Year of Award

2013

Document Type

Thesis

Degree Type

Master of Science (MS)

Degree Name

Medicinal Chemistry

Department or School/College

Department of Biomedical and Pharmaceutical Sciences

Committee Chair

Nicholas R. Natale

Commitee Members

Howard D. Beall, Kent D. Sugden

Keywords

1, 3-dipolar cycloaddition, g4, isoxazole, quadruplex

Abstract

As a promising new target for chemotherapy G-quadruplexes (G4) have drawn great interest from the scientific community. Current chemotherapeutic agents exhibit broad toxicity to patients; G4 has the potential to be selectively targeted by novel chemotherapeutic agents that exhibit toxicity specific towards cancer cells. Anthracenyl isoxazolyl amides (AIMs) have shown potent anti-tumor activity and have evidence to support them as G4 binding molecules. Studies of the AIMs’ unique mechanism of action require an efficient synthesis of target molecules. For our system, methods traditionally used to synthesize isoxazoles were inefficient and gave poor yields. A critical comparison of methods to prepare sterically hindered 3-aryl isoxazoles containing fused aromatic rings using the nitrile oxide cycloaddition (NOC) revealed that modification of the method of Bode, Hachisu, Matsuura and Suzuki (BHMS), was far superior to that of the enamine method. Utilization of either triethyl amine as a base or sodium enolates of diketone, ketoester and ketoamide dipolarophiles gave much higher yields as well as fewer by-products from the NOC. Here-in is reported the improved synthesis of 3-aryl-isoxazoles via an adaption of the BHMS method. Included in this report is the crystallographic data for Ethyl 3-(10'-bromo-9'-anthracenyl)-5-methyl-4-isoxazolcarboxylate. As seen in the crystal structure of the chapter 2 title compound the isoxazole plane is nearly orthogonal to the plane of the anthracene; which is thought to be a necessity for the AIMs to interact with G4. This conformation is ideal for both pi-stacking with the guanine decks and polar interactions with the phosphate backbone of quadruplex DNA.

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© Copyright 2013 Matthew Jacob Weaver