Publication Date

5-2018

Date of Final Oral Examination (Defense)

3-9-2018

Type of Culminating Activity

Thesis

Degree Title

Master of Science in Chemistry

Department

Chemistry

Major Advisor

Don Warner, Ph.D.

Advisor

Kenneth A. Cornell, Ph.D.

Advisor

Eric Brown, Ph.D.

Abstract

Mitomycin C (MC) is a naturally occurring antitumor agent isolated from a soil bacterium. MC is effective against solid hypoxic tumors that respond poorly to radiotherapy, such as colorectal, gastric, and lung tumors. Also, it has a role in the treatment of bladder, head and neck, and non-small cell lung cancers in combination with other chemotherapeutic.

MC and other members of the mitomycin family of antitumor agents fight cancer by forming DNA interstrand crosslinks (ICLs), which leads to apoptosis. In order to form ICLs, MC requires a reductive activation step that produces reactive oxygen species. This activation step is proposed to lead to adverse side effects, such as myelosuppression and hemolytic uremic syndrome. Aziridinomitosenes (AZMs) are structurally related to MC and are believed to form during in vivo reduction of MC. AZMs are relatively stable but are more sensitive than the parent mitomycins due to an activated aziridine ring. Consequently, AZMs do not require the reductive activation step in order to alkylate DNA.

The purpose of this work is to synthesize and study an AZM that is substituted with methyl groups at two potential electrophilic sites. It is hypothesized that certain synthetic AZMs crosslink DNA under non-reductive conditions as a result of a nucleophilic activation sequence involving the quinone ring. To test this hypothesis, analogs were prepared that would either reduce the rate of the activation step or prevent it from occurring. The synthetic route starts with commercially available reagents to form an oxazole, followed by the addition of a protected aldehyde that is converted to the required aziridine ring via a Mitsunobu reaction. Once the aziridine ring is formed, all of the reaction conditions must be conducted using mild conditions in order to prevent ring-opening.

The completion of the synthesis and formation of the tetracyclic core was achieved by performing an oxazolium salt/azomethine ylide [3+2] cycloaddition sequence. This sequence was conducted multiple times, and the highest yield obtained was 44%. The final steps were the most challenging, requiring several transformations to accomplish a deprotection and oxidation to give a diketone that was oxidized to a quinone. Finally, the carbamate was attached in two steps using FmocNCO to yield the desired AZM product in an overall yield of 0.04% from the starting diol over the 22 step reaction sequence. The stability of the AZM was tested in buffered methanolic solutions, and the results were compared to other aziridinomitosenes. While unsubstituted AZMs decompose in basic solutions, the C6/C7 dimethyl AZM showed high stability under these conditions.

DOI

10.18122/td/1404/boisestate

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