There are six essential hallmarks of cancer that are targeted by current therapies to overcome the progression and metastasis of cancer cells. Many current treatments lack continued efficacy due to problematic side effects including off-target toxicity and the development of resistance mechanisms. One such strategy to overcome these limitations that has been implemented involves targeting multiple sites within cancer cells. This thesis discusses projects that contribute to the development of more beneficial cancer therapeutics using this approach.Apicularen A is a polyketide natural product that has been shown to act as an inhibitor of the V-ATPase enzyme. This enzyme plays a critical role in maintaining the homeostasis of the pH within a cell. Up-regulation of this enzyme has been observed in cancer cells. We have developed a formal synthesis of apicularen A, incorporating our ether transfer methodology and Diels-Alder chemistry to produce the macrolactone of the natural product. This synthetic route can be applied to the synthesis of a chimera that consists of the apicularen A macrolactone and the side chain of cruentaren A, an F-ATPase inhibitor. The addition of the cruentaren A side chain to create a chimeric analogue was envisioned to shift the selectivity of apicularen A to a dual-target drug, both a V- and an F-ATPase inhibitor. The ability of a drug to influence different components of a cell limits the cancer cell's propensity to develop resistance to the compound. Therefore, this chimeric analogue could lead to more effective treatment than the parent compound. Natural products such as paclitaxel (Taxol®) and the epothilone analogue Ixempra® are microtubule stabilizing agents that are used for the treatment of various cancers. We have been interested in the conformational profile of the epothilones in relation to their activity. Our group has previously published the major conformational profiles of this class of natural products. In the second part of this thesis we have synthesized two novel epothilone analogues that are designed to assess the importance of the C7OH moiety in the molecule's activity profile. Our conformational profiles suggest that removal of this functionality will minimize the inactive conformation, resulting in a more active compound. The synthesis of the analogues without the C7OH is carried out and their activity in cancer cells was determined. The results showed that while conformation is important for the design of analogues, key intermolecular bonding within the target site can override these preferences.The last project investigates the use of the epothilones in a combination treatment. Subtle differences in the role of microtubules during the cell cycle can provide an opportunity to increase the susceptibility of specific protein targets. We have shown using fixed and live cell imaging that the combination of epothilone and the aurora kinase inhibitor ZM447439 leads to a highly penetrant mitotic defect that was distinct from the observed phenotype in individual treatment. This novel mechanism of cell death is further investigated by the synthesis of an epothilone – aurora kinase inhibitor conjugate. Covalently combining these drugs has two main advantages: ensuring each cell is delivered both compounds for the novel effect, and driving the aurora kinase inhibitor into the cell by utilizing the known effect of high accumulation of epothilones within the cells. Our synthesized conjugate was shown to exhibit nanomolar activity. Together the projects described in this thesis demonstrate that both enzymatic and structural components of the cell can serve as useful targets for the development of cancer therapeutics. Furthermore, the combination of known molecules in different ways can lead to novel therapeutics with the potential to be more effective cancer treatments.