Conformationally-Controlled Late-Stage Modifications for SAR Studies of the C-3-Glcp Moiety of Ipomoeassin F

<p>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. </p>

Name thesis:degree_name

Doctor of Philosophy in Chemistry (PhD)

Level thesis:degree_level

Dissertation

Year dc:date.available

2018

Author dc:creator

• Whisenhunt, Lucas

Advisor dc:contributor.advisor

• Shi, Wei

Contributors dc:contributor

• Stenken, Julie A.
• Thallapuranam, Suresh

• Ipomoea Squamosa
• Ipomoeassin F
• Natural Products Chemistry
• Resin Glycosides
• Structure-Activity Relationship
• Cancer Biology
• Cell Biology
• Medicinal-Pharmaceutical Chemistry
• Organic Chemistry

Repository record dc:identifier

https://scholarworks.uark.edu/etd/2926

OAI identifier oai:identifier

oai:scholarworks.uark.edu:etd-4475