Publication Date

5-2018

Date of Final Oral Examination (Defense)

12-1-2017

Type of Culminating Activity

Thesis

Degree Title

Master of Science in Chemistry

Department

Chemistry

Supervisory Committee Chair

Don Warner, Ph.D.

Supervisory Committee Member

Kenneth A. Cornell, Ph.D.

Supervisory Committee Member

Kristen A. Mitchell, Ph.D.

Abstract

After nearly half a century since medical approval, the anthracycline doxorubicin (DOX) remains one of the most potent and clinically useful anticancer agents. In spite of its long history, however, the cytotoxic mechanisms of DOX have been debated and remain controversial. Several well-supported mechanisms will be discussed, such as the potential to intercalate DNA and induce apoptosis through topoisomerase poisoning, free radical formation, and DNA cross-linking. While DOX has substantial medical importance, it is plagued by a life-threatening dose-dependent cardiotoxic side effect associated with several structural groups. A number of modifications to DOX have been accomplished to attempt to remove treatment-induced cardiotoxicity, including the reduction of the C-13 carbonyl to a methylene and conversion of the quinone moiety to a less reactive iminoquinone. This modified form, termed 5-imino-13-deoxydoxorubicin (DIDOX), has displayed no cardiotoxic side effects in any clinical setting. However, these structural changes have reduced the potency of the drug more than four-fold.

In this work, six different analogs of DIDOX were synthesized and evaluated for in vitro cytotoxicity against an array of cancer cell lines. The six analogs were designed to incorporate reactive moieties attached to the 3'-amine of the daunasamine sugar. Of the six synthesized, four were at least as cytotoxic as DOX, and several were up to 100-fold more potent. Preliminary results also suggest that modifications to the 3'-amine attenuate the multidrug resistance observed during anthracycline treatment. In addition to the synthesis and preliminary evaluation of new anthracycline analogs, this work explored methods for improving the synthesis of DIDOX. Specifically, the reduction of DOX’s carbonyl to produce C-13-deoxydoxorubicin (DeoxyDOX) was explored using six different sulfonylhydrazones, and the relative production of the reduced form was compared. Four of the new hydrazones exhibited the potential to improve the overall amount of DeoxyDOX generated, compared to the currently used methods. In summary, the work described presents both the findings for the synthesis of potent and non-cardiotoxic derivatives of doxorubicin that show promise for overcoming multi-drug resistance and potential improvements toward enhancing the overall yield of DIDOX and related analogs.

DOI

10.18122/td/1387/boisestate

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