy in Chemistry (PhD)

Degree Level

Graduate

Department

Chemistry & Biochemistry

Advisor/Mentor

Shi, Wei

Committee Member

Stenken, Julie A.

Second Committee Member

Thallapuranam, Suresh

Third Committee Member

Striegler, Susanne

Fourth Committee Member

Allison, Neil T.

Keywords

Ipomoea Squamosa; Ipomoeassin F; Natural Products Chemistry; Resin Glycosides; Structure-Activity Relationship

Abstract

The resin glycoside, ipomoeassin F has been shown to be extremely potent against multiple cancer lines (IC50 = 4.2-36 nM). However, the mechanism of action of this potent and complex natural product is still not fully understood. The α,β-unsaturated esters of the glucosyl moiety have been shown to be vital for the overall cytotoxicity of ipomoeassin F. Nevertheless, the importance of the tigloyl ester of the glucosyl moiety is still largely unknown. This work aimed to study the pharmacophore importance of the tigloyl ester by creating, an efficient, scalable, and flexible synthesis route for various analogs. The 18-linear step synthesis utilized multiple regio-selective and chemo-selective reactions, while not affecting the highly functionalized (1→2)-β-disaccharide moiety. The synthesis route modified the C-3 glucosyl position in the penultimate step, making medicinal chemistry studies of the tigloyl moiety possible. The late-stage conformationally-controlled highly regio-selective esterification allowed for the completion of ipomoeassin F and other tigloyl modified analogs. The in-house cytotoxicity data conveyed that large aromatic modifications greatly reduced the cytotoxicity against multiple cancer cell lines. The ipomoeassin F was submitted for NCI-60 cell line screening that showed good sensitivity against breast, renal, and melanoma cell lines (GI50 = ⁓30 nM). To determine the importance of α,β-methyl groups of tigloyl moiety, acrylic modifications were envisioned but were difficult to obtain using the developed synthesis route. Therefore, we believe the α,β-unsaturated double bond should be tri-substituted to effectively study the tigloyl moiety. This work advanced the scientific knowledge of an underexplored natural product with an unknown mechanism of action and unreached therapeutic potential.

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