Synthesis of molecular probes for one-electron reduction

Abstract

Controlled drug release plays an important role in medicine because it can be a factor in human health care. It is defined as the ability to release a drug inside the body at a specific time. Radiation-sensitive functionalized materials can be controlled by outside triggers such as radiation and have great potential for application in controlled and targeted drug delivery. Radiation-sensitive functional groups are known and studied, however, there are very few examples. Previous studies have revealed that 2-oxoalkyl group can successfully undergo radiolytic cleavage, but under relatively high doses of radiation. It is desirable that the radiolysis efficiency of 2-oxoalkyl group be improved in order to gain applications in clinical medicine. Thus, one objective of this thesis was to study the effect of a few substituents on the radiolysis efficiency of substituted 2-oxoalkyl groups. Therefore, a few molecular probes that contain an aryl 2-oxoalkyl group with substituted acetophenone of monoesters of adipic acid, and coumarin scaffold of monoesters of adipic acid have been successfully synthesized. These compounds were studied under X-ray radiation at various doses to assess the potential of selective cleavage of the aryl oxo-methyl ester linkage. The radiolysis studies showed that less than 10% of the ester linkages in these compounds were degraded under a dose of up to 20 Gy of radiation. Compounds were also studied for their hydrolytic rate for the aryl oxomethyl ester linkage using TLC method. Hydrolysis at around neutral pH happened at a slower rate for compounds that are sterically more hindered at the oxo-methyl position. Poly-L-glutamic acid (PGA) is a natural polypeptide that is biodegradable and biocompatible. Therefore, it has been exploited as drug carrier system. In this thesis, PGA has been modified with a phenacyl group. The lipophilic phenacyl group is assumed to assist the formation of nanoparticles for the modified PGA. Radiolysis studies of such modified PGA showed that the grafted phenacyl group can be selectively cleaved upon radiation with a clinically relevant dose. Lawsone is a commercially available natural product. It has been used as starting material for the synthesis of different biologically active compounds. Lawsone also has various biological effects including anticancer activity. One anticancer mechanism of lawsone is associated with its ability to undergo one-electron reduction. Thus, another aspect of this thesis was to synthesize lawsone derivatives as potential anticancer agents. The preparation of glycosylated lawsone derivatives was of particularly interest. Direct glycosylation of lawsone using a number of methods was unsuccessful in providing fully deprotected lawsone glycosides. Then the Mannich reaction was employed to produce a group of lawsone derivatives including one compound bearing a glucose residue. The synthesized lawsone derivatives will be evaluated for anticancer activity in the future work.