A Structure-Activity Relationship Study of Dihydroajoenes as Anti-Cancer Agents

Biwi, James Tapiwa

A Structure-Activity Relationship Study of Dihydroajoenes as Anti-Cancer Agents

Master Thesis

2014

Publisher

University of Cape Town

Department

Department of Chemistry

Faculty

Faculty of Science

Abstract

Ajoene (( E-/Z )-4,5,9-trithiadodeca-1,6,11-triene-9-oxide), a constituent of garlic is known to possess in vitro and in vivo anticancer activity based on the presence of a vinyl disulfide as its pharmacophore. This thesis reports on the synthesis of dihydroajoenes, a novel set of ajoene analogues, containing a saturated double bond, in which the intention was to study the influence of removing the double bond on biological activity and metabolic stability, since ajoenes are unstable in blood. A divergent synthetic route to 6 new dihydroajoene analogues has been developed in which a phenolic hydroxyl group at the disulfide end served as a platform for modulating aqueous solubility. The dihydroajoene analogues synthesized retained good in vitro anti-proliferation activity against a WHCO1 oesophageal cancer cell line, with the phenol derivative showing the greatest activity, with an IC 50 of 4.1 μM as about 7-times more active than the parent ajoene. In addition the dihydroajoenes were found to be significantly more stable in the red blood cell fraction of mouse blood, when compared with ajoene analogues retaining the double bond. This opens up the possibility of exploring them as anti-cancer agents in an in vivo setting. This thesis also describes a preliminary study towards the synthesis of an ajoene-drug (fludarabine) conjugate for chemosensitization studies, in which an advanced synthetic intermediate was secured.

Description

Includes bibliographical references.

Keywords

Chemistry

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