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Design and Conformational Analysis of Structurally-Related Analogues of Polyketide Natural Products

thesis
posted on 2016-10-06, 00:00 authored by Erik Matthew Larsen

The conformation of a small molecule is crucial to its biological activity, as ideal binding requires both ligand and protein to spatially complement one another. This is particularly important when considering compounds such as the polyketide class of bioactive natural products, in which evolution has included a wide variety of structural features designed to limit local conformational preferences. As such, these molecules, particularly the macrocyclic varieties, will adopt preferred low-energy conformations. We believe that understanding these preferences for a given polyketide is a necessary precursor to analogue design, as any modifications to the structure should be mindful of how conformation will be affected. As such, our research uses techniques based around high-field NMR and molecular modeling experiments to analyze polyketide conformational preferences.

Neopeltolide is a 14-membered marine polyketide natural product that has demonstrated considerable antifungal and anticancer potential. Our conformational analysis of its macrolide found that it adopts a single conformation in solution, which minimizes syn-pentane interactions between substituents at the C9, C11, and C13 positions. Further analyses found that C2 substitution should not affect this conformation, and a methyl group was attached synthetically to probe any potential biological effects. Additionally, a preliminary analysis was made of neopeltolide’s purported biological target, cytochrome bc1, for potential binding sites, which found a potentially new allosteric region that fits neopeltolide better than either of the known sites of inhibition.

Zampanolide and dactylolide are related 20-membered marine polyketides that exhibit considerable cytotoxicity against multiple human cancer cell lines and act as a microtubule stabilizing agents. Our research used material from a synthesis of dactylolide to elucidate its solution structure and conformational preferences. This work found that the shared macrolide interconverts between three major families in DMSO-d6, one of which bears considerable resemblance to the bound conformation of zampanolide. We used this work to design a simplified analogue that omits the C17 methyl and C13 exocyclic alkene, which possessed a considerably shortened synthetic route in comparison with the parent compound.

Finally, the misidentification of the bioactive conformation of the polyketide epothilone prompted us to investigate whether the notable structural elements that influence polyketide conformation could be affected by a solid state environment. This research involved searching the Cambridge Structural Database for a variety of features, including syn-pentane interactions, the gauche effect, allylic strain and others. Our results found that high-energy features relying on steric effects will be unaffected by crystal packing forces, while features reliant upon lower-energy stereoelectronic effects or hydrogen bonds were far more likely to be influenced.

History

Date Created

2016-10-06

Date Modified

2022-03-14

Defense Date

2016-09-05

Research Director(s)

Richard E. Taylor

Committee Members

Olaf G. Wiest Seth N. Brown

Degree

  • Doctor of Philosophy

Degree Level

  • Doctoral Dissertation

Alternate Identifier

961213694

Library Record

4471789

OCLC Number

961213694

Program Name

  • Chemistry and Biochemistry

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