"Chain walking” catalytic polymerization CWCP is a powerful tool for the one-pot synthesis of a unique class of hyperbranched polyethylene HBPE-based macromolecules with a controllable molecular weight, topology, and composition. This dissertation focuses on new synthetic routes to prepare HBPE-based macromolecular architectures by combining the CWCP technique with ring opening polymerization ROP, atom–transfer radical polymerization ATRP, and “click” chemistry. Taking advantage of end-functionalized HBPE, and a new ethynyl-soketal star-shape agent, we were able to synthesize different types of the HBPE-based architectures including hyperbranched-on-hyperbranched core-shell nanostructure, and miktoarm-star-HBPE-based block copolymers. The first part of the dissertation provides a general introduction to the synthesis of polyethylene types with controllable structures. Well-defined polyethylene with different macromolecule architectures were synthesized either for academic or industrial purposes. In the second part, the HBPE with different topologies was synthesized by CWCP, using a α-diimine Pd (II) catalyst. The effect of the temperature and pressure on the catalyst activity and polymer properties, including branch content, molecular weight, distribution, and thermal properties were studied. Two series of samples were synthesized: a) serial samples (A) under pressures of 1, 5, and 27 atm at 5˚C, and b) serial samples (B) at temperatures of 5, 15, and 35 ˚C under 5 atm. Proton nuclear magnetic resonance spectroscopy, 1H NMR, and gel permeation chromatography, GPC, analysis were used to calculate the branching content, molecular weight, and distribution, whereas differential scanning calorimetry, DSC, was used to record the melting and glass transition temperatures as well as the degree of the crystallinity. Well-defined HBPE-based core diblock copolymers with predictable amphiphilic properties are studied in the third part of the project. Hyperbranched polyethylene-b-poly(N-isopropylacrylamide), HBPE-b-PNIPAM, and hyperbranched polyethylene-b-poly(solketal acrylate), HBPE-b-PSA, were successfully synthesized by combining CWCP and ATRP. The synthetic methodology includes the following steps; a) synthesis of multifunction hyperbranched polyethylene initiators HBPE-MI by direct copolymerization of ethylene with 2-(2-bromoisobutyryloxy)ethyl acrylate BIEA in the presence of a α-diimine Pd(II) catalyst, and b) HBPE-MI with α-bromoester groups used as initiation sites for ATRP. Proton nuclear magnetic resonance spectroscopy, 1H NMR, gel permeation chromatography,GPC, and Fourier transform infrared, FT-IR, spectroscopy, were used for determining the molecular and composition structures. Also, differential scanning calorimetry, DSC, and thermogravimetric analysis, TGA, were used to record the melting temperature and to study the thermal stability, respectively. In the fourth part, a well-defined 3-miktoarm star copolymer 3μ-HBPE(PCL)2 (HBPE: hyperbranched polyethylene, PCL: poly(ε-caprolactone) was synthesized by combining CWCP, ring opening polymerization, ROP, and “click” chemistry. The synthetic methodology includes the following steps: a) synthesis of azido-functionalized hyperbranched polyethylene HBPE-N3 by CWCP of ethylene with the α-diimine Pd(II) catalyst, followed by quenching with an excess of 4-vinylbenzyl chloride and transformation of –Cl to the azido group with sodium azide, b) synthesis of in-chain ethynyl-functionalized poly(ε-caprolactone), (PCL)2-C≡CH by ROP of ε-CL with ethynylfunctionalized solketal [3-(prop-2-yn-1-yloxy) propane-1,2-diol] as a bifunctional initiator, in the presence of P2-t-Bu phosphazene super base, and c) “clicking” HBPE-N3 and (PCL)2-C≡CH using the copper(I)-catalyzed alkyne–azide cycloaddition CuAAC. Proton nuclear magnetic resonance spectroscopy, 1H NMR, gel permeation chromatography, GPC, and Fourier transform infrared, FT-IR, spectroscopy, were used to determine the molecular and composition structures. Also, the differential scanning calorimetry, DSC, was used to record the melting point temperature. The fifth part illustrates the self-assembly behavior of the HBPE-based block copolymers of poly(N-isopropylacrylamide), NIPAM, and poly(ε-caprolactone), PCL, at room temperature in water and a petroleum ether-selective solvent for NIPAM and PCL respectively. The synthesized copolymers HBPE-b-NIPAM and 3μ-HBPE(PCL)2 revealed either core-shell nanostructure in vesicles or worms and worm-likes branches, as confirmed by combining the analysis of dynamic light scattering, DLS, transmission electron microscopy, TEM, and atomic force spectroscopy, AFM. All the findings presented in this dissertation emphasize the utility of "living" CWCP to synthesize end-functionalized HBPE, and new star-linkage HBPE-based complex architectures. The summary and future works concerning predictable properties and applications are discussed in the sixth part.

The proteasome, a multiprotease complex, is clinically validated as an anticancer target by the FDA approval of bortezomib and carfilzomib for the treatment of multiple myeloma. The emergence of resistance to proteasome inhibitors however remains a major clinical challenge. Recently, distinct types of proteasomes termed ‘intermediate proteasomes’, which contain unconventional mixtures of catalytic subunits, have been implicated with drug resistance of tumor cells. In elucidating the role of intermediate proteasomes in drug resistance, a crucial step is to unequivocally determine the subunit composition of intermediate proteasomes in cells. With this in mind, the goal of the studies reported in this dissertation is to develop novel chemical tools which can facilitate the investigation of intermediate proteasomes via two complementary approaches: a FRET-based approach and a bifunctional cross-linking approach. Chapter 2 describes the structure-based design, synthesis, and characterization of a peptide epoxyketone-based fluorescent probe, named as LKS01-B650, which selectively targets the immunoproteasome subunit β5i/LMP7. In addition to its utility in determining the identity of intermediate proteasomes as FRET-based probe, this imaging agent may also serve as a valuable tool in visualizing the immunoproteasome in living cells. Chapter 3 describes the design and synthesis of various epoxyketone-based bifunctional agents. The ability of these bifunctional agents to cross-link different catalytic subunits within a proteasome complex is shown by mobility shift assays.These bifunctional agents may provide important information in determining the subunit composition of proteasomes. Chapter 4 describes a systematic study of the relationship between the proteasome inhibitor structure and the inhibitory activity against critical subunits of the proteasome. Given the reported role of β5i/LMP7 in autoimmune diseases, this study may provide useful insights in developing therapeutic agents for autoimmune diseases as well as other diseases. Chapter 5 describes a separate study which is not related to proteasome biology. A concise approach to synthesize 1-azaspirocyclic ring systems is developed by utilizing a novel semi-pinacol/Beckmann rearrangement. Additionally, an environmentally benign, microwave-assisted, and solvent-free self-condensation of carbonyl compounds is reported.