Molecules from the Sea: Exploration of the Chemical Diversity and Bioactivity of Marine Macro-Organisms from Fiji and Solomon Islands
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Khatri Chhetri, Bhuwan
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Abstract
Natural products represent a substantial portion of the medications that we use today, making them a cornerstone of human civilization. More than 45% of all therapeutic agents that were approved between 1981 to 2019 are either unaltered natural products (3.8%), natural product derivatives (18.9%), botanical drugs (defined mixture, 0.8%), or synthetic drugs that mimic a natural product or incorporate natural product bioactive pharmacophores (25.7%). Some remarkable examples include the chemotherapeutic agent paclitaxel, isolated from the bark of Taxus brevifolia (the Pacific yew tree), antibiotics such as penicillin and vancomycin, produced by fungi of the genus Penicillium and the soil dwelling bacterium Streptomyces orientalis, respectively, the antimalarial drug artemisinin produced by the sweet wormwood plant Artemisia annua, and the antiarrhythmic medication digoxin from Digitalis lanata (foxglove). Exploration of understudied natural environments, in conjunction with an understanding of the underlying chemical ecological interactions that drive the production of bioactive secondary metabolites, has expanded our reaches into an enormous natural products chemical space that offers unusual chemical diversity and bioactivity. As a prime example, coral reefs and other nearshore marine environments are complex ecological settings where under extreme pressure resulting from disease, predation, and competition for resources, organisms have evolved a variety of ways to protect themselves, including the production of potent bioactive secondary metabolites. Realization of the chemical diversity harbored by marine organisms has already led to several FDA approved drug including eribulin mesylate, trabectedin, and cytarabine. These success stories have inspired our exploration of understudied marine environments. Consequently, research presented in Chapters 2 and 4 report the promising bioactivities of homofascaplysin A, (+)-aureol, and bromophycolide A against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), and duryne against a virulent strain of Mycobacterium tuberculosis (Mtb). These novel bioactivities were discovered by distinct approaches. While duryne was isolated using conventional bioactivity-guided screening against Mtb, the bioactivity of anti-SARS-CoV-2 compounds was realized by screening carefully chosen natural products from our pure compound library. These natural products were selected based on structural comparison with antiviral small molecules in the literature. Chapters 2 and 4 reinforce the idea that although re-discovery of known compounds is a major bottle neck for all natural product drug discovery programs, validation of their bioactivity against novel disease targets should be an essential dimension of natural product drug discovery efforts, albeit one that is often overlooked.
Leveraging the technological advancements available with modern high resolution mass spectrometry and high field NMR spectroscopy, UPLC separation, and advanced data processing, Chapter 5 explores the chemical diversity harbored by 32 distinct collections of an understudied marine red alga Peyssonnelia spp. Chapter 5 demonstrates the use of LC/MS and 1H NMR-based untargeted metabolomics for the exploration and prioritization of marine organisms with unique chemical profiles. Further analysis with MS/MS based Global Natural Products Social Molecular Networking (GNPS) followed with MS-based targeted isolation led to the characterization of three new triterpene glycosides (peyssobaricanosides) with a novel rearranged isomalabaricane carbon skeleton. As reported in Chapter 3, antimicrobial bioassay-guided exploration of diverse collections the aforementioned algal genus Peyssonelia led to the discovery of peyssonnosides A–B, unusual diterpene glycosides with a novel cyclopropane-containing carbon skeleton. While peyssonnosides A–B displayed only moderate antimicrobial activity against human pathogens, they exhibited potent bioactivity against marine saprophytic fungi, indicating a likely ecological role as antifungal agents. Structure elucidation of the novel natural products reported in Chapters 3 and 5 required the implementation of modern NMR pulse sequences that facilitated acquisition of spectroscopic data tailored towards the needs of the structural problems at hand. Additionally, the application of density functional theory (DFT) predictions of spectroscopic and spectrometric properties including 1H, 13C NMR chemical shifts, 1H-13C coupling constants, and optical rotatory dispersion (ORD) data enabled integration of empirical and modeling approaches, illustrating the present status of natural products structure elucidation. Chapters 3 and 5 emphasize the significance of exploring unique and understudied ecological niches for the discovery of novel chemistry with important biological properties. In conclusion, the chapters presented in this dissertation exemplify the exploration of natural product chemical space from a contemporary perspective and emphasize on the exploration of understudied ecological niches for the discovery of novel bioactive small molecules.
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2022-08-01
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Dissertation