Small molecules from natural sources are vital to drug discovery by providing molecular diversity and novel chemical scaffolds for further pharmacological development. The emergence of multiple drug resistant pathogens and problems associated with natural product dereplication emphasize the continuing need for the discovery of new and relevant bioactive molecules for the treatment of human disease. This thesis describes the biological activity guided chemical investigation of several marine taxa with emphasis on the isolation and structure elucidation of new secondary metabolites with therapeutic efficacy against cancer and infectious disease. Chapter I introduces the context, rationale and background which form the foundation of the thesis research. Chapter II describes the bioactivity guided discovery of a new cancer compound from a Panamanian marine cyanobacterium Symploca sp. The linear tetrapeptide contains unusual and modified amino residues and exhibits sub-micromolar cancer toxicity with a classic antimitotic mechanism of action. Chapter III describes the discovery of DMMC a new cyclic depsipeptide isolated from a Fijian strain of Lyngbya majuscula. The antitumor effects displayed by this compound were very potent and selective for solid tumor cell lines. A linear analog of DMMC was generated during structure determination, this analog proved to maintain the exquisite and selective activity of the parent molecule. Chapter IV describes the discovery of the viridamides A and B from the cyanobacterium Oscillatoria nigro-viridis. Structure elucidation of these linear lipodepsipeptides revealed the presence of the novel 5-methoxydec-9-ynonic acid residue and subsequent biological evaluation indicated low micromolar efficacy against two species of disease causing protozoan pathogens. Chapter V describes the bioassay guided isolation and structure elucidation of kaviol A, a halogenated phenolic inhibitor of histone deacetylase (HDAC) from a Papua New Guinean strain of the green alga Boodlea sp. This unique C₆-C₄-C₆ structure contains multiple sites of halogenations and inhibits six isoforms of class II HDAC enzymes with very low micromolar IC₅₀ values. Chapter VI provides a conclusion of this thesis research

Reef-building coral species are experiencing an unprecedented decline owing to increasing frequency and intensity of marine heatwaves and associated bleaching-induced mortality. Closely related species from the Acropora hyacinthus species complex differ in heat tolerance and in their association with heat-tolerant symbionts. We used low-coverage full genome sequencing of 114 colonies monitored across the 2015 bleaching event in American Samoa to determine the genetic differences among four cryptic species (termed HA, HC, HD and HE) that have diverged in these species traits. Cryptic species differed strongly at thousands of single nucleotide polymorphisms across the genome which are enriched for amino acid changes in the bleaching-resistant species HE. In addition, HE also showed two particularly divergent regions with strong signals of differentiation. One approximately 220 kb locus, HES1, contained the majority of fixed differences in HE. A second locus, HES2, was fixed in HE but polymorphic in the other cryptic species. Surprisingly, non-HE individuals with HE-like haplotypes at HES2 were more likely to bleach. At both loci, HE showed particular sequence similarity to a congener, Acropora millepora. Overall, resilience to bleaching during the third global bleaching event was strongly structured by host cryptic species, buoyed by differences in symbiont associations between these species.

While digital computers rely on software-generated pseudo-random number generators, hardware-based true random number generators (TRNGs), which employ the natural physics of the underlying hardware, provide true stochasticity, and power and area efficiency. Research into TRNGs has extensively relied on the unpredictability in phase transitions, but such phase transitions are difficult to control given their often abrupt and narrow parameter ranges (e.g., occurring in a small temperature window). Here we demonstrate a TRNG based on self-oscillations in LaCoO₃ that is electrically biased within its spin crossover regime. The LaCoO₃ TRNG passes all standard tests of true stochasticity and uses only half the number of components compared to prior TRNGs. Assisted by phase field modeling, we show how spin crossovers are fundamentally better in producing true stochasticity compared to traditional phase transitions. As a validation, by probabilistically solving the NP-hard max-cut problem in a memristor crossbar array using our TRNG as a source of the required stochasticity, we demonstrate solution quality exceeding that using software-generated randomness.