Date of Completion

8-21-2015

Embargo Period

8-21-2015

Major Advisor

Dr. Mark W. Peczuh

Associate Advisor

Dr. Xudong Yao

Associate Advisor

Dr. Alfredo Angeles-Boza

Field of Study

Chemistry

Degree

Doctor of Philosophy

Open Access

Open Access

Abstract

The overall structure of macrocycles is intimately linked to its biological activities and chemical reactivities. Delineating the factors that control the macrocycle structure will be very useful in developing novel probes, therapeutics and chemical transformations. Using a systematic strategy with the [13]-macrodilactones as model system and a combinational of X-ray crystallography and computational methods, a general model that explains the effect of stereogenic elements (stereogenic centers and stereogenic plane) on the overall structure (planar chirality, shape and topology) of the [13]-macrodilactone was constructed. A specific geometrical arrangement in the stereogenic centers set the planar chirality (either pS or pR), shape (either ribbon or alternate) and consequently, the overall topology of substituted [13]-macrodilactones. This specific geometrical arrangement is fundamentally governed by the preference of the substituents to be in pseudo-equatorial position. The general model constructed has useful implications in synthesizing macrocycles with designed structural properties and in optimizing the biological and pharmacological activities of bioactive macrocycles.

The cardiac glycosides ouabain and digitoxin, established Na+/K+ ATPase inhibitors, were found to inhibit MDA-MB-231 breast cancer cell migration through an unbiased chemical genetics screen for cell motility. The Na+/K+ ATPase acts both as an ion-transporter and as a receptor for cardiac glycosides. To delineate which function is related to breast cancer cell migration, structure–activity relationship (SAR) profiles of cardiac glycosides were established at the cellular (cell migration inhibition), molecular (Na+/K+ ATPase inhibition), and atomic (computational docking) levels. Correlation of SAR profiles across these assays established links between cellular activity and specific protein–small molecule interactions. The antimigratory effect in MDA-MB-231 breast cancer cells are directly related to the inhibition of Na+/K+ transport. Specifically, the orientation of cardiac glycosides at the putative cation permeation path correlates with the Na+ pump activity and cell migration. Other Na+/K+ ATPase inhibitors that are structurally distinct from cardiac glycosides also exhibit antimigratory activity, corroborating the conclusion that the antiport function of Na+/K+ ATPase and not the receptor function is important for supporting the motility of MDA-MB-231 breast cancer cells. Correlative SAR can establish new relationships between specific biochemical functions and higher-level cellular processes.

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