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Concurrent Crises: An Integrative Approach to Chemical Ecology and Natural Products Chemistry in the Anthropocene
AdvisorJeffrey, Christopher S.
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Understanding the ecological and public health consequences of anthropogenic climate change poses one of the greatest scientific challenges of the Anthropocene. Concomitant extinctions and changes in community composition necessitate the cataloging of chemically mediated interactions, while the development of new drugs becomes critical in the face of changes in human health as the planet warms. A framework through which chemical ecology and drug discovery efforts can be integrated would accelerate innovation in these concurrent crises. Guided by foreknowledge of relevant ecological interactions, the expansive chemical space provided by natural products serves as a pool from which new drug leads can be discovered. The goal of this dissertation is to establish a framework connecting ecological and natural products discovery pipelines while cross-pollenating ecological and drug discovery concepts, leading to new tools which can advance both ecological and drug discovery endeavors. In chapter one, methods are developed for utilizing chemical diversity to improve semi-purification and screening prioritization in a drug discovery pipeline while simultaneously adapting compound activity mapping to an ecological application wherein related volatile chemicals in Piper spp. are associated with specific manifestations of herbivory. Chapter two describes a framework for considering structural complexity in the context of phytochemical diversity while examining how compositional diversity and molecular complexity are manifested spectroscopically. Methods are also developed to correct the concentration dependence of chemical diversity indices. In chapter three, a novel method for classification of structurally related phytochemicals based upon chromatographic and mass spectrometric data is described. This method is complementary to existing correlative methods of classification for chemical ecology studies, and could also prove useful in drug discovery efforts by elucidating relationships between bioactivity and groups of structurally related compounds. Chapter four outlines the discovery and quantitation of octopamine and tyramine in flower nectar establishing biologically relevant doses for behavioral experiments. Additionally, I apply discriminant analysis of principal components to the classification of individual plants based on the phytochemical profile of their nectar and annotate the phytochemicals involved in differentiating these nectars – all of which expand the understanding of nectar rewards in plant-insect systems. This represents another tool which was developed for an ecological application but could also be used for chemotyping in drug discovery bioassays. This work represents an advance in the conceptual integration between chemical ecology and NP drug discovery, as well as the development of statistical tools which can be applied in both areas. These advances towards developing an integrated framework will facilitate future experiments which pursue chemical ecology and drug discovery objectives.