Development and application of bioorthogonal palladium- labile derivatives of cytotoxic pyrimidine analogues
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Weiss2015.doc (81.22Mb)
Date
04/07/2015Author
Weiss, Jason Thomas
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Abstract
Chemotherapy is widely used to treat various forms of cancer. However, some
chemotherapeutic drugs, due to their antineoplastic properties, also act upon healthy
cells which normally replicate rapidly causing a plethora of undesirable side effects.
One rising and promising therapeutic strategy is the development of prodrugs.
Prodrugs are derivatives of the pharmaceutically active drugs but require an
enzymatic or biochemical transformation within a certain biological space in order
for it to become activated and capable of exerting the desired pharmacological effect.
As a novel prodrug approach, this thesis describes the pioneering use of a
bioorthogonal organometallic (BOOM) activation strategy to develop spatially-controlled
anticancer treatments.
Bioorthogonal reactions are selective chemical processes between two abiotic
reagents in a biological system that do not interfere with the system’s biotic
components. In BOOM reactions, one of the reagents is a metal catalyst, which if
immobilized, could in principle allow for the local transformation of a continuous
flow of a bioorthogonal chemo-substrate indefinitely. To exploit the benefits of this
paradigm in anticancer therapy, this thesis reports the design, synthesis and screening
of a set of prodrugs masked with bioorthogonal protecting groups sensitive to
activation by a catalysts-based “activating device”. Specifically, it describes the
synthesis of palladium (Pd0) functionalized resins (the activating device) capable of
activating cytotoxic pyrimidine analogue prodrugs masked with Pd0-labile protecting
groups. Both the Pd0 functionalized resins and the BOOM-activated prodrugs are
independently non-cytotoxic. However, once in combination together, the Pd0 is
capable of mediating the removal of the masking groups in situ and rendering the
drugs in their cytotoxic state with comparable antiproliferative properties to the
unmodified parental drugs in vitro. The Pd0 resins also display biocompatibility and
local catalytic activity inside zebrafish embryos. This approach is intended to
generate a more targeted therapeutic treatment regime while minimizing harm to
normal healthy tissues through the local generation of prodrugs which are not
dependent on intrinsic biological activators but by an external activating device, thus
reducing the systemic presence of the drug.