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Abstract

Effective treatment of cancer using existing drugs remains a challenge due to side effects experienced by cancer patients during therapy. Research towards discovering new anticancer agents with less side effects is an ongoing effort which unfortunately requires huge investments from lead compound discovery to clinical trials. Conventional methods used in treating cancer include chemotherapy, radiation, as well as surgery. These methods have seen tremendous improvements, but a lot remains to be done to slay the cancer dragon. In the recent past, attention has turned to exploring the use of photo active molecules to treat cancer and other ailments such as microbials in a process known as photodynamic therapy (PDT). These molecules are commonly known as photosensitizers (PS) and should possess adequate structural characteristics that promote synergy effects when exposed to certain wavelengths of light. Ideally, the absorption wavelength of PS should range between ~ 500-800 nm which is critical for tissue penetration. Popular PS include Porphyrin whose derivatives have been successfully applied in PDT treatment. Alternatives to the widely studied porphyrin scaffold also exist, and more scaffolds need to be added onto the wide therapeutics required to treat cancer. In this work, a theoretical investigation of embelin which has a benzoquinone scaffold has been carried out. Interesting properties are explored including electronic resonance, proton transfer pathways and the ability to generate singlet oxygen. Furthermore, its ability to bind the X-linked inhibitor of apoptosis is investigated and the binding mechanisms as well as binding energies are reported. Advanced hybrid QM/MM studies have also been carried out to investigate its spectral signatures within the protein environment. This work begins by addressing embelin’s ground- and -excited state properties in chapter 3. The aim of this chapter is to highlight embelin’s individual molecular properties. The calculations are carried out with and withoutsolvation models. Results obtained are the excitation energies of embelin, the nature of its geometrical parameters in the ground and excited state potential energy surfaces (PES), and its general ability to generate singlet oxygen. The Algebraic Diagrammatic Construction ii (ADC) and Time-dependent Density Functional Theory (TD-DFT) methods are extensively used to approximate the excitation energies and molecular properties of embelin. Particularly, ADC(3) accurately reproduces the excitation energy at 4.32 eV compared to the experimental absorption energy of 4.31 eV. In the ground state, embelin is found to exhibit a weak intramolecular hydrogen bond confirming previous reported results on the existence of electronic resonance within its structure. This property is enhanced on photon absorption by hyperbonds within the structure, meaning that photon absorption stabilizes embelin in the exited state and promotes resonance. In fact, a detailed investigation using potential energy surface (PES) scans resulted in intermediates which are in complete agreement with the excited state stabilizations which favor excited state intramolecular proton transfer (ESIPT). The intermediates formed in the excited state further promote efficient intersystem crossing to the triplet state with enough excess energy to generate reactive oxygen species (ROS) such as singlet oxygen. In chapter 4, the binding pattern of embelin against X-linked Inhibitor of apoptosis (XIAP) is presented. Here, focus is turned towards identifying the “active site” where embelin prefers to bind the baculoviral inhibitor of the apoptosis (BIR3) domain of XIAP. XIAPs are known to bind caspases hence interfere with normal cell death which results in proliferation of abnormal cells. Embelin is found to bind mostly to Glu and Tyr residues (which have been experimentally identified as one of the critical amino acids in embelin’s binding pattern). The binding is measured as a function of the hydrogen bonding percentage with values as high as 60%. The dominating binding pattern is a hydrogen donating mechanism with the protein residue pairs acting as proton acceptors. The binding energy is calculated to be -24.7 kJ/mol which agrees nicely with -25.1 kJ/mol (the experimental value of Human serum albumin). Since the overall aim of the thesis is to address the applicability of embelin in PDT which occurs within a protein environment, advanced hybrid QM/MM calculations are presented in chapter 5. The major results in this chapter are the spectral signature of embelin embedded within the BIR3 environment. The reported vertical excitation energies are comparable to the values obtained in chapter 3. More importantly, embelin is stable within the protein environment and absorbs light with similar wavelengths reported by experiment. The absorption wavelengths are however iii slightly shifted when only electrostatics are taken into consideration. Inclusion of polarization effects simulated using PE-ADC resulted in slightly red-shifted excitation energies. In general, the results obtained within this chapter are consistent and predict the ability of embelin to generate singlet oxygen.