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.