Date Approved

2-29-2024

Embargo Period

2-29-2024

Document Type

Dissertation

Degree Name

Doctor of Philosophy (Ph.D.) in Pharmaceutical Chemistry

Department

Chemistry and Biochemistry

College

College of Science & Mathematics

Advisor

Kandalam Ramanujachary, Ph.D.

Committee Member 1

Subash Jonnalagadda, Ph.D.

Committee Member 2

Manoj Pandey, Ph.D.

Committee Member 3

Amos Mugweru, Ph.D.

Committee Member 4

Samuel Lofland, Ph.D.

Keywords

Cancer;Medicinal Chemistry;Organic Chemistry;Pharmacology;Salinomycin;Salinomycin Derivatives

Subject(s)

Antineoplastic agents; Antibiotics

Disciplines

Medicinal-Pharmaceutical Chemistry

Abstract

Salinomycin is a poly-ionophore antibiotic that was originally isolated from Streptomyces albus by Miyazaki and colleagues from Kaken Chemicals Co., Ltd., Tokyo, Japan. Salinomycin exhibits antimicrobial activity against Gram-positive bacteria including Bacillus subtilis, Staphylococcus aureus, Micrococcus flavus, Sarcina lutea, Mycobacterium spp. Some filamentous fungi, Plasmodium falciparum, and Eimeria spp. as well as protozoan parasites responsible for the poultry disease coccidiosis. Hence, it is used in veterinary medicine. In 2009 Gupta et al demonstrated that salinomycin selectively killed human breast cancer stem cells (CSCs) with great efficacy, and the mechanism of action of this novel CSCs molecule was explored. To name a few mechanisms of action salinomycin possesses, it interferes with ABC transporters, inhibits the Wnt/β-catenin signaling pathway, inhibits oxidative phosphorylation, disrupts the cytoplasmic and mitochondrial K+ concentration via K+ efflux, and interferes with cancer stem cell differentiation. Based on the knowledge and previous literature of the anti-cancer activity of Salinomycin herein, a series of derivatives of Salinomycin were synthesized in the modification of the C1 carboxylic acid functional group by synthesizing various salinomycin-N, N’- diacylhydrazine, and salinomycin amide derivatives from amine substituted hydrazines, aromatic substituted hydrazines, substituted thiadiazoles, imidazoles, pyridines, and quinolone intermediates. Biological evaluation of these molecules was performed in vitro and in vivo and showed promising anti-cancer activity with two lead compounds identified with thiadiazole pharmacophores (SAL-032 and SAL-034). Salinomycin was also derivatized at the C20 position to synthesize ironomycin and derivatization of the thiadiazole analogs (SAL-032 and SAL-034) was performed with an oxidation of the C20 alcohol, followed by amination yielding the respective ironomycin derivatives (IRO-032 and IRO-034). C20-ironomycin triazole conjugates were synthesized employing the synthesis of ironomycin, Baylis-Hilman azido-cinnamamides, and Click Chemistry. The biological evaluation of these molecules is currently underway.

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